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WO2000037608A2 - Genes de $i(micromonospora echinospora) codant pour la biosynthese de calicheamicine et auto-resistance a cette derniere - Google Patents

Genes de $i(micromonospora echinospora) codant pour la biosynthese de calicheamicine et auto-resistance a cette derniere Download PDF

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Publication number
WO2000037608A2
WO2000037608A2 PCT/US1999/029110 US9929110W WO0037608A2 WO 2000037608 A2 WO2000037608 A2 WO 2000037608A2 US 9929110 W US9929110 W US 9929110W WO 0037608 A2 WO0037608 A2 WO 0037608A2
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WO
WIPO (PCT)
Prior art keywords
nucleic acid
calicheamicin
acid molecule
gene
isolated nucleic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1999/029110
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English (en)
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WO2000037608A3 (fr
Inventor
Jon Thorson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Memorial Sloan Kettering Cancer Center
Original Assignee
Memorial Sloan Kettering Cancer Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Memorial Sloan Kettering Cancer Center filed Critical Memorial Sloan Kettering Cancer Center
Priority to EP99972435A priority Critical patent/EP1137796A4/fr
Priority to CA002354030A priority patent/CA2354030A1/fr
Priority to JP2000589664A priority patent/JP2002533067A/ja
Publication of WO2000037608A2 publication Critical patent/WO2000037608A2/fr
Publication of WO2000037608A3 publication Critical patent/WO2000037608A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/52—Genes encoding for enzymes or proenzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C12P19/60—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin
    • C12P19/62—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin the hetero ring having eight or more ring members and only oxygen as ring hetero atoms, e.g. erythromycin, spiramycin, nystatin

Definitions

  • the present invention relates to a biosynthetic gene cluster of Micromonospora
  • calicheamicin s aryltetrasaccharide and aglycone, and the gene conferring
  • the present invention also relates to isolated genes of the
  • the invention relates to
  • the invention also relates to expression vectors containing the biosynthetic gene
  • Enediyne antibiotics were originally derived by
  • microorganisms including Micromonospora, Actinomedura, and
  • chromophore core structure which also requires a specific associated protein for
  • the second category of enediyne is classified as non-
  • chromoprotein enediynes contain a 10-membered ring, which requires
  • This enediyne ring structure is often referred to as the
  • warhead induces DNA damage, which is frequently a double-stranded
  • the 9-membered ring chromoprotein enediyne subfamily is comprised of:
  • pluricolorescens (Yamaguchi. T.. et al., J Antibiot.. XXIII 369-372 (1970));
  • the non-chromophore enediyne subfamily is comprised of calicheamicin from
  • lithostrotum lithostrotum
  • esperamicin from Actinomadura verrucosospora
  • dynemicin from Actinomadura verrucosospora
  • Micromonospora chersina Micromonospora chersina.
  • Enediyne antibiotics have potential as anticancer agents because of their ability to
  • Calicheamicin has two distinct structural regions: the aryltetrasaccharide and the
  • aglycone also known as the warhead.
  • the aryltetrasaccharide displays a highly unusual
  • calicheamicin consists of a highly functionalized
  • CMA-676 calicheamicin-antibody conjugates
  • calicheamicin analogs random mutagenesis of M. echinospora and screening for mutant
  • Nacelle's procedure only provides approximately a 0.007% yield and requires
  • calicheamicin DNA opens the door for genetic analysis of calicheamicin
  • DNA For example, one can study calicheamicin biosynthesis by mutagenesis of M.
  • calicheamicin biosynthesis and the subsequent analysis of their defective or partial calicheamicin products. Additionally, particular enzyme could be overexpressed or
  • biosynthetic genes can ultimately result in increased yields of the gene product by cloning
  • calicheamicin i.e. aromatization of the bicyclo[7.3.1]tridecadiynene core
  • this invention relates to the first identification, isolation, and cloning of a
  • calicheamicin self-resistance gene and protein have been isolated as have the genes and resulting enzymes for steps within the calicheamicin
  • the invention also provides for construction of enediyne overproducing strains
  • the present invention thus, also relates to a biosynthetic modification of bioactive
  • ligands which serve as molecular recognition elements critical for biological activity.
  • the present invention utilizes the fact that glycosyltransferases,
  • invention discloses a method using the recruitment and collaborative action of sugar
  • the present invention provides an isolated nucleic acid molecule from
  • biosynthetic gene cluster the protein coding region of the gene or a biologically active
  • the present invention provides an isolated nucleic acid
  • invention also relates to nucleic acids capable of hybridizing with a nucleic acid molecule
  • nonchromoprotein enediyne biosynthetic gene cluster In a further embodiment the
  • invention provides an expression vector comprising an isolated nucleic acid molecule
  • the invention provides a cosmid comprising an
  • nucleic acid molecule from Micromonospora echinospora comprising a nucleic
  • the invention provides the isolated nucleic acid sequence encoding for a nonchromoprotein enediyne biosynthetic gene cluster.
  • the invention provides the isolated nucleic acid
  • the present invention provides a host cell
  • Host cells can optionally
  • the host cell is the bacterium
  • the invention is directed to a
  • the invention provides a transformed host cell with an
  • the invention further provides a method of expressing a protein by culturing a
  • nonchromoprotein enediyne biosynthetic gene cluster incubating the host cell for a
  • invention provides a method of purifying calicheamicin using affinity chromatography.
  • sample containing calicheamicin is contacted with an affinity matrix having the protein CalC bound thereto, for a time and under conditions allowing calicheamicin to bind to the
  • the invention further provides a method of conferring calicheamicin resistance to
  • a subject comprising obtaining cells from the subject, transforming the cells with the
  • calicheamicin self-resistance gene and returning the cells to the subject.
  • the calicheamicin self-resistance gene can be targeted and delivered to the desired host
  • Figure 1 depicts the summary of the cosmid clones isolated from M. echinospora
  • genomic library This figure illustrates the results of the screening of the genomic library
  • Figure 2 shows a restriction map of a portion of cosmid clones 4b, 13a, and 56 and
  • Figure 3 is a table of the open reading frames ("orfs " ) in the calicheamicin
  • biosynthetic cluster This table lists the polypeptides that the genes encode for as well as
  • Figure 4 is a graph of the UV-visible absorption spectra of purified mbp-CalC.
  • the purified mpb-CalC was analyzed in the following solution: 52 ⁇ M mpb-CalC; 10
  • Figure 4(b) provides the results of the mbp-CalC in vitro assay.
  • FIG. 5 depicts the postulated routes for the biosynthesis of required nucleotide
  • E ep epimerase
  • E met methyltransferase
  • E od 4,6-dehydratase
  • E ox
  • E p nucleotidyltransferase
  • E red reductase
  • E sh sulfhydrytransferase
  • Figure 6 illustrates a schematic representation of the in vivo production of
  • Figure 7 depicts the Streptomyces Venezuela methymycin/pikromycin gene cluster.
  • Figure 8 illustrates calicheamicin's (6) four unique sugars which are crucial to
  • Sugar (9) is derived from 4-amino-4,6-dideoxyglucose (8) and is part
  • Compound 8 is derived from
  • calicheamicin biosynthetic cluster This cluster encodes the genes that encode the
  • the calicheamicin biosynthetic gene cluster comprises the following genes: calA.
  • calB calC
  • calD calE
  • calF calG
  • calH call, call, calK, calL, ca M, calN, calO, cal?
  • Orf3 (209 amino acids).
  • Orf4 (521 amino acids), Orf5 (175 amino acids),
  • Orf6 (139 amino acids), Orf7 (187 amino acids), and IS-element (402 amino acids).
  • the cosmid library was generated by isolating chromosomal DNA of
  • calicheamicin aglycone would be polyketide derived.
  • Polyketide metabolites encompass
  • PKS polyketide synthase
  • sequence homology (from pathway to pathway and organism to organism) and are often
  • the second screening was based on the assumption that calicheamicin's
  • biosynthetic cluster would also contain genes encoding for deoxysugar ligand synthesis.
  • dehydratase gene encoding the putative enzymes E p and E od . respectively. See figure 5.
  • nucleotide transferase from Salmonella has been characterized as an
  • calicheamicin synthesis would begin from a similar precursor found in E. coli,
  • DNA probe (designated ⁇ od ') was designed from the conserved NAD -binding site of
  • E od ' probe revealed cross-hybridization with clones 4b, 10a, 13a. 56. and 60.
  • hybridization established similarity between clones 3a, 4a. 4b, 10a, 13a. 16a and 56.
  • the positive cosmid clones corresponded to a continuous region of the M. echinospora
  • the present invention thus provides for cosmids having
  • nucleic acid molecule from Micromonospora echinospora encoding for a
  • genes participating in the construction of the aryltetrasaccharide include: a)
  • genes encoding nucleotide sugar biosynthesis (calG H, K, O, Q, and S); b) genes encoding for aryltetrasaccharide assembly (calE and N); and c) genes encoding for
  • One aspect of the invention relates to transformation of a host cell with M.
  • invention further provides that the host cell can be but is not limited to bacteria, yeast,
  • plant or mammalian cells are performed by methods known in the art.
  • One aspect of the invention relates to an isolated
  • present invention also relates to an isolated protein CalC, having the amino acid sequence,
  • the invention further provides for calC gene fragments coding for a
  • CalC bioactive CalC.
  • the polypeptide, CalC confers calicheamicin resistance and has 181
  • the invention also provides for CalC fragments conferring calicheamicin
  • the calC locus was isolated by identifying calicheamicin genomic cosmid clones
  • LB luria bertani
  • iron metalloprotein that functions via inhibition of calicheamicin-induced DNA cleavage
  • Another aspect of the invention is an expression vector containing calC or a
  • host cell preferably bacteria, more preferably, E. coli containing calC or a fragment of
  • the present invention provides for the transformation of human cells with the
  • calC gene This allows bone marrow cells, for example, to be removed from a patient
  • calicheamicin or allows the patient to receive higher doses of calicheamicin as the
  • Another aspect of the invention relates to an isolated DNA strand containing the
  • caM. gene having the DNA sequence S ⁇ Q ID. No: 3.
  • the invention also relates to the
  • polypeptide CalH having amino acid sequence S ⁇ Q ID. No. 4.
  • the invention furthermore, having amino acid sequence S ⁇ Q ID. No. 4.
  • CalH is involved in the
  • CalH were overexpressed as a (histidine), 0 -fusion protein and subsequently
  • TDP-perosamine TDP-4.6-dideoxy-4-amino-D-mannose
  • one aspect of the present invention further relates to the construction of a
  • invention further provides an expression vector having a calicheamicin gene operably
  • the regulatory sequence is a Streptomyces promoter.
  • the present invention also provides a Streptomyces promoter.
  • Compound 11 has the formula:
  • Compound 12 has the formula:
  • One aspect of the invention relates to an isolated DNA strand containing the calG
  • Another aspect of the invention is a gene and having the DNA sequence SEQ ID. NO.: 5. Another aspect of the invention is a gene and having the DNA sequence SEQ ID. NO.: 5. Another aspect of the invention is a gene and having the DNA sequence SEQ ID. NO.: 5. Another aspect of the invention is a gene and having the DNA sequence SEQ ID. NO.: 5. Another aspect of the invention is a gene and having the DNA sequence SEQ ID. NO.: 5. Another aspect of the invention is
  • CalG appears to be a TDP-D-glucose 4,6-dehydratase which catalyzes the conversion of
  • a transformed host cell preferably bacteria, more
  • E. coli. containing calG or a fragment of calG encoding for a bioactive
  • CalS appears to be a P450-oxidase
  • the oxidation may occur at the nucleotide sugar level or hydroxylamine formation after
  • a transformed host cell preferably bacteria, more preferably, E. coli,
  • the present invention allows genetic manipulation of the biosynthetic gene cluster
  • the present invention provides for producing
  • calicheamicin analogs by constructing deletions or substitutions of the genes involved in
  • the invention further provides for in vitro
  • glycosylation by altering the glycosylation pattern of calicheamicin (via a
  • glycosyltransferase to produce additional analogs.
  • the invention also provides for
  • the invention provides for a method of purifying calicheamicin through affinity
  • the invention relates to the expression of the genes located in the biosynthetic gene
  • the present invention also provides a gene to produce the protein encoded by the inserted gene.
  • biosynthetic gene cluster which encode for biologically active proteins
  • thermocycle sequencing was performed by:
  • sequence data was acquired using two Applied Biosystems automated 310 genetic
  • Brujene. MacVector is a commercially available software package which provides the
  • calicheamicin (0.25 ⁇ g ml "1 ).
  • six clones (3a, 4a, 4b, 10a. 13a and 16a)
  • the proximal 1 kb of this fragment carried a single orf (calD).
  • CalD its respective protein
  • IPTG Isopropyl Beta-D-thiogalactoside
  • the protein mbp-CalC was overexpressed and purified for further analysis.
  • mbp-CalC was purified from pRE7/E. coli to homogeneity as judged by SDS-PAG ⁇ .
  • buffer A 50mM Tris-Cl, pH 7.5, 200 mM NaCl, ImM ⁇ DTA
  • ICP-MS inductively coupled plasma atomic mass spectrometry
  • nucleotide sequence of the mbp-calC gene fusion which is consistent with the determined
  • hydrolysate was subsequently determined by ICP-MS on four distinct mbp-CalC
  • calicheamicin-induced DNA cleavage assay would inhibit DNA cleavage.
  • pBS pBS
  • DTT dithiothreitol
  • DNA fragmentation was assessed by electrophoresis on a 1% agarose gel
  • FeSO 4 Fe ⁇ 2
  • FeCl 3 Fe *3
  • the 1.2 kb calH gene was amplified by polymerase chain reaction (PCR) from
  • pJSTl 192 pn7 which is a subclone containing a 7.0 kb Kpnl fragment of cosmid 13a.
  • amplified gene was cloned into the EcoR /Xbal site of the expression vector pDHS617.
  • This expression vector contains an apramycin resistance marker.
  • pLZ-C242 (containing the cal ⁇ gene insert and the promoter sequence) was introduced by
  • the culture was centrifuged to remove cellular debris and mycella.
  • the supernatant was adjusted to pH 9.5 with concentrated KOH. followed by chloroform extraction.
  • the crude product was extracted from the crude cells.

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  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Plant Pathology (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Saccharide Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention concerne un groupe de gènes isolés de Micromonospora echinospora qui code pour la biosynthèse de calichéamicine. Ce groupe de gènes biosynthétique contient des gènes codant pour les protéines et les enzymes que l'on utilise dans la production biosynthétique de calichéamicine, y compris un aryltetrasaccharide et un aglycone. Ce groupe de gènes comprend également un gène conférant une résistance à la calichéamicine. Cette invention concerne également des gènes isolés de ce groupe biosynthétique ainsi que leurs protéines correspondantes. Cette invention concerne en outre un ADN qui s'hybride au groupe de gènes de calichéamicine ainsi qu'aux gènes isolés de ce groupe. Cette invention concerne aussi des vecteurs d'expression contenant des gènes du groupe biosynthétique, ainsi que leurs variantes fonctionnelles. Cette invention concerne enfin des cellules hôtes qui sont conjuguées à l'ADN isolé à partir du génome de Micromonospora echinospora spp. $i(calichensis.)
PCT/US1999/029110 1998-12-07 1999-12-07 Genes de $i(micromonospora echinospora) codant pour la biosynthese de calicheamicine et auto-resistance a cette derniere Ceased WO2000037608A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP99972435A EP1137796A4 (fr) 1998-12-07 1999-12-07 Genes de micromonospora echinospora codant pour la biosynthese de calicheamicine et auto-resistance a cette derniere
CA002354030A CA2354030A1 (fr) 1998-12-07 1999-12-07 Genes de micromonospora echinospora codant pour la biosynthese de calicheamicine et auto-resistance a cette derniere
JP2000589664A JP2002533067A (ja) 1998-12-07 1999-12-07 カリケアマイシンの生合成とカリケアマイシンに対する自己耐性をコードするミクロモノスポラ・エキノスポラ遺伝子

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11132598P 1998-12-07 1998-12-07
US60/111,325 1998-12-07

Publications (2)

Publication Number Publication Date
WO2000037608A2 true WO2000037608A2 (fr) 2000-06-29
WO2000037608A3 WO2000037608A3 (fr) 2000-11-23

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JP (1) JP2002533067A (fr)
CA (1) CA2354030A1 (fr)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002094861A3 (fr) * 2001-05-21 2003-07-03 Ecopia Biosciences Inc Genes et proteines impliques dans la biosynthese de structures cycliques enediyne
WO2002079465A3 (fr) * 2000-11-28 2003-09-04 Sloan Kettering Inst Cancer Codage de genes de micromonospora echinospora pour la biosynthese de la calicheamicine, et autoresistance vis-a-vis de cette substance
US6733998B1 (en) 1998-12-07 2004-05-11 Sloan-Kettering Institute For Cancer Research Micromonospora echinospora genes coding for biosynthesis of calicheamicin and self-resistance thereto
US7257562B2 (en) 2000-10-13 2007-08-14 Thallion Pharmaceuticals Inc. High throughput method for discovery of gene clusters

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SI2029750T1 (sl) * 2006-06-22 2011-11-30 Dsm Ip Assets Bv Proizvajanje pravastatina

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5276159A (en) * 1990-08-01 1994-01-04 The Scripps Research Institute Dynemicin analogs: syntheses, methods of preparation and use
US5712146A (en) * 1993-09-20 1998-01-27 The Leland Stanford Junior University Recombinant combinatorial genetic library for the production of novel polyketides

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6733998B1 (en) 1998-12-07 2004-05-11 Sloan-Kettering Institute For Cancer Research Micromonospora echinospora genes coding for biosynthesis of calicheamicin and self-resistance thereto
US7257562B2 (en) 2000-10-13 2007-08-14 Thallion Pharmaceuticals Inc. High throughput method for discovery of gene clusters
WO2002079465A3 (fr) * 2000-11-28 2003-09-04 Sloan Kettering Inst Cancer Codage de genes de micromonospora echinospora pour la biosynthese de la calicheamicine, et autoresistance vis-a-vis de cette substance
WO2002094861A3 (fr) * 2001-05-21 2003-07-03 Ecopia Biosciences Inc Genes et proteines impliques dans la biosynthese de structures cycliques enediyne
US6912470B2 (en) 2001-05-21 2005-06-28 Ecopia Biosciences, Inc. Genes and proteins involved in the biosynthesis of enediyne ring structures
US7462705B2 (en) 2001-05-21 2008-12-09 Thallion Pharmaceuticals Inc. Nucleic acids encoding an enediyne polyketide synthase complex

Also Published As

Publication number Publication date
EP1137796A2 (fr) 2001-10-04
CA2354030A1 (fr) 2000-06-29
WO2000037608A3 (fr) 2000-11-23
JP2002533067A (ja) 2002-10-08
EP1137796A4 (fr) 2005-05-25

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