EP4646426A1 - Host cells capable of producing sequiterpenoids and methods of use thereof - Google Patents

Abstract

Provided herein are recombinant host cells, compositions, and methods for the production of the sesquiterpenoids: alpha-humulene, beta-caryophyllene, valencene, delta-cadinene, delta-guaiene, germacrene A, germacrene D, beta- cubebene, valerena-4,7(11)-diene, nerolidol, and bisabolol. The host cells are genetically modified to contain heterologous nucleic acids that express novel enzymes that enable the host cell to produce the sesquiterpenoids from a carbon source such as sucrose. The host cells, compositions, and methods disclosed herein provide an efficient route for the heterologous production of alpha-humulene, beta-caryophyllene, valencene, delta-cadinene, delta-guaiene, germacrene A, germacrene D, beta-cubebene, valerena-4,7(11)-diene, nerolidol, or bisabolol.

Description

HOST CELLS CAPABLE OF PRODUCING SESQUITERPENOIDS AND METHODS OF USE THEREOF

FIELD OF THE INVENTION

The present disclosure relates to recombinant host cells that produce alpha-humulene, beta-caryophyllene, valencene, delta-cadinene, delta-guaiene, germacrene A, germacrene D, bcta-cubcbcnc, valcrcna-4,7(l l)-dicnc, nerolidol, or cpi-alpha-bisabolol, and methods of producing these sequiterpenoids using the host cells.

BACKGROUND

Sesquiterpenes are terpenes composed of three isoprene units and often have a molecular formula of C15H24. Sesquiterpenes are produced by plants and insects and compose the largest group of plant secondary metabolites. The sesquiterpene scaffold is frequently further derivatized; the broad class of sesquiterpenes and other compounds derived from FPP are defined as sesquiterpenoids. Many of these molecules possess antifungal, antibacterial, and antiviral activities and function as part of the plant’s defense mechanism. A number of sesquiterpenoids have commercial applications and arc sought for their unique properties. Harvesting isoprenoids like sesquiterpenoids from natural sources is often detrimental to the plant species, inefficient, unsustainable, or environmentally unsound. Accordingly, sustainable and environmentally favorable methods of producing useful sesquiterpenoids are needed.

SUMMARY OF THE INVENTION

As provided herein one aspect of the invention is a recombinant host cell capable of producing beta-caryophyllene containing a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 39, SEQ ID NO: 45, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, and SEQ ID NO: 56. In an embodiment of the invention the polypeptide has a sequence selected from SEQ ID NO: 39, SEQ ID NO: 45, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, and SEQ ID NO: 56.

In another aspect the invention provdes a recombinant host cell capable of producing delta-cadinene containing a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 51, and SEQ ID NO: 52. In an embodiment the polypeptide has a sequence selected from SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 51, and SEQ ID NO: 52. In another aspect the invention provides a recombinant host cell capable of producing epi-alpha-bisabolol containing a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: SEQ ID NO: 2, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 30, SEQ ID NO: 46, and SEQ ID NO: 47. In an embodiment the polypeptide has a sequence selected from SEQ ID NO: SEQ ID NO: 2, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 30, SEQ ID NO: 46, and SEQ ID NO: 47. In another aspect the invention provides a recombinant host cell capable of producing alpha-humulene comprising a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 1, SEQ ID NO: 39, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, and SEQ ID NO: 57. In an embodiment the polypeptide has a sequence selected from SEQ ID NO: 1, SEQ ID NO: 39, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, and SEQ ID NO: 57. In another aspect the invention provides a recombinant host cell capable of producing nerolidol containing a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 28, SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42. In an embodiment the polypeptide has a sequence selected from SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 28, SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42. In another aspect the invention provides a recombinant host cell capable of producing valencene containing a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 3, SEQ ID NO: 13, SEQ ID NO: 36, SEQ ID NO: 37, and SEQ ID NO: 38. In an embodiment the polypeptide has a sequence selected from SEQ ID NO: 3, SEQ ID NO: 13, SEQ ID NO: 36, SEQ ID NO: 37, and SEQ ID NO: 38. In another aspect the invention provides a recombinant host cell capable of producing beta-cubebene containing a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 58, SEQ ID NO: 65, SEQ ID NO: 72, and SEQ ID NO: 73. In an embodiment the polypeptide has a sequence selected from SEQ ID NO: 58, SEQ ID NO: 65, SEQ ID NO: 72, and SEQ ID NO: 73. In another aspect the invention provides a recombinant host cell capable of producing delta-guaiene containing a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 59, SEQ ID NO: 60, and SEQ ID NO: 67. In an embodiment the polypeptide has a sequence selected from SEQ ID NO: 59, SEQ ID NO: 60, and SEQ ID NO: 67. In another aspect the invention provides a recombinant host cell capable of producing germacrene A containing a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 61, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 71. In an embodiment the polypeptide has a sequence selected from SEQ ID NO: 61, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 71. In another aspect the invention provides a recombinant host cell capable of producing germacrene D containing a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 66, and SEQ ID NO: 68. In an embodiment the polypeptide has a sequence selected from SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 66, and SEQ ID NO: 68. In another aspect the invention provides a recombinant host cell capable of producing valerena-4,7(11)-diene containing a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence of SEQ ID NO: 62. In an embodiment the polypeptide has the sequence of SEQ ID NO: 62. In further embodiments of the invention the host cells contain one or more heterologous nucleic acids that encode one or more polypeptides having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12. In additional embodiments the one or more polypeptides have a sequence selected from SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12. In yet another embodiment the host cell can be a plant cell, a yeast cell, or a bacterial cell. In a preferred embodiment the host cell is a yeast cell. In a preferred embodiment the host cell is a Saccharomyces cerevisiae cell. In yet another aspect the invention provides a method of producing beta- caryophyllene including: culturing a population of recombinant host cell of any one of claims 1, 2, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making beta-caryophyllene; and recovering the beta-caryophyllene from the culture medium. In another aspect the invention provides a method of producing delta-cadinene including: culturing a population of recombinant host cell of any one of claims 3, 4, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making delta-cadinene; and recovering the delta-cadinene from the culture medium. In another aspect the invention provides a method of producing epi-alpha-bisabolol including: culturing a population of recombinant host cell of any one of claims 5, 6, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making epi- alpha-bisabolol; and recovering the epi-alpha-bisabolol from the culture medium. In another aspect the invention provides a method of producing alpha-humulene including: culturing a population of recombinant host cell of any one of claims 7, 8, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making alpha-humulene; and recovering the alpha-humulene from the culture medium. In another aspect the invention provides a method of producing nerolidol including: culturing a population of recombinant host cell of any one of claims 9, 10, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making nerolidol; and recovering the nerolidol from the culture medium. In another aspect the invention provides a method of producing valencene including: culturing a population of recombinant host cell of any one of claims 11, 12, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making valencene; and recovering the valencene from the culture medium. In another aspect the invention provides a method of producing beta-cubebene including: culturing a population of recombinant host cell of any one of claims 13, 14, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making beta-cubebene; and recovering the beta-cubebene from the culture medium. In another aspect the invention provides a method of producing delta-guaiene including: culturing a population of recombinant host cell of any one of claims 15, 16, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making delta-guaiene; and recovering the delta-guaiene from the culture medium. In another aspect the invention provides a method of producing germacrene A comprising: culturing a population of recombinant host cell of any one of claims 17, 18, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making germacrene A; and recovering the germacrene A from the culture medium. In another aspect the invention provides a method of producing germacrene D including: culturing a population of recombinant host cell of any one of claims 19, 20, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making germacrene D; and recovering the germacrene D from the culture medium. In another aspect the invention provides a method of producing valerena-4,7(11)- diene including: culturing a population of recombinant host cell of any one of claims 21, 22, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making valerena-4,7(11)-diene; andrecovering the valerena-4,7(11)-diene from the culture medium. In an embodiment the recombinant host cell produces beta- caryophyllene with a yield of greater than 12 (wt%) and a productivity of greater than 0.9 g/l/h. In another embodiment the recombinant host cell produces delta-cadinene with a yield of greater than 11 (wt%) and a productivity of greater than 1 g/l/h. In a further embodiment the recombinant host cell produces alpha-humulene with a yield of greater than 10 (wt%) and a productivity of greater than 0.7 g/l/h. In an additional embodiment the recombinant host cell produces valencene with a yield of greater than 4 (wt%) and a productivity of greater than 0.3 g/l/h. In a further embodiment the recombinant host cell produces delta-guaiene with a yield of greater than 3 (wt%) and a productivity of greater than 0.1 g/l/h. In an additional embodiment drudthe recombinant host cell produces germacrene A with a yield of greater than 5 (wt%) and a productivity of greater than 0.4 g/l/h. BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a schematic showing an enzymatic pathway from the native metabolite acetyl- CoA to FPP, which is then enzymatically derivatized to the heterologous compounds beta- caryophyllene, delta-cadinene, epi-alpha-bisabolol, alpha-humulene, nerolidol, valencene, beta-cubebene, delta-guaiene, germacrene A, germacrene D, and valerena-4,7(11)-diene. Figure 2 is a graph that shows the maximum 96-well plate titer observed for each strain. DETAILED DESCRIPTION OF THE EMBODIMENTS As used herein the terms “comprising,” “including,” “containing,” and “characterized by” are inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, the term “heterologous” refers to what is not normally found in nature. The term “heterologous nucleotide sequence” refers to a nucleotide sequence not normally found in a given cell in nature. As such, a heterologous nucleotide sequence may be: (a) foreign to its host cell (i.e., is “exogenous” to the cell); (b) naturally found in the host cell (i.e., “endogenous”) but present at an unnatural quantity in the cell (i.e., greater or lesser quantity than naturally found in the host cell); or (c) be naturally found in the host cell but positioned outside of its natural locus. As used herein, the term “parent cell” refers to a cell that has an identical genetic background as a genetically modified host cell disclosed herein except that it does not comprise one or more particular genetic modifications engineered into the modified host cell. As used herein, the term “medium” refers to culture medium and/or fermentation medium. As used herein, the term “production” generally refers to an amount of sesquiterpenoids produced by a recombinant host cell provided herein. In some embodiments, production is expressed as a titer of sesquiterpenoids by the host cell. In some embodiments, production is expressed as a yield of sesquiterpenoids by the host cell. In other embodiments, production is expressed as the productivity of the host cell in producing the sesquiterpenoids. As used herein, the term “titer” refers to production of a sesquiterpenoid by a host cell, expressed as the mass concentration of sesquiterpenoid per volume of fermentation broth. As used herein, the term “yield” refers to production of a sesquiterpenoid by a host cell, expressed as the mass of sesquiterpenoid produced per mass of carbon source consumed by the host cell, multiplied by 100%. As used herein, the term “productivity” refers to the production rate of a sesquiterpenoid by a host cell, expressed as the mass of sesquiterpenoid produced per unit volume of fermentation broth in which the host cell is cultured per unit time. As used herein, the term “recombinant host cell” refers to a host cell that has been genetically modified to express one or more heterologous amino acids that make the host cell capable of producing a particular sesquiterpenoid. The terms “recombinant host cell,” “host cell,” and “genetically modified host cell” may be used interchangeably to refer to the host cells of the invention. As used herein, the term “sesquiterpenoids” refer to a class of terpenes that consist of three isoprene units. In particular the sesquiterpenoids of the invention include beta- caryophyllene, delta-cadinene, epi-alpha-bisabolol, alpha-humulene, nerolidol, valencene, beta-cubebene, delta-guaiene, germacrene A, germacrene D, and valerena-4,7(11)-diene. As used herein, the term “beta-caryophyllene” refers to a sesquiterpene that is also known as (+)-beta-caryophyllene or as (-)-beta-caryophyllene or (1R,4E,9S)-4,11,11-trimethyl-8- methylidenebicyclo[7.2.0]undec-4-ene or (1S,4E,9E)-4,11,11-trimethyl-8-

methylidenebicyclo[7.2.0]undec-4-ene or a mixture of (+)-beta-caryophyllene and (-)-beta- caryophyllene isomers, which has the following structures: . As used herein, the term “delta-cadinene” refers to a sesquiterpene that is also known as (1S,8aR)-4,7-dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene or 1R,8aS)-4,7- dimethyl-1-(propan-2-yl)-1,2,3,5,6,8a-hexahydronaphthalene or (-)-delta-cadinene or (+)- delta-cadinene or the mixture of (+)-delta-cadinene and (-)-delta-cadinene isomers and which has the following structures: . As used herein, the term “epi-alpha-bisabolol” refers to a sesquiterpene alcohol that is also known as (+)-epi-alpha-bisabolol, (-)-epi-alpha-bisabolol, (R)-6-methyl-2-((S)-4- methylcyclohex-3-en-1-yl)hept-5-en-2-ol or (S)-6-methyl-2-((R)-4-methylcyclohex-3-en-1- yl)hept-5-en-2-ol or a mixture of (+)-epi-alpha-bisabolol and (-)-epi-alpha-bisabolol isomers and which has the following structures: . As used herein, the term “alpha-humulene” refers to a sesquiterpene that is also known as (1E,4E,8E)-2,6,6,9-Tetramethylcycloundeca-1,4-8-triene and which has the following structure: As used herein, the term “nerolidol” refers to a sesquiterpene alcohol that is also known as (+)-nerolidol, (-)-nerolidol, (R,E)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol, (S,E)- 3,7,11-trimethyldodeca-1,6,10-trien-3-ol, or a mixture of the (+)-nerolidol and (-)-nerolidol isomers, and which has the following structures: As used herein, the term “-valencene” refers to a sesquiterpene that is also known as (+)-valencene or (-)-valencene or (3R,4aS,5R)-4a,5-Dimethyl-3-(prop-1-en-2-yl)- 1,2,3,4,4a,5,6,7-octahydronaphthalene or (3S,4aR,5S)-4a,5-Dimethyl-3-(prop-1-en-2-yl)- 1,2,3,4,4a,5,6,7-octahydronaphthalene or a mixture of (+)-valencene and (-)-valencene isomers and which has the following structures: . As used herein, the term “beta-cubebene” refers to a sesquiterpene that is also known as beta-cubebene, 6-epi-beta-cubebene, (3aS,3bR,4S,7R,7aR)-4-isopropyl-7-methyl-3- methyleneoctahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene, (3aR,3bS,4S,7S,7aR)-4- isopropyl-7-methyl-3-methyleneoctahydro-1H-cyclopenta[1,3]cyclopropa[1,2]benzene, or a mixture of beta-cubebene and 6-epi-beta-cubebene, which has the following structures: . As used herein, the term “delta-guaiene” refers to a sesquiterpene that is also known as (3S,3aS,5R)-3,8-dimethyl-5-prop-1-en-2-yl-1,2,3,3a,4,5,6,7-octahydroazulene or and which has the following structure: As used herein, the term “germacrene A” refers to a sesquiterpene that is also known as (1E,5E,8S)-1,5-dimethyl-8-(prop-1-en-2-yl)cyclodeca-1,5-diene or (1E,5E,8R)-1,5- dimethyl-8-(prop-1-en-2-yl)cyclodeca-1,5-diene or (+)-germacrene A or (-)- germacrene A or a mixture of both (+)-germacrene A and (-)- germacrene A isomers and which has the following structure: . As used herein, the term “germacrene D” refers to a sesquiterpene that is also known as (-)-germacrene D or (+)-germacrene D or (1E,5E,8S)-1,5-dimethyl-8-(prop-1-en-2- yl)cyclodeca-1,5-diene (1E,5E,8R)-1,5-dimethyl-8-(prop-1-en-2-yl)cyclodeca-1,5-diene or a mixture of (-)-germacrene D and (+)-germacrene D isomers and which has the following structures: . As used herein, the term “valerena-4,7(11)-diene” refers to a sesquiterpene that is also known as (4S,7R,7aR)-3,7-dimethyl-4-(2-methylprop-1-enyl)-2,4,5,6,7,7a-hexahydro- 1H-indene and which has the following structure: As used herein, the term “sequence identity” or “percent identity” in the context of two or more polynucleotide or polypeptide sequences, refers to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same. For example, the sequence may have a percent identity of at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or higher identity over a specified region to a reference sequence when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using a sequence comparison algorithm or by manual alignment and visual inspection. For example, percent of identity is determined by calculating the ratio of the number of identical nucleotides (or amino acid residues) in the sequence divided by the length of the total nucleotides (or amino acid residues) minus the lengths of any gaps. For convenience, the extent of identity between two sequences can be ascertained using computer programs and mathematical algorithms known in the art. Such algorithms that calculate percent sequence identity generally account for sequence gaps and mismatches over the comparison region. Programs that compare and align sequences, like Clustal W (Thompson et al. (1994) Nuclei Acids Res., vol.22, pp.4673-4680), ALIGN (Myers et al., (1988) CABIOS, vol.4, pp.11-17), FASTA (Pearson et al., (1988) PNAS, vol.85, pp.2444- 2448; Pearson (1990) Methods Enzymol., vol.183, pp.63-98), and gapped BLAST (Altschul et al., (1997) Nucleic Acids Res., vol.25, pp.3389-3402) are useful for this purpose. The BLAST or BLAST 2.0 (Altschul et al., (1990) J. Mol. Biol., vol.215 pp.403-410) are available from several sources, including the National Center for Biological Information (NCBI) and on the Internet, for use in connection with the sequence analysis programs BLASTP, BLASTN, BLASTX, TBLASTN, and TBLASTX. Additional information can be found at the NCBI web site. In certain embodiments, the sequence alignments and percent identity calculations can be determined using the BLAST program using its standard, default parameters. For nucleotide sequence alignment and sequence identity calculations, the BLASTN program is used with its default parameters (Gap opening penalty = 5, Gap extension penalty = 2, Nucleic match = 2, Nucleic mismatch = -3, Expectation value = 10.0, Word size = 11, Max matches in a query range = 0). For polypeptide sequence alignment and sequence and sequence identity calculations, BLASTP program is used with its default parameters (Alignment matrix = BLOSUM62; Gap costs: Existence = 11, Extension = 1; Compositional adjustments = Conditional compositional score, matrix adjustment; Expectation value = 10.0; Word size = 6; Max matches in a query range = 0). Alternatively, the following program and parameters can be used: Align Plus software of Clone Manager Suite, version 5 (Sci-Ed Software); DNA comparison: Global comparison, Standard Linear Scoring matrix, Mismatch penalty = 2, Open gap penalty = 4, Extend gap penalty = 1. Amino acid comparison: Global comparison, BLOSUM 62 Scoring matrix. In the embodiments described herein, the sequence identity is calculated using BLASTN or BLASTP programs using their default parameters. In the embodiments described herein, the sequence alignment of two or more sequences are performed using Clustal W using the suggested default parameters (Dealign input sequences: no; Mbed-like clustering guide-tree: yes; Mbed-like clustering iteration: yes; number of combined iterations: default(0); Max guide tree iterations: default; Max HMM iterations: default; Order: input). Cell Strains Host cells of the invention provided herein include archae, prokaryotic, and eukaryotic cells. Suitable prokaryotic host cells include, but are not limited to, any of a gram- positive, gran-negative, and gram-variable bacteria. Examples include, but are not limited to, cells belonging to the genera: Agrobacterium, Alicyclobacillus, Anabaena, Anacystis, Arhrobacter, Azobacter, Bacillus, Brevibacterium, Chromatium, Clostridium, Corynebacterium, Enterobacter, Erwinia, Escherichia, Lactobacillus, Lactococcus, Mesorhizobium, Methylobacterium, Microbacterium, Phormidium, Pseudomonas, Rhodobacter, Rhodopseudomonas, Rhodospirillum, Rhodococcus, Salmonella, Scenedesmun, Serratia, Shigella, Staphlococcus, Strepromyces, Synnecoccus, and Zymomonas. Examples of prokaryotic strains include, but are not limited to: Bacillus subtilis, Bacillus amyloliquefacines, Brevibacterium ammoniagenes, Brevibacterium immariophilum, Clostridium beigerinckii, Enterobacter sakazakii, Escherichia coli, Lactococcus lactis, Mesorhizobium loti, Pseudomonas aeruginosa, Pseudomonas mevalonii, Pseudomonas pudica, Rhodobacter capsulatus, Rhodobacter sphaeroides, Rhodospirillum rubrum, Salmonella enterica, Salmonella typhi, Salmonella typhimurium, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, and Staphylococcus aureus. In a particular embodiment, the host cell is an Escherichia coli cell. Suitable archae hosts include, but are not limited to, cells belonging to the genera: Aeropyrum, Archaeglobus, Halobacterium, Methanococcus, Methanobacterium, Pyrococcus, Sulfolobus, and Thermoplasma. Examples of archae strains include, but are not limited to: Archaeoglobus fulgidus, Halobacterium sp., Methanococcus jannaschii, Methanobacterium thermoautotrophicum, Thermoplasma acidophilum, Thermoplasma volcanium, Pyrococcus horikoshii, Pyrococcus abyssi, and Aeropyrum pernix. Suitable eukaryotic hosts include, but are not limited to, fungal cells, algal cells, insect cells, and plant cells. In some embodiments, yeasts useful in the present methods include yeasts that have been deposited with microorganism depositories (e.g. IFO, ATCC, etc.) and belong to the genera Aciculoconidium, Ambrosiozyma, Arthroascus, Arxiozyma, Ashbya, Babjevia, Bensingtonia, Botryoascus, Botryozyma, Brettanomyces, Bullera, Bulleromyces, Candida, Citeromyces, Clavispora, Cryptococcus, Cystofilobasidium, Debaryomyces, Dekkara, Dipodascopsis, Dipodascus, Eeniella, Endomycopsella, Eremascus, Eremothecium, Erythrobasidium, Fellomyces, Filobasidium, Galactomyces, Geotrichum, Guilliermondella, Hanseniaspora, Hansenula, Hasegawaea, Holtermannia, Hormoascus, Hyphopichia, Issatchenkia, Kloeckera, Kloeckeraspora, Kluyveromyces, Kondoa, Kuraishia, Kurtzmanomyces, Leucosporidium, Lipomyces, Lodderomyces, Malasserzia, Metschnikowia, Mrakia, Myxozyma, Nadsonia, Nakazawaea, Nematospora, Ogataea, Oosporidium, Pachysolen, Phachytichospora, Phaffia, Pichia, Rhodosporidium, Rhodotorula, Saccharomyces, Saccharomycodes, Saccharomycopsis, Saitoella, Sakaguchia, Saturnospora, Schizoblastoporion, Schizosaccharomyces, Schwanniomyces, Sporidiobolus, Sporobolomyces, Sporopachydermia, Stephanoascus, Sterigmatomyces, Sterigmatosporidium, Symbiotaphrina, Sympodiomyces, Sympodiomycopsis, Torulaspora, Trichosporiella, Trichosporon, Trigonopsis, Tsuchiyaea, Udeniomyces, Waltomyces, Wickerhamia, Wickerhamiella, Williopsis, Yamadazyma, Yarrowia, Zygoascus, Zygosaccharomyces, Zygowilliopsis, and Zygozyma. In some embodiments, the host microbe is Saccharomyces cerevisiae, Pichia pastoris, Schizosaccharomyces pombe, Dekkera bruxellensis, Kluyveromyces lactis (previously called Saccharomyces lactis), Kluveromyces marxianus, Arxula adeninivorans, or Hansenula polymorpha (now known as Pichia angusta). In some embodiments, the host microbe is a strain of the genus Candida, such as Candida lipolytica, Candida guilliermondii, Candida krusei, Candida pseudotropicalis, or Candida utils. In preferred embodiments, the host microbe is Saccharomyces cerevisiae. In some embodiments, the host is a strain of Saccharomyces cerevisiae selected from Baker’s yeast, CEN.PK2, CBS 7959, CBS 7960, CBS 7961, CBS 7962, CBS 7963, CBS 7964, IZ- 1904, TA, BG-1, CR-1, SA-1, M-26, Y-904, PE-2, PE-5, VR-1 BR-1, BR-2, ME-2, VR-2, MA-3, MA-4, CAT-1, CB-1, NR-1, BT-1, and AL-1. In some embodiments, the host microbe is a strain of Saccharomyces cerevisiae selected from PE-2, CAT-1, VR-1, BG-1, CR-1, and SA-1. In a particular embodiment, the strain of Saccharomyces cerevisiae is PE-2. In another particular embodiment, the strain of Saccharomyces cerevisiae is CAT-1. In another particular embodiment, the strain of Saccharomyces cerevisiae is BG-1. MEV Pathway FPP In some embodiments, a genetically modified host cell provided herein comprises one or more heterologous enzymes of the MEV pathway, useful for the formation of FPP. The one or more enzymes of the MEV pathway may include an enzyme that condenses acetyl- CoA with malonyl-CoA to form acetoacetyl-CoA; an enzyme that condenses two molecules of acetyl-CoA to form acetoacetyl-CoA; an enzyme that condenses acetoacetyl-CoA with acetyl-CoA to form HMG-CoA; or an enzyme that converts HMG-CoA to mevalonate. In addition, the genetically modified host cells may include a MEV pathway enzyme that phosphorylates mevalonate to mevalonate 5-phosphate; a MEV pathway enzyme that converts mevalonate 5-phosphate to mevalonate 5-pyrophosphate; a MEV pathway enzyme that converts mevalonate 5-pyrophosphate to isopentenyl pyrophosphate; or a MEV pathway enzyme that converts isopentenyl pyrophosphate to dimethylallyl diphosphate. In particular, the one or more enzymes of the MEV pathway are selected from acetyl-CoA thiolase, acetoacetyl-CoA synthetase, HMG-CoA synthase, HMG-CoA reductase, mevalonate kinase, phosphomevalonate kinase, mevalonate pyrophosphate decarboxylase, and isopentyl diphosphate:dimethylallyl diphosphate isomerase (IDI or IPP isomerase). The genetically modified host cell of the invention may express one or more of the heterologous enzymes of the MEV from one or more heterologous nucleotide sequences comprising the coding sequence of the one or more MEV pathway enzymes. In some embodiments, the genetically modified host cell comprises a heterologous nucleic acid encoding an enzyme that can convert isopentenyl pyrophosphate (IPP) into dimethylallyl pyrophosphate (DMAPP). In addition, the host cell may contain a heterologous nucleic acid encoding an enzyme that may condense IPP and/or DMAPP molecules to form a polyprenyl compound. In some embodiments, the genetically modified host cell further contains a heterologous nucleic acid encoding an enzyme that may modify IPP or a polyprenyl to form an isoprenoid compound such as FPP. Conversion of Acetyl-CoA to Acetoacetyl-CoA The genetically modified host cell may contain a heterologous nucleic acid that encodes an enzyme that may condense two molecules of acetyl-coenzyme A to form acetoacetyl-CoA (an acetyl-CoA thiolase). Examples of nucleotide sequences encoding acetyl-CoA thiolase include (accession no. NC_000913 REGION: 2324131.2325315 (Escherichia coli)); (D49362 (Paracoccus denitrificans)); and (L20428 (Saccharomyces cerevisiae)). Acetyl-CoA thiolase catalyzes the reversible condensation of two molecules of acetyl- CoA to yield acetoacetyl-CoA, but this reaction is thermodynamically unfavorable; acetoacetyl-CoA thiolysis is favored over acetoacetyl-CoA synthesis. Acetoacetyl-CoA synthase (AACS) (also referred to as acetyl-CoA:malonyl-CoA acyltransferase; EC 2.3.1.194) condenses acetyl-CoA with malonyl-CoA to form acetoacetyl-CoA. Conversion of Acetoacetyl-CoA to HMG-CoA In some embodiments, the host cell comprises a heterologous nucleotide sequence encoding an enzyme that can condense acetoacetyl-CoA with another molecule of acetyl- CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), e.g., a HMG-CoA synthase. Examples of nucleotide sequences encoding such an enzyme include: (NC_001145. complement 19061.20536; Saccharomyces cerevisiae), (X96617; Saccharomyces cerevisiae), (X83882; Arabidopsis thaliana), (AB037907; Kitasatospora griseola), (BT007302; Homo sapiens), and (NC_002758, Locus tag SAV2546, GeneID 1122571; Staphylococcus aureus). Conversion of HMG-CoA to Mevalonate In some embodiments, the host cell comprises a heterologous nucleotide sequence encoding an enzyme that can convert HMG-CoA into mevalonate, e.g., a HMG-CoA reductase. Examples of nucleotide sequences encoding an NADPH-using HMG-CoA reductase include: (NM_206548; Drosophila melanogaster), (NC_002758, Locus tag SAV2545, GeneID 1122570; Staphylococcus aureus), (AB015627; Streptomyces sp. KO 3988), (AX128213, providing the sequence encoding a truncated HMG-CoA reductase; Saccharomyces cerevisiae), and (NC_001145: complement (115734.118898; Saccharomyces cerevisiae). Conversion of Mevalonate to Mevalonate-5-Phosphate The host cell may contain a heterologous nucleotide sequence encoding an enzyme that can convert mevalonate into mevalonate 5-phosphate, e.g., a mevalonate kinase. Illustrative examples of nucleotide sequences encoding such an enzyme include: (L77688; Arabidopsis thaliana) and (X55875; Saccharomyces cerevisiae). Conversion of Mevalonate-5-Phosphate to Mevalonate-5-Pyrophosphate The host cell may contain a heterologous nucleotide sequence encoding an enzyme that can convert mevalonate 5-phosphate into mevalonate 5-pyrophosphate, e.g., a phosphomevalonate kinase. Illustrative examples of nucleotide sequences encoding such an enzyme include: (AF429385; Hevea brasiliensis), (NM_006556; Homo sapiens), and (NC_001145. complement 712315.713670; Saccharomyces cerevisiae). Conversion of Mevalonate-5-Pyrophosphate to IPP The host cell may contain a heterologous nucleotide sequence encoding an enzyme that can convert mevalonate 5-pyrophosphate into isopentenyl diphosphate (IPP), e.g., a mevalonate pyrophosphate decarboxylase. Illustrative examples of nucleotide sequences encoding such an enzyme include: (X97557; Saccharomyces cerevisiae), (AF290095; Enterococcus faecium), and (U49260; Homo sapiens). Conversion of IPP to DMAPP The host cell may contain a heterologous nucleotide sequence encoding an enzyme that can convert IPP generated via the MEV pathway into dimethylallyl pyrophosphate (DMAPP), e.g., an IPP isomerase. Illustrative examples of nucleotide sequences encoding such an enzyme include: (NC_000913, 3031087.3031635; Escherichia coli), and (AF082326; Haematococcus pluvialis). Polyprenyl Synthases In some embodiments, the host cell further comprises a heterologous nucleotide sequence encoding a polyprenyl synthase that can condense IPP and/or DMAPP molecules to form polyprenyl compounds containing more than five carbons. The host cell may contain a heterologous nucleotide sequence encoding an enzyme that can condense two molecules of IPP with one molecule of DMAPP, or add a molecule of IPP to a molecule of GPP, to form a molecule of farnesyl pyrophosphate (“FPP”), e.g., a FPP synthase. Non-limiting examples of nucleotide sequences that encode a FPP synthase include: (ATU80605; Arabidopsis thaliana), (ATHFPS2R; Arabidopsis thaliana), (AAU36376; Artemisia annua), (AF461050; Bos taurus), (D00694; Escherichia coli K-12), (AE009951, Locus AAL95523; Fusobacterium nucleatum subsp. nucleatum ATCC 25586), (GFFPPSGEN; Gibberella fujikuroi), (CP000009, Locus AAW60034; Gluconobacter oxydans 621H), (AF019892; Helianthus annuus), (HUMFAPS; Homo sapiens), (KLPFPSQCR; Kluyveromyces lactis), (LAU15777; Lupinus albus), (LAU20771; Lupinus albus), (AF309508; Mus musculus), (NCFPPSGEN; Neurospora crassa), (PAFPS1; Parthenium argentatum), (PAFPS2; Parthenium argentatum), (RATFAPS; Rattus norvegicus), (YSCFPP; Saccharomyces cerevisiae), (D89104; Schizosaccharomyces pombe), (CP000003, Locus AAT87386; Streptococcus pyogenes), (CP000017, Locus AAZ51849; Streptococcus pyogenes), (NC_008022, Locus YP_598856; Streptococcus pyogenes MGAS10270), (NC_008023, Locus YP_600845; Streptococcus pyogenes MGAS2096), (NC_008024, Locus YP_602832; Streptococcus pyogenes MGAS10750), (MZEFPS; Zea mays), (AE000657, Locus AAC06913; Aquifex aeolicus VF5), (NM_202836; Arabidopsis thaliana), (D84432, Locus BAA12575; Bacillus subtilis), (U12678, Locus AAC28894; Bradyrhizobium japonicum USDA 110), (BACFDPS; Geobacillus stearothermophilus), (NC_002940, Locus NP_873754; Haemophilus ducreyi 35000HP), (L42023, Locus AAC23087; Haemophilus influenzae Rd KW20), (J05262; Homo sapiens), (YP_395294; Lactobacillus sakei subsp. sakei 23K), (NC_005823, Locus YP_000273; Leptospira interrogans serovar Copenhageni str. Fiocruz L1-130), (AB003187; Micrococcus luteus), (NC_002946, Locus YP_208768; Neisseria gonorrhoeae FA 1090), (U00090, Locus AAB91752; Rhizobium sp. NGR234), (J05091; Saccharomyces cerevisae), (CP000031, Locus AAV93568; Silicibacter pomeroyi DSS-3), (AE008481, Locus AAK99890; Streptococcus pneumoniae R6), and (NC_004556, Locus NP 779706; Xylella fastidiosa Temecula1). Methods of Producing Sesquiterpenoids The invention provides for the production of sesquiterpenoids by (a) culturing a population of any of the genetically modified host cells described herein that are capable of producing a sesquiterpenoid in a medium with a carbon source under conditions suitable for making the sesquiterpenoid compound, and (b) recovering the sesquiterpenoid compound from the medium. The genetically modified host cell produces an increased amount of the sesquiterpenoid compared to a parent cell not having the genetic modifications, or a parent cell having only a subset of the genetic modifications, but is otherwise genetically identical. In some embodiments, the increased amount is at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or greater than 100%, as measured, for example, in yield, production, and/or productivity, in grams per liter of cell culture, milligrams per gram of dry cell weight, on a per unit volume of cell culture basis, on a per unit dry cell weight basis, on a per unit volume of cell culture per unit time basis, or on a per unit dry cell weight per unit time basis. In some embodiments, the host cell may produce an elevated level of a sesquiterpenoid that is greater than about 1 gram per liter of fermentation medium. In some embodiments, the host cell produces an elevated level of a sesquiterpenoid that is greater than about 5 grams per liter of fermentation medium. In some embodiments, the host cell produces an elevated level of a sesquiterpenoid that is greater than about 10 grams per liter of fermentation medium. In some embodiments, the sesquiterpenoid is produced in an amount from about 10 to about 50 grams, from about 10 to about 15 grams, more than about 15 grams, more than about 20 grams, more than about 25 grams, or more than about 40 grams per liter of cell culture. In some embodiments, the host cell produces an elevated level of a sesquiterpenoid that is greater than about 50 milligrams per gram of dry cell weight. In some such embodiments, the sesquiterpenoid is produced in an amount from about 50 to about 1500 milligrams, more than about 100 milligrams, more than about 150 milligrams, more than about 200 milligrams, more than about 250 milligrams, more than about 500 milligrams, more than about 750 milligrams, or more than about 1000 milligrams per gram of dry cell weight. In some embodiments, the host cell produces an elevated level of a sesquiterpenoid that is at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 2.5-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 75-fold, at least about 100-fold, at least about 200-fold, at least about 300-fold, at least about 400-fold, at least about 500-fold, or at least about 1,000-fold, or more, higher than the level of sesquiterpenoid produced by a parent cell, on a per unit volume of cell culture basis. In some embodiments, the host cell produces an elevated level of a sesquiterpenoid that is at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 2.5-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 75-fold, at least about 100-fold, at least about 200-fold, at least about 300-fold, at least about 400-fold, at least about 500-fold, or at least about 1,000-fold, or more, higher than the level of sesquiterpenoid produced by the parent cell, on a per unit dry cell weight basis. In some embodiments, the host cell produces an elevated level of a sesquiterpenoid that is at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 2.5-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 75-fold, at least about 100-fold, at least about 200-fold, at least about 300-fold, at least about 400-fold, at least about 500-fold, or at least about 1,000-fold, or more, higher than the level of sesquiterpenoid produced by the parent cell, on a per unit volume of cell culture per unit time basis. In some embodiments, the host cell produces an elevated level of a sesquiterpenoid that is at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 2.5-fold, at least about 5-fold, at least about 10-fold, at least about 20-fold, at least about 30-fold, at least about 40-fold, at least about 50-fold, at least about 75-fold, at least about 100-fold, at least about 200-fold, at least about 300-fold, at least about 400-fold, at least about 500-fold, or at least about 1,000-fold, or more, higher than the level of sesquiterpenoid produced by the parent cell, on a per unit dry cell weight per unit time basis. In most embodiments, the production of the elevated level of sesquiterpenoid by the host cell is inducible by the presence of an inducing compound. Such a host cell can be manipulated with ease in the absence of the inducing compound. The inducing compound is then added to induce the production of the elevated level of sesquiterpenoid by the host cell. In other embodiments, production of the elevated level of sesquiterpenoid by the host cell is inducible by changing culture conditions, such as, for example, the growth temperature, media constituents, and the like. Culture Media and Conditions Materials and methods for the maintenance and growth of microbial cultures are well known to those skilled in the art of microbiology or fermentation science (see, for example, Bailey et al., Biochemical Engineering Fundamentals, second edition, McGraw Hill, New York, 1986). Consideration must be given to appropriate culture medium, pH, temperature, and requirements for aerobic, microaerobic, or anaerobic conditions, depending on the specific requirements of the host cell, the fermentation, and the process. The methods of producing sesquiterpenoids provided herein may be performed in a suitable culture medium (e.g., with or without pantothenate supplementation) in a suitable container, including but not limited to a cell culture plate, a microtiter plate, a flask, or a fermentor. Further, the methods can be performed at any scale of fermentation known in the art to support industrial production of microbial products. Any suitable fermentor may be used including a stirred tank fermentor, an airlift fermentor, a bubble fermentor, or any combination thereof. In particular embodiments utilizing Saccharomyces cerevisiae as the host cell, strains can be grown in a fermentor as described in detail by Kosaric, et al, in Ullmann's Encyclopedia of Industrial Chemistry, Sixth Edition, vol.12, pp.398-473, Wiley- VCH Verlag GmbH & Co. KDaA, Weinheim, Germany. In some embodiments, the culture medium is any culture medium in which a genetically modified microorganism capable of producing a sesquiterpenoid can subsist. The culture medium may be an aqueous medium comprising assimilable carbon, nitrogen and phosphate sources. Such a medium can also include appropriate salts, minerals, metals, and other nutrients. The carbon source and each of the essential cell nutrients may be added incrementally or continuously to the fermentation media, and each required nutrient may be maintained at essentially the minimum level needed for efficient assimilation by growing cells, for example, in accordance with a predetermined cell growth curve based on the metabolic or respiratory function of the cells which convert the carbon source to a biomass. Suitable conditions and suitable media for culturing microorganisms are well known in the art. For example, the suitable medium may be supplemented with one or more additional agents, such as, for example, an inducer (e.g., when one or more nucleotide sequences encoding a gene product are under the control of an inducible promoter), a repressor (e.g., when one or more nucleotide sequences encoding a gene product are under the control of a repressible promoter), or a selection agent (e.g., an antibiotic to select for microorganisms comprising the genetic modifications). The carbon source may be a monosaccharide (simple sugar), a disaccharide, a polysaccharide, a non-fermentable carbon source, or one or more combinations thereof. Non- limiting examples of suitable monosaccharides include glucose, galactose, mannose, fructose, xylose, ribose, and combinations thereof. Non-limiting examples of suitable disaccharides include sucrose, lactose, maltose, trehalose, cellobiose, and combinations thereof. Non- limiting examples of suitable polysaccharides include starch, glycogen, cellulose, chitin, and combinations thereof. Non-limiting examples of suitable non-fermentable carbon sources include acetate and glycerol. The concentration of a carbon source, such as glucose, in the culture medium may be sufficient to promote cell growth but is not so high as to repress growth of the microorganism used. Typically, cultures are run with a carbon source, such as glucose, being added at levels to achieve the desired level of growth and biomass. The concentration of a carbon source, such as glucose, in the culture medium may be greater than about 1 g/L, preferably greater than about 2 g/L, and more preferably greater than about 5 g/L. In addition, the concentration of a carbon source, such as glucose, in the culture medium is typically less than about 100 g/L, preferably less than about 50 g/L, and more preferably less than about 20 g/L. It should be noted that references to culture component concentrations can refer to both initial and/or ongoing component concentrations. In some cases, it may be desirable to allow the culture medium to become depleted of a carbon source during culture. Sources of assimilable nitrogen that can be used in a suitable culture medium include simple nitrogen sources, organic nitrogen sources and complex nitrogen sources. Such nitrogen sources include anhydrous ammonia, ammonium salts and substances of animal, vegetable and/or microbial origin. Suitable nitrogen sources include protein hydrolysates, microbial biomass hydrolysates, peptone, yeast extract, ammonium sulfate, urea, and amino acids. Typically, the concentration of the nitrogen sources, in the culture medium is greater than about 0.1 g/L, preferably greater than about 0.25 g/L, and more preferably greater than about 1.0 g/L. Beyond certain concentrations, however, the addition of a nitrogen source to the culture medium is not advantageous for the growth of the microorganisms. As a result, the concentration of the nitrogen sources, in the culture medium is less than about 20 g/L, preferably less than about 10 g/L and more preferably less than about 5 g/L. Further, in some instances it may be desirable to allow the culture medium to become depleted of the nitrogen sources during culture. The effective culture medium may contain other compounds such as inorganic salts, vitamins, trace metals or growth promoters. Such other compounds may also be present in carbon, nitrogen or mineral sources in the effective medium or can be added specifically to the medium. The culture medium may also contain a suitable phosphate source. Such phosphate sources include both inorganic and organic phosphate sources. Preferred phosphate sources include phosphate salts such as mono or dibasic sodium and potassium phosphates, ammonium phosphate and mixtures thereof. Typically, the concentration of phosphate in the culture medium is greater than about 1.0 g/L, preferably greater than about 2.0 g/L and more preferably greater than about 5.0 g/L. Beyond certain concentrations, however, the addition of phosphate to the culture medium is not advantageous for the growth of the microorganisms. Accordingly, the concentration of phosphate in the culture medium is typically less than about 20 g/L, preferably less than about 15 g/L and more preferably less than about 10 g/L. A suitable culture medium can also include a source of magnesium, preferably in the form of a physiologically acceptable salt, such as magnesium sulfate heptahydrate, although other magnesium sources in concentrations that contribute similar amounts of magnesium can be used. Typically, the concentration of magnesium in the culture medium is greater than about 0.5 g/L, preferably greater than about 1.0 g/L, and more preferably greater than about 2.0 g/L. Beyond certain concentrations, however, the addition of magnesium to the culture medium is not advantageous for the growth of the microorganisms. Accordingly, the concentration of magnesium in the culture medium is typically less than about 10 g/L, preferably less than about 5 g/L, and more preferably less than about 3 g/L. Further, in some instances it may be desirable to allow the culture medium to become depleted of a magnesium source during culture. The culture medium can also include a biologically acceptable chelating agent, such as the dihydrate of trisodium citrate. In such instance, the concentration of a chelating agent in the culture medium is greater than about 0.2 g/L, preferably greater than about 0.5 g/L, and more preferably greater than about 1 g/L. Beyond certain concentrations, however, the addition of a chelating agent to the culture medium is not advantageous for the growth of the microorganisms. Accordingly, the concentration of a chelating agent in the culture medium is typically less than about 10 g/L, preferably less than about 5 g/L, and more preferably less than about 2 g/L. The culture medium may also initially include a biologically acceptable acid or base to maintain the desired pH of the culture medium. Biologically acceptable acids include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and mixtures thereof. Biologically acceptable bases include, but are not limited to, ammonium hydroxide, sodium hydroxide, potassium hydroxide and mixtures thereof. In some embodiments, the base used is ammonium hydroxide. The culture medium may also include a biologically acceptable calcium source, including, but not limited to, calcium chloride. Typically, the concentration of the calcium source, such as calcium chloride, dihydrate, in the culture medium is within the range of from about 5 mg/L to about 2000 mg/L, preferably within the range of from about 20 mg/L to about 1000 mg/L, and more preferably in the range of from about 50 mg/L to about 500 mg/L. The culture medium may also include sodium chloride. Typically, the concentration of sodium chloride in the culture medium is within the range of from about 0.1 g/L to about 5 g/L, preferably within the range of from about 1 g/L to about 4 g/L, and more preferably in the range of from about 2 g/L to about 4 g/L. The culture medium may also include trace metals. Such trace metals can be added to the culture medium as a stock solution that, for convenience, can be prepared separately from the rest of the culture medium. Typically, the amount of such a trace metals solution added to the culture medium is greater than about 1 ml/L, preferably greater than about 5 mL/L, and more preferably greater than about 10 mL/L. Beyond certain concentrations, however, the addition of a trace metals to the culture medium is not advantageous for the growth of the microorganisms. Accordingly, the amount of such a trace metals solution added to the culture medium is typically less than about 100 mL/L, preferably less than about 50 mL/L, and more preferably less than about 30 mL/L. It should be noted that, in addition to adding trace metals in a stock solution, the individual components can be added separately, each within ranges corresponding independently to the amounts of the components dictated by the above ranges of the trace metals solution. The culture media may include other vitamins, such as pantothenate, biotin, calcium, pantothenate, inositol, pyridoxine-HCl, and thiamine-HCl. Such vitamins can be added to the culture medium as a stock solution that, for convenience, can be prepared separately from the rest of the culture medium. Beyond certain concentrations, however, the addition of vitamins to the culture medium is not advantageous for the growth of the microorganisms. The fermentation methods described herein can be performed in conventional culture modes, which include, but are not limited to, batch, fed-batch, cell recycle, continuous and semi-continuous. In some embodiments, the fermentation is carried out in fed-batch mode. In such a case, some of the components of the medium are depleted during culture, including pantothenate during the production stage of the fermentation. In some embodiments, the culture may be supplemented with relatively high concentrations of such components at the outset, for example, of the production stage, so that growth and/or sesquiterpenoid production is supported for a period of time before additions are required. The preferred ranges of these components are maintained throughout the culture by making additions as levels are depleted by culture. Levels of components in the culture medium can be monitored by, for example, sampling the culture medium periodically and assaying for concentrations. Alternatively, once a standard culture procedure is developed, additions can be made at timed intervals corresponding to known levels at particular times throughout the culture. As will be recognized by those in the art, the rate of consumption of nutrient increases during culture as the cell density of the medium increases. Moreover, to avoid introduction of foreign microorganisms into the culture medium, addition is performed using aseptic addition methods, as are known in the art. In addition, an anti-foaming agent may be added during the culture. The temperature of the culture medium can be any temperature suitable for growth of the genetically modified cells and/or production of sesquiterpenoid. For example, prior to inoculation of the culture medium with an inoculum, the culture medium can be brought to and maintained at a temperature in the range of from about 20°C to about 45°C, preferably to a temperature in the range of from about 25°C to about 40°C, and more preferably in the range of from about 28°C to about 32°C. The pH of the culture medium can be controlled by the addition of acid or base to the culture medium. In such cases when ammonium hydroxide is used to control pH, it also conveniently serves as a nitrogen source in the culture medium. Preferably, the pH is maintained from about 3.0 to about 8.0, more preferably from about 3.5 to about 7.0, and most preferably from about 4.0 to about 6.5. The carbon source concentration, such as the glucose concentration, of the culture medium is monitored during culture. Glucose concentration of the culture medium can be monitored using known techniques, such as, for example, use of the glucose oxidase enzyme test or high pressure liquid chromatography, which can be used to monitor glucose concentration in the supernatant, e.g., a cell-free component of the culture medium. The carbon source concentration is typically maintained below the level at which cell growth inhibition occurs. Although such concentration may vary from organism to organism, for glucose as a carbon source, cell growth inhibition occurs at glucose concentrations greater than at about 60 g/L, and can be determined readily by trial. Accordingly, when glucose is used as a carbon source the glucose is preferably fed to the fermentor and maintained below detection limits. Alternatively, the glucose concentration in the culture medium is maintained in the range of from about 1 g/L to about 100 g/L, more preferably in the range of from about 2 g/L to about 50 g/L, and yet more preferably in the range of from about 5 g/L to about 20 g/L. Although the carbon source concentration can be maintained within desired levels by addition of, for example, a substantially pure glucose solution, it is acceptable, and may be preferred, to maintain the carbon source concentration of the culture medium by addition of aliquots of the original culture medium. The use of aliquots of the original culture medium may be desirable because the concentrations of other nutrients in the medium (e.g. the nitrogen and phosphate sources) can be maintained simultaneously. Likewise, the trace metals concentrations can be maintained in the culture medium by addition of aliquots of the trace metals solution. Other suitable fermentation medium and methods are described in, e.g., WO 2016/196321. Recovery of Sesquiterpenoids Once the sesquiterpenoid is produced by the host cell, it may be recovered or isolated for subsequent use using any suitable separation and purification methods known in the art. For example, a clarified liquid phase containing the sesquiterpenoid may be separated from the fermentation by centrifugation. Alternatively, a clarified liquid phase containing the sesquiterpenoid may be separated from the fermentation broth by adding a demulsifier into the fermentation broth. Examples of demulsifiers include surfactants, flocculants and coagulants. The sesquiterpenoid produced in the host cells may be present in the culture supernatant and/or associated with the host cells. Where some of the sesquiterpenoid is associated with the host cell, the recovery of the sesquiterpenoid may involve a method of improving the release of the sesquiterpenoids from the cells. This could take the form of washing the cells with hot water or buffer treatment, with or without a surfactant, and with or without added buffers or salts. The temperature may be any temperature deemed suitable for releasing the sesquiterpenoids. For example, the temperature may be in a range from 40 to 95 °C; or from 60 to 90 °C; or from 75 to 85 °C. Alternatively, the temperature may be 40, 45, 50, 55, 65, 70, 75, 80, 85, 90, or 95 °C. Physical or chemical cell disruption may be used to enhance the release of sesquiterpenoids from the host cell. Alternatively, and/or subsequently, the sesquiterpenoid in the culture medium may be recovered using an isolation- unit operations including, solvent extraction, membrane clarification, membrane concentration, adsorption, chromatography, evaporation, chemical derivatization, crystallization, and drying. Methods of Making Genetically Modified Cells Also provided herein are methods for producing a host cell that is genetically engineered to contain one or more of the modifications described above, e.g., one or more heterologous nucleic acids encoding kaurenoic acid hydroxylase, and/or biosynthetic pathway enzymes, e.g., for a sesquiterpenoid compound. Expression of a heterologous enzyme in a host cell can be accomplished by introducing into the host cells a nucleic acid comprising a nucleotide sequence encoding the enzyme under the control of regulatory elements that permit expression in the host cell. The nucleic acid may be an extrachromosomal plasmid, a chromosomal integration vector that can integrate the nucleotide sequence into the chromosome of the host cell, or a linear piece of double stranded DNA that can integrate via homology the nucleotide sequence into the chromosome of the host cell. Nucleic acids encoding these proteins can be introduced into the host cell by any method known to one of skill in the art (see, e.g., Hinnen et al., (1978) Proc. Natl. Acad. Sci. USA, vol.75, pp.1292-1293; Cregg et al., (1985), Mol. Cell. Biol., vol.5, pp.3376-3385; Goeddel et al. eds, 1990, Methods in Enzymology, vol.185, Academic Press, Inc. , CA; Krieger, 1990, Gene Transfer and Expression -- A Laboratory Manual, Stockton Press, NY; Sambrook et al., 1989, Molecular Cloning -- A Laboratory Manual, Cold Spring Harbor Laboratory, NY; and Ausubel et al., eds. , Current Edition, Current Protocols in Molecular Biology, Greene Publishing Associates and Wiley Interscience, NY). Exemplary techniques include, spheroplasting, electroporation, PEG 1000 mediated transformation, and lithium acetate or lithium chloride mediated transformation. The amount of an enzyme in a host cell may be altered by modifying the transcription of the gene that encodes the enzyme. This can be achieved by modifying the copy number of the nucleotide sequence encoding the enzyme (e.g., by using a higher or lower copy number expression vector comprising the nucleotide sequence, or by introducing additional copies of the nucleotide sequence into the genome of the host cell or by deleting or disrupting the nucleotide sequence in the genome of the host cell), by changing the order of coding sequences on a polycistronic mRNA of an operon or breaking up an operon into individual genes each with its own control elements, or by increasing the strength of the promoter or operator to which the nucleotide sequence is operably linked. Alternatively, or in addition, the copy number of an enzyme in a host cell may be altered by modifying the level of translation of an mRNA that encodes the enzyme. This can be achieved by modifying the stability of the mRNA, modifying the sequence of the ribosome binding site, modifying the distance or sequence between the ribosome binding site and the start codon of the enzyme coding sequence, modifying the entire intercistronic region located “upstream of” or adjacent to the 5’ side of the start codon of the enzyme coding region, stabilizing the 3’- end of the mRNA transcript using hairpins and specialized sequences, modifying the codon usage of enzyme, altering expression of rare codon tRNAs used in the biosynthesis of the enzyme, and/or increasing the stability of the enzyme, as, for example, via mutation of its coding sequence. The activity of an enzyme in a host cell may be altered in a number of ways, including expressing a modified form of the enzyme that exhibits increased or decreased solubility in the host cell, expressing an altered form of the enzyme that lacks a domain through which the activity of the enzyme is inhibited, expressing a modified form of the enzyme that has a higher or lower K_cat or a lower or higher K_m for the substrate, expressing a modified form of the enzyme that has a higher or lower thermostability, expressing a modified form of the enzyme that has a higher or lower activity at the pH of the cell, expressing a modified form of the enzyme that has a higher or lower accumulation in a subcellular compartment or organelle, expressing a modified form of the enzyme that has increased or decreased ability to insert into or associate with cellular membranes, expressing a modified form of the enzyme that has a higher or lower affinity for accessory proteins needed to carry out a reaction, expressing a modified form of the enzyme that has a higher or lower affinity for necessary cofactors or ligands, expressing a modified form of the enzyme that has a increased or decreased space in the active site (thereby differentially allowing or excluding different substrates for the reaction), or expressing an altered form of the enzyme that is more or less affected by feed-back or feed-forward regulation by another molecule in the pathway. A nucleic acid used to genetically modify a host cell may contain one or more selectable markers useful for the selection of transformed host cells and for placing selective pressure on the host cell to maintain the foreign DNA. The selectable marker may be an antibiotic resistance marker. Examples of antibiotic resistance markers include the BLA, NAT1, PAT, AUR1-C, PDR4, SMR1, CAT, mouse dhfr, HPH, DSDA, KAN^R, and SH BLE gene products. The BLA gene product from E. coli confers resistance to beta-lactam antibiotics (e.g., narrow-spectrum cephalosporins, cephamycins, and carbapenems (ertapenem), cefamandole, and cefoperazone) and to all the anti-gram-negative-bacterium penicillins except temocillin; the NAT1 gene product from S. noursei confers resistance to nourseothricin; the PAT gene product from S. viridochromogenes Tu94 confers resistance to bialophos; the AUR1-C gene product from Saccharomyces cerevisiae confers resistance to Auerobasidin A (AbA); the PDR4 gene product confers resistance to cerulenin; the SMR1 gene product confers resistance to sulfometuron methyl; the CAT gene product from Tn9 transposon confers resistance to chloramphenicol; the mouse dhfr gene product confers resistance to methotrexate; the HPH gene product of Klebsiella pneumonia confers resistance to Hygromycin B; the DSDA gene product of E. coli allows cells to grow on plates with D-serine as the sole nitrogen source; the KAN^R gene of the Tn903 transposon confers resistance to G418; and the SH BLE gene product from Streptoalloteichus hindustanus confers resistance to Zeocin (bleomycin). The antibiotic resistance marker may be deleted after the genetically modified host cell disclosed herein is isolated. The selectable marker may function by rescue of an auxotrophy (e.g., a nutritional auxotrophy) in the genetically modified microorganism. In auxotrophy, a parent microorganism contains a functional disruption in one or more gene products that function in an amino acid or nucleotide biosynthetic pathway and that renders the parent cell incapable of growing in media without supplementation with one or more nutrients. Such gene products include the HIS3, LEU2, LYS1, LYS2, MET15, TRP1, ADE2, and URA3 gene products in yeast. The auxotrophic phenotype can then be rescued by transforming the parent cell with an expression vector or chromosomal integration construct encoding a functional copy of the disrupted gene product, and the genetically modified host cell generated can be selected for based on the loss of the auxotrophic phenotype of the parent cell. Utilization of the URA3, TRP1, and LYS2 genes as selectable markers has a marked advantage because both positive and negative selections are possible. Positive selection is carried out by auxotrophic complementation of the URA3, TRP1, and LYS2 mutations, whereas negative selection is based on specific inhibitors, i.e., 5-fluoro-orotic acid (FOA), 5-fluoroanthranilic acid, and aminoadipic acid (aAA), respectively, that prevent growth of the prototrophic strains but allows growth of the URA3, TRP1, and LYS2 mutants, respectively. The selectable marker may rescue other non-lethal deficiencies or phenotypes that can be identified by a known selection method. Described herein are specific genes and proteins useful in the methods, compositions, and host cells of the invention; however, the absolute identity to such genes is not necessary. For example, changes in a particular gene or polynucleotide containing a sequence encoding a polypeptide or enzyme can be performed and screened for activity. Typically, such changes involve conservative mutations and silent mutations. Such modified or mutated polynucleotides and polypeptides can be screened for expression of a functional enzyme using methods known in the art. Due to the inherent degeneracy of the genetic code, other polynucleotides which encode substantially the same or functionally equivalent polypeptides may also be used to express the enzymes. It can be advantageous to modify a coding sequence to enhance its expression in a particular host. The genetic code is redundant with 64 possible codons, but most organisms typically use a subset of these codons. The codons that are utilized most often in a species are called optimal codons, and those not utilized very often are classified as rare or low-usage codons. Codons can be substituted to reflect the preferred codon usage of the host, in a process sometimes called “codon optimization” or “controlling for species codon bias.” Codon optimization for other host cells can be readily determined using codon usage tables or can be performed using commercially available software, such as CodonOp from Integrated DNA Technologies. Optimized coding sequences containing codons preferred by a particular prokaryotic or eukaryotic host (Murray et al., (1989), Nucl Acids Res., vol.17, pp.477-508) can be prepared, to increase the rate of translation or to produce recombinant RNA transcripts having desirable properties, such as a longer half-life, as compared with transcripts produced from a non-optimized sequence. Translation stop codons can also be modified to reflect host preference. For example, typical stop codons for S. cerevisiae and mammals are UAA and UGA, respectively. The typical stop codon for monocotyledonous plants is UGA, whereas insects and E. coli commonly use UAA as the stop codon (Dalphin et al., (1996), Nucl Acids Res., vol.24, pp.216-218). Due to the degenerate nature of the genetic code, a variety of DNA molecules differing in their nucleotide sequences may be used to encode a given enzyme of the disclosure. The native DNA sequence encoding the biosynthetic enzymes described above are referenced herein merely to illustrate an embodiment of the disclosure, and the disclosure includes DNA molecules of any sequence that encode the amino acid sequences of the polypeptides and proteins of the enzymes utilized in the methods of the invention. In similar fashion, a polypeptide can typically tolerate one or more amino acid substitutions, deletions, and insertions in its amino acid sequence without loss or significant loss of a desired activity. The invention includes such polypeptides with different amino acid sequences than the specific proteins described herein so long as the modified or variant polypeptides have the enzymatic activity of the reference polypeptide. Furthermore, the amino acid sequences encoded by the DNA sequences shown herein merely illustrate examples of the invention. In addition, homologs of enzymes useful for the practice of the compositions, methods, or host cells are encompassed by the invention. Two proteins (or a region of the proteins) are considered to be substantially homologous when the amino acid sequences have at least about 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity. To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). The length of a reference sequence aligned for comparison purposes may be at least 30%, typically at least 40%, more typically at least 50%, even more typically at least 60%, and even more typically at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. When “homologous” is used in reference to proteins or peptides, it is recognized that residue positions that are not identical often differ by conservative amino acid substitutions. A “conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of homology may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well known to those of skill in the art (See, e.g., Pearson W. R., (1994), Methods in Mol Biol, vol.25, pp.365-389). The following six groups each contain amino acids that are conservative substitutions for one another: 1) Serine (S), Threonine (T); 2) Aspartic Acid (D), Glutamic Acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Alanine (A), Valine (V), and 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W). Sequence homology for polypeptides, which is also referred to as percent sequence identity, is typically measured using sequence analysis software. A typical algorithm used for comparing a molecule sequence to a database containing a large number of sequences from different organisms is the computer program BLAST. When searching a database containing sequences from a large number of different organisms, it is typical to compare amino acid sequences. Furthermore, any of the genes encoding the foregoing enzymes or any of the regulatory elements that control or modulate their expression may be optimized by genetic/protein engineering techniques, such as directed evolution or rational mutagenesis. Such action allows those of ordinary skill in the art to optimize the enzymes for expression and activity in yeast. In addition, genes encoding these enzymes can be identified from other fungal and bacterial species and can be expressed for the modulation of the sesquiterpenoid pathway. A variety of organisms may serve as sources for these enzymes, including Saccharomyces spp., including S. cerevisiae and S. uvarum, Kluyveromyces spp., including K. thermotolerans, K. lactis, and K. marxianus, Pichia spp., Hansenula spp., including H. polymorpha, Candida spp., Trichosporon spp., Yamadazyma spp., including Y. spp. stipitis, Torulaspora pretoriensis, Issatchenkia orientalis, Schizosaccharomyces spp., including S. pombe, Cryptococcus spp., Aspergillus spp., Neurospora spp., or Ustilago spp. Sources of genes from anaerobic fungi include Piromyces spp., Orpinomyces spp., or Neocallimastix spp. Sources of prokaryotic enzymes that are useful include Escherichia. coli, Zymomonas mobilis, Staphylococcus aureus, Bacillus spp., Clostridium spp., Corynebacterium spp., Pseudomonas spp., Lactococcus spp., Enterobacter spp., and Salmonella spp. Techniques known to those skilled in the art may be suitable to identify additional homologous genes and enzymes. Generally, analogous genes and/or analogous enzymes can be identified by functional analysis and will have functional similarities. Techniques known to be suitable to identify analogous genes and analogous enzymes include PCR, degenerate PCR, low stringency nucleic acid hybridization, expression cloning, and high through-put screening. For example, to identify homologous or analogous terpene synthase, or any sesquiterpenoid biosynthetic pathway genes, proteins, or enzymes, techniques may include, but are not limited to, cloning a gene by PCR using primers based on a published sequence of a gene/enzyme of interest, or by degenerate PCR using degenerate primers designed to amplify a conserved region among a gene of interest. Further, one may use techniques to identify homologous or analogous genes, proteins, or enzymes with functional homology or similarity. Techniques include examining a cell or cell culture for the catalytic activity of an enzyme through in vitro enzyme assays for said activity (e.g. as described herein or in Kiritani, K., Branched-Chain Amino Acids Methods Enzymology, 1970), then isolating the enzyme with said activity through purification, determining the protein sequence of the enzyme through techniques such as Edman degradation, design of PCR primers to the likely nucleic acid sequence, amplification of said DNA sequence through PCR, and cloning of said nucleic acid sequence. To identify homologous or similar genes and/or homologous or similar enzymes, analogous genes and/or analogous enzymes or proteins, techniques also include comparison of data concerning a candidate gene or enzyme with databases such as BRENDA, KEGG, or MetaCYC. The candidate gene or enzyme may be identified within the above-mentioned databases in accordance with the teachings herein. EXAMPLES Example 1: Yeast transformation methods Each DNA construct was integrated into Saccharomyces cerevisiae (CEN.PK113-7D) using standard molecular biology techniques in an optimized lithium acetate transformation. Briefly, cells were grown overnight in yeast extract peptone dextrose (YPD) media at 28 °C with shaking (200 rpm), diluted to an OD600 of 0.1 in 100 mL YPD, and grown to an OD600 of 0.6 – 0.8. For each transformation, 5 mL of culture were harvested by centrifugation, washed in 5 mL of sterile water, spun down again, resuspended in 1 mL of 100 mM lithium acetate, and transferred to a microcentrifuge tube. Cells were spun down (13,000x g) for 30 s, the supernatant was removed, and the cells were resuspended in a transformation mix consisting of 240 µL 50% PEG, 36 µL 1 M lithium acetate, 10 µL boiled salmon sperm DNA, and 74 µL of donor DNA. For transformations that require expression of the endonuclease F-CphI, the donor DNA included a plasmid carrying the F-CphI gene expressed under the yeast TDH3 promoter. F-CphI endonuclease expressed in such a manner cuts a specific recognition site engineered in a host strain to facilitate integration of the target gene of interest. Following a heat shock at 42 °C for 40 min, cells were recovered overnight in YPD media before plating on selective media. Example 2: Generation of a base strain capable of high flux to farnesyl pyrophosphate (FPP) Figure 1 shows the native yeast biosynthetic pathway from acetyl-CoA to FPP. Strains with a high flux to FPP were created from a wildtype Saccharomyces cerevisiae strain (CEN.PK113-7D) by expressing the genes of the mevalonate pathway under the control of native GAL promoters. The base strain comprised the following chromosomally integrated mevalonate pathway genes from S. cerevisiae: acetyl-CoA thiolase, HMG-CoA synthase, HMG-CoA reductase, mevalonate kinase, phosphomevalonate kinase, mevalonate pyrophosphate decarboxylase, IPP:DMAPP isomerase, and farnesyl pyrophosphate synthase. The strains expressed GAL80 under a maltose-regulated switch, as described in EP3663392A1 and WO2016210343A1, and the strains also upregulated GAL4. Several intergenic regions in the base strain were pre-engineered with targeting sequences for the F- CphI endonuclease to facilitate high-efficiency integration of downstream genes to produce the final target molecule. Examples of methods for creating S. cerevisiae strains with high flux to FPP are described in the U.S. Patent No.8,415,136 and U.S. Patent No.8,236,512 which are incorporated herein in their entireties. Example 3: Generation of strains producing eleven isoprenoids: Beta-Caryophyllene, Delta-Cadinene, Epi-Alpha-Bisabolol, alpha-Humulene, Nerolidol, Valencene, Beta- Cubebene, Delta-Guaiene, Germacrene A, Germacrene D, and Valerena-4,7(11)-Diene The FPP base strain described above was further engineered to have high flux to the isoprenoidsBeta-Caryophyllene, Delta-Cadinene, Epi-Alpha-Bisabolol, alpha-Humulene, Nerolidol, Valencene, Beta-Cubebene, Delta-Guaiene, Germacrene A, Germacrene D, and Valerena-4,7(11)-Diene. Additional heterologous genes were integrated into the FPP base strain to allow them to convert FPP into each of the final target molecules (Error! Reference source not found.). In some cases, additional engineering was also added intended to supplement the base strain and further upregulate flux to FPP. The genetic designs containing all of the additional genes were integrated into the base strain genome at intergenic regions in the genome, under control of either a native, strong GAL-regulon promoter, such as GAL1 or GAL10 . All heterologous genes were codon optimized using publicly available or other suitable algorithms. In some cases, DNA sequence corresponding to an N-terminal signal sequence was trimmed from the gene to result in the truncated amino acid sequence in the table. In other cases, DNA sequence for a GB1 expression tag was fused to the N-terminus of the protein, resulting in the final amino acid sequence in the table. The genetic designs for each molecule are shown in: Table 1 (-Beta-Caryophyllene); Table 2 (Delta-Cadinene), Table 3 (Epi-Alpha-Bisabolol); Table 4 (alpha-Humulene); Table 5 (Nerolidol); Table 6 (Valencene); Table 7 (Beta-Cubebene); Table 8 (Delta-Guaiene); Table 9 (-Germacrene A); Table 10 (germacrene D); and Table 11 (Valerena-4,7(11)-Diene). Each table is a listing of Design IDs which provide for the identity (gene name, Uniprot number, and SEQ ID NO:) and copy number of the added genes in each test strain that produces the identified molecule. Table 1: Genetic designs depicting the additional genes integrated into the FPP base strain to produce Beta-Caryophyllene Table 2: Genetic designs depicting the additional genes integrated into the FPP base strain to produce Delta-Cadinene Table 3: Genetic designs depicting the additional genes integrated into the FPP base strain to produce Epi-Alpha-Bisabolol p ypp y synthase NO: 7

cytosolic

synthase NO: 8

Guaiene NO: 59

Example 4: Yeast culturing conditions in 96-well plates Yeast colonies transformed with the genetic designs were picked into 96-well microtiter plates containing Bird Seed Media (BSM, originally described by van Hoek et al., Biotechnology and Bioengineering 68(5), 2000, pp.517-523) with 14 g/L sucrose, 7 g/L maltose, 37.5 g/L ammonium sulfate, and 1 g/L lysine. Cells were cultured at 28 °C in a high capacity microtiter plate incubator shaking at 1000 rpm and 80% humidity for 3 days until the cultures reached carbon exhaustion. The growth-saturated cultures were subcultured into fresh plates containing BSM with 40 g/L sucrose, 37.5 g/L ammonium sulfate, and 1 g/L lysine by taking 14.4 µL from the saturated cultures and diluting into 360 µL of fresh media. Cells in the production media were cultured at 30 °C in a high capacity microtiter plate shaker at 1000 rpm and 80% humidity for additional 3 days prior to extraction and analysis. The 96-well plate titers observed for 273 strains producing the eleven target molecules are detailed in Table 12. Table 12.96-well plate titers observed for strains producing 11 target isoprenoids

Example 5: Yeast sample preparation conditions for analysis of terpene titers To quantify the amount of sesquiterpenoid produced, the whole cell broth was diluted with 360 µL of an ethyl acetate containing 100 mg/L concentrations of internal standards (undecane, heptadecane and pentacosane), sealed with a foil seal, and shaken at 1500 rpm for 60 min. The plate was centrifuged for 5 min at 2000 rpm to pellet solids and 25 µL of the organic layer was transferred into a 96-well plate containing 225 µL ethyl acetate (10x dilution) before analysis by gas chromatography–mass spectrometry (GC-MS). Example 6: Analytical methods Samples derived from yeast producing sesquiterpenoids were routinely analyzed using GC- MS. GC-MS samples were loaded onto Gerstel MSP2 (Gerstel, Inc, Linthicum, MD, USA) autosampler and analyses were performed using a GC-MSD system (5975C Agilent Technologies Inc., Santa Rosa, CA, USA) equipped with DB-1 MS (Agilent Technologies Inc., Santa Rosa, CA, USA) capillary column of 20 m x 0.10 mm with a phase thickness of 0.10mm. The injection volume of each sample was 1 µL using split mode with split ratio of 20:1. Helium (99.999%) was used as the carrier gas at a flowrate of 0.45 mL/min. The temperature of the injection port was 275° C, and the column temperature program was as follows: 60° C for 0 min, followed by an increase to 320° C at a rate of 30° C/min. The MS conditions included an EI ion source temperature of 230° C, quad temperature of 150°, an ionization energy of ~1100 to 1250 eV, and a mass scan range of 40–600 Amu. Quantification of terpenes in crude extracts were calculated by comparing internal-standard normalized peak area of the molecules identified with calibration curves of authentic standards, when available. Sample peak areas were normalized using the sum of the peak areas of three internal standards, undecane, heptadecane and pentacosane (Sigma Aldrich, St Louis, MO, USA). If an authentic chemical standard was not available for calibration for a molecule, a calibration curve for the nearest chemical relative with a chemical standard was used as a surrogate instead. Example 7: Yeast culturing conditions in bench scale bioreactors Strains were streaked onto petri plates (YP with 3% maltose, 2 g/L lysine) and incubated at 28 ° C for 3 days. A ~2 mm loopful of colonies were inoculated into 50 ml of BSM with 50 mM succinate pH 5.0, and 20 g/L sucrose, 40 g/L maltose, 5 g/L lysine, and 2 g/L yeast extract and cultured at 28C. After 24h, 6 mL was transferred to a 1-L baffled flask containing 200 mL of the same medium and culture conditions. After 24h of additional growth, 2-L, 0.5-L or 0.25L bioreactors containing BSM were inoculated with a 20 v/v% inoculum. The fermentation temperature was controlled at 30°C. To control foaming 0.1 mL of L-81 was added to at inoculation. Additionally, 5% v/v of durasyn 164 was added as an overlay for in situ extraction of terpenes. pH 5 was maintained throughout the run using ammonium hydroxide. Stirring was controlled and the fermentor was continuously sparged with air to maintain a maximal oxygen transfer rate of >100 mmol O₂/L/h. Fermentations were fed a 90/10% VHP sucrose/molasses blend with a total reducing sugar (TRS) concentration of 66.6% g/g or other suitable feedstock. This feed was delivered at a rate to hold the dissolved oxygen constant at 30% or lower set point. Feed was periodically reduced to confirm substrate limitation and then restored to rate required to hold the dissolved oxygen set point. Tanks were sampled daily starting 24 hours after inoculation. Whole cell broth (WCB) was collected and stored at -20C. At the end of the fermentation run, samples were thawed and extracted as described previously. Example 8: Sesquiterpenoid production in bench scale bioreactors Table 13. Strain performances in bench-scale bioreactors. Example 9: Sesquiterpenoid isolation in bench scale equipment Sesquiterpenoid-enriched overlay was isolated from their respective pilot fermentation whole cell broth by methods like those described in patent application US 2012/0040396A1 and patent US 11,312,976 B2. Once fermentations were completed, the terpene-enriched overlay phase was separated from the water and cells in the fermentation broth. First samples of the fermentation broth were screened for the minimal L-81 surfactant concentration required to break the oil/water emulsions for each terpene. After the minimum surfactant amount was selected, the fermentation broth was demulsified at 70^oC for 1h in a stirred 2L demulsification vessel in the presence the target quantity of L-81. After demulsification, the broth was centrifuged at 8000 RPM for 1h, to separate the phases by density. The low- density, terpene-enriched overlay fraction was carefully removed and centrifuged again at 4000 RPM for 30 min to remove any residual water and cells carried over from the first fermentation. This polished overlay material was then subjected to a vacuum distillation at 0.1 Torr and 70-80^oC to isolate the low boiling point terpenes from the higher boiling point overlay. Example 10: Fermentation scale up results The beta-caryophyllene and delta cadinene strains were taken to the pilot scale for additional testing. For the 1000L fermentation process, two seed vials were thawed and 0.75 mL from each was inoculated into a 250 ml baffled flask containing 50 ml of BSM with 50 mM succinate pH 5.0, and 20 g/L sucrose, 40 g/L maltose, 5 g/L lysine, and 2 g/L yeast extract and cultured at 28°C. After 24 hours, four 2.8 L Fernbach flasks each containing 800 mL of fresh medium were inoculated with 16 mL of broth from the preceding flasks and cultured at 28°C. After 24 hours, 2.66L of inoculum was then transferred to a 1000 L stirred tank fermentation vessel containing 197 kg BSM with 7g/L (NH4)2SO4, 5 g/L Lysine and 40 g/L maltose. An initial pulse of 90:10 VHP/molasses feedstock was added to deliver 20 g/L of sucrose. The fermentation temperature was controlled at 28°C. To control foaming 0.1 mL of L-81 was added to at inoculation. pH 5 was maintained throughout the run using ammonium hydroxide. Stirring was controlled and the fermentor was continuously sparged with air to maintain dissolved oxygen above 0%. After 24 hours, broth mass was drained to 100 kg and 400 kg of BSM medium with 7g/L (NH4)2SO4 (100 mL/L), 3mL/L Bird Vitz 3.5, 5mL/L Bird TM, 2 g/L Lysine, and 10 g/L maltose was added.36 kg of Durasyn 164 overlay was added. An initial pulse of 90:10 VHP/molasses feedstock was added to deliver 14 g/L of sucrose, and then delivered as needed for the remainder of the fermentation to maintain optimal culture performance. The fermentation temperature was controlled at 30°C. To control foaming, 0.1 mL of L-81 was added to at inoculation. Additionally, 5% v/v of durasyn 164 was added as an overlay for in situ extraction of terpenes. pH 5 was maintained throughout the run using ammonium hydroxide. Stirring was controlled and the fermentor was continuously sparged with air to maintain a maximal oxygen transfer rate of >100 mmol O₂/L/h. Sufficient broth was removed and saved every 48 hours to maintain a working volume below 700 L. Nutrients and overlay were replenished after broth removals. For the 20L fermentation process, three seed vials were thawed and 0.75 mL from each was inoculated into a 250 ml baffled flask containing 50 ml of BSM with 50 mM succinate pH 5.0, and 20 g/L sucrose, 40 g/L maltose, 5 g/L lysine, and 2 g/L yeast extract and cultured at 28°C. After 24 hours, four 2.8 L Fernbach flasks each containing 800 mL of fresh medium were inoculated with 16 mL of broth from the preceding flasks and cultured at 28°C. After 24 hours, 2L of inoculum was then transferred to a 20 L stirred tank fermentation vessel containing 10 kg BSM with 7g/L (NH4)2SO4, 2 g/L Lysine and 10 g/L maltose.600 mL of Durasyn 164 overlay was added. An initial pulse of 90:10 VHP/molasses feedstock was added to deliver 14 g/L of sucrose, and then delivered as needed for the remainder of the fermentation to maintain optimal culture performance. The fermentation temperature was controlled at 30°C. To control foaming 0.1 mL of L-81 was added to at inoculation. pH 5 was maintained throughout the run using ammonium hydroxide. Stirring was controlled and the fermentor was continuously sparged with air to maintain dissolved oxygen above 0%. pH 5 was maintained throughout the run using ammonium hydroxide. Stirring was controlled and the fermentor was continuously sparged with air to maintain a maximal oxygen transfer rate of >100 mmol O₂/L/h. Sufficient broth was removed and saved every 48 hours to maintain a working volume below 20 L. Nutrients and overlay were replenished after broth removals. Table 14. Strain performances in 20L and 1000L scale-up fermentors. Example 11: DSPD scale up results Beta-caryophyllene and delta-cadinene enriched overlay was isolated from their respective pilot fermentation draws and harvest broth by methods similar to those described in patent application US 2012/0040396A1 and patent US 11,312,976 B2. Once fermentations were completed, the terpene-enriched overlay phase was separated from the water and cells in the fermentation broth. First the fermentation broth was centrifuged in a liquid/solid (L/S) centrifuge to remove the cells. One mL samples of the solids free L/S light phases were then screened for the minimal L62 surfactant concentration required to break the oil/water emulsions for each terpene. After the minimum surfactant amount was selected, the L/S light phase was heated to 70^oC in the presence the target quantity of L62, fed to a liquid-liquid centrifuge and the low-density, overlay/terpene light phase was collected. To ensure ensure <1% water was retained, a polishing centrifugation step in a bucket centrifuge or second L/L centrifugation was repeated. For final isolation of the low boiling point terpenes from the higher boiling point overlay, the polished overlay material was then subjected to a vacuum distillation or wiped-film evaporation.

Claims

CLAIMS 1. A recombinant host cell capable of producing beta-caryophyllene comprising a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 39, SEQ ID NO: 45, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, and SEQ ID NO: 56.

2. The recombinant host cell of claim 1, wherein the polypeptide has a sequence selected from SEQ ID NO: 39, SEQ ID NO: 45, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, and SEQ ID NO: 56.

3. A recombinant host cell capable of producing delta-cadinene comprising a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 51, and SEQ ID NO: 52.

4. The recombinant host cell of claim 3, wherein the polypeptide has a sequence selected from SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 51, and SEQ ID NO: 52.

5. A recombinant host cell capable of producing epi-alpha-bisabolol comprising a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: SEQ ID NO: 2, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 30, SEQ ID NO: 46, and SEQ ID NO: 47.

6. The recombinant host cell of claim 5, wherein the polypeptide has a sequence selected from SEQ ID NO: SEQ ID NO: 2, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 30, SEQ ID NO: 46, and SEQ ID NO: 47.

7. A recombinant host cell capable of producing alpha-humulene comprising a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 1, SEQ ID NO: 39, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, and SEQ ID NO: 57.

8. The recombinant host cell of claim 7, wherein the polypeptide has a sequence selected from SEQ ID NO: 1, SEQ ID NO: 39, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, and SEQ ID NO: 57.

9. A recombinant host cell capable of producing nerolidol comprising a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 28, SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42.

10. The recombinant host cell of claim 9, wherein the polypeptide has a sequence selected from SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 28, SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 42.

11. A recombinant host cell capable of producing valencene comprising a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 3, SEQ ID NO: 13, SEQ ID NO: 36, SEQ ID NO: 37, and SEQ ID NO: 38.

12. The recombinant host cell of claim 11, wherein the polypeptide has a sequence selected from SEQ ID NO: 3, SEQ ID NO: 13, SEQ ID NO: 36, SEQ ID NO: 37, and SEQ ID NO: 38.

13. A recombinant host cell capable of producing beta-cubebene comprising a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 58, SEQ ID NO: 65, SEQ ID NO: 72, and SEQ ID NO: 73.

14. The recombinant host cell of claim 13, wherein the polypeptide has a sequence selected from SEQ ID NO: 58, SEQ ID NO: 65, SEQ ID NO: 72, and SEQ ID NO: 73.

15. A recombinant host cell capable of producing delta-guaiene comprising a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 59, SEQ ID NO: 60, and SEQ ID NO: 67.

16. The recombinant host cell of claim 15, wherein the polypeptide has a sequence selected from SEQ ID NO: 59, SEQ ID NO: 60, and SEQ ID NO: 67.

17. A recombinant host cell capable of producing germacrene A comprising a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 61, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 71.

18. The recombinant host cell of claim 17, wherein the polypeptide has a sequence selected from SEQ ID NO: 61, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, and SEQ ID NO: 71.

19. A recombinant host cell capable of producing germacrene D comprising a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 66, and SEQ ID NO: 68.

20. The recombinant host cell of claim 19, wherein the polypeptide has a sequence selected from SEQ ID NO: 61, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 66, and SEQ ID NO: 68.

21. A recombinant host cell capable of producing valerena-4,7(11)-diene comprising a heterologous nucleic acid that encodes a polypeptide having a sequence having at least 90% identity to a sequence of SEQ ID NO: 62.

22. The recombinant host cell of claim 21, wherein the polypeptide has the sequence of SEQ ID NO: 62.

23. The recombinant host cell of any of the preceding claims further comprising one or more heterologous nucleic acids that encode one or more polypeptides having a sequence having at least 90% identity to a sequence selected from SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12.

24. The recombinant host cell of claim 23, wherein the one or more polypeptides have a sequence selected from SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12.

25. The recombinant host cell of any of the preceding claims wherein the host cell comprises a plant cell, a yeast cell, or a bacterial cell.

26. The recombinant host cell of claim 25, wherein the host cell is a yeast cell.

27. The recombinant host cell of claim 26, wherein the host cell is a Saccharomyces cerevisiae cell.

28. A method of producing beta-caryophyllene comprising: culturing a population of recombinant host cell of any one of claims 1, 2, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making beta-caryophyllene; and recovering the beta-caryophyllene from the culture medium.

29. A method of producing delta-cadinene comprising: culturing a population of recombinant host cell of any one of claims 3, 4, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making delta-cadinene; and recovering the delta-cadinene from the culture medium.

30. A method of producing epi-alpha-bisabolol comprising: culturing a population of recombinant host cell of any one of claims 5, 6, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making epi-alpha-bisabolol; and recovering the epi-alpha-bisabolol from the culture medium.

31. A method of producing alpha-humulene comprising: culturing a population of recombinant host cell of any one of claims 7, 8, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making alpha-humulene; and recovering the alpha-humulene from the culture medium.

32. A method of producing nerolidol comprising: culturing a population of recombinant host cell of any one of claims 9, 10, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making nerolidol; and recovering the nerolidol from the culture medium.

33. A method of producing valencene comprising: culturing a population of recombinant host cell of any one of claims 11, 12, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making valencene; and recovering the valencene from the culture medium.

34. A method of producing beta-cubebene comprising: culturing a population of recombinant host cell of any one of claims 13, 14, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making beta-cubebene; and recovering the beta-cubebene from the culture medium.

35. A method of producing delta-guaiene comprising: culturing a population of recombinant host cell of any one of claims 15, 16, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making delta-guaiene; and recovering the delta-guaiene from the culture medium.

36. A method of producing germacrene A comprising: culturing a population of recombinant host cell of any one of claims 17, 18, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making germacrene A; and recovering the germacrene A from the culture medium.

37. A method of producing germacrene D comprising: culturing a population of recombinant host cell of any one of claims 19, 20, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making germacrene D; and recovering the germacrene D from the culture medium.

38. A method of producing valerena-4,7(11)-diene comprising: culturing a population of recombinant host cell of any one of claims 21, 22, and 23 – 27 in a culture medium comprising a carbon source under conditions suitable for making valerena-4,7(11)-diene; andrecovering the valerena-4,7(11)-diene from the culture medium.

39. The method of claim 28, wherein the recombinant host cell produces beta- caryophyllene with a yield of greater than 12 (wt%) and a productivity of greater than 0.9 g/l/h.

40. The method of claim 29, wherein the recombinant host cell produces delta-cadinene with a yield of greater than 11 (wt%) and a productivity of greater than 1 g/l/h.

41. The method of claim 31, wherein the recombinant host cell produces alpha-humulene with a yield of greater than 10 (wt%) and a productivity of greater than 0.7 g/l/h.

42. The method of claim 33, wherein the recombinant host cell produces valencene with a yield of greater than 4 (wt%) and a productivity of greater than 0.3 g/l/h.

43. The method of claim 35, wherein the recombinant host cell produces delta-guaiene with a yield of greater than 3 (wt%) and a productivity of greater than 0.1 g/l/h.

44. The method of claim 36, wherein the recombinant host cell produces germacrene A with a yield of greater than 5 (wt%) and a productivity of greater than 0.4 g/l/h.