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WO2016136508A1 - Procédé de production de 2-aza-8-oxohypoxanthine - Google Patents

Procédé de production de 2-aza-8-oxohypoxanthine Download PDF

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WO2016136508A1
WO2016136508A1 PCT/JP2016/054182 JP2016054182W WO2016136508A1 WO 2016136508 A1 WO2016136508 A1 WO 2016136508A1 JP 2016054182 W JP2016054182 W JP 2016054182W WO 2016136508 A1 WO2016136508 A1 WO 2016136508A1
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aoh
ahx
bacteria
reaction
concentration
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Japanese (ja)
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真治 徳山
宰熏 崔
河岸　洋和
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Shizuoka University NUC
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    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
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    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
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    • C12N1/14—Fungi; Culture media therefor
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    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
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    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi
    • C12R2001/885—Trichoderma

Definitions

  • the present invention relates to a method for producing 2-aza-8 oxohypoxanthine.
  • Patent Document 1 discloses a method for obtaining AOH by allowing xanthine oxidase (hereinafter, sometimes referred to as “XOD”) to act on 2-azahypoxanthine (hereinafter, sometimes referred to as “AHX”). Yes.
  • XOD xanthine oxidase
  • AHX 2-azahypoxanthine
  • a method for mass production of AOH by chemical synthesis has not been established. Further, the method of obtaining AOH by causing XOD to act on AHX is not suitable for producing a large amount of AOH because the production efficiency is low and the XOD is very expensive.
  • the object of the present invention is to provide a novel method capable of producing AOH.
  • the present invention is a method for producing AOH, which includes a step of reacting AHX with a microorganism to thereby generate AOH, and a step of isolating AOH from the reaction solution.
  • the microorganism is a Burkholderia genus, Butiauxella genus, Pseudomonas genus, Escherichia coli, Bacillus genus, Saccharomyces genus, Kriveromyces genus, Candida genus, Chizosaccharomyces genus, Pichia genus, It is preferably at least one selected from the group consisting of Aspergillus and Trichoderma.
  • the above microorganisms include Burkholderia Contaminance, Burkhoharta cepacia, Burkhostagea hungorum, Butiauxera Gabiniae, Butiauxera Aggressis, Shuudomonas petitda, Shudomonas synxanta, Shuudomonasnadooubenensis More preferably, it is at least one selected from the group consisting of Pseudomonas plecogrossida.
  • a novel method capable of producing AOH can be provided.
  • the method for producing AOH according to the present embodiment includes a step of reacting AHX with a microorganism to thereby generate AOH, and a step of isolating AOH from the reaction solution.
  • 2-Aza-8 oxohypoxanthine is also represented by 3H-imidazo [4,5-d] [1,2,3] triazine-4,6 (5H, 7H) -dione and has the following formula (I) It is a compound represented by these.
  • AHX 2-Azahypoxanthine
  • 7H-imidazo [4,5-d] [1,2,3] triazin-4 (3H) -one is also represented by 7H-imidazo [4,5-d] [1,2,3] triazin-4 (3H) -one, and is a compound represented by the following formula (II). is there.
  • the microorganism used in the present embodiment may be any microorganism that has the ability to generate AOH from AHX. According to the production method according to the present embodiment, reaction inhibition by the product (AOH) is suppressed compared to the case of using XOD, and therefore AOH can be produced efficiently even if the AHX concentration in the reaction solution is high. Can do. Moreover, it is not necessary to use expensive XOD, and AOH can be manufactured at low cost.
  • microorganisms include bacteria and fungi.
  • bacteria that can be used include Burkholderia bacteria, Butiauxella bacteria, Pseudomonas bacteria, Escherichia coli, Bacillus bacteria, and the like.
  • fungi that can be used include Saccharomyces sp., Criveromyces sp., Candida sp., Tizosaccharomyces sp., Pichia sp., Aspergillus sp., Trichoderma sp.
  • These microorganisms may be used individually by 1 type, and may use multiple types together.
  • the microorganism is preferably a Burkholderia bacterium, a Butiauxella bacterium, or a Pseudomonas bacterium, and more preferably a Butiauxella bacterium or a Pseudomonas bacterium. When these microorganisms are used, AOH can be generated with higher efficiency.
  • Examples of bacteria belonging to the genus Burkholderia include Burkholderia contamination, Burkholderia cepacia, Burkholderia, and the like.
  • Examples of the bacteria belonging to the genus Butiauxella include Butiauxella gaviniae, Butiauxella agretis, and the like.
  • Pseudomonas genus bacterium Pseudomonas putida (Pseudomonas putida), Pseudomonas and new Santa (Pseudomonas synxantha), Pseudomonas & vandalism Belem cis (Pseudomonas vancouverensis), Pseudomonas & Jesusenyi (Pseudomonas jessenii), Pseudomonas & plecos Gross Shi fern (Pseudomonas plecoglossicida ) And the like.
  • microorganisms include Burkholderia Contaminance, Burkho foundeda cepacia, Burkho foundeda hungorum, Butiauxera Gabiniae, Butiauxera Aggressis, Pseudomonas petitda, Pseudomonas synxantha, Pseudomonas sayhouberensis It is preferably Jesseni, more preferably Burkholderia Contaminance, Butiauxera Gabiniae, Butiauxera Aggressis, Pseudomonas petitda, Pseudomonas synxanta, Pseudomonas vancouverensis or Pseudomonas jesuseni Gabiniae, Pseudomonas petitda, Pseudomonas synxanta or Pseudomonas More preferably from vandalism Belem cis, particularly preferably Butiaukusera-Gabinia
  • the step of reacting AHX with microorganisms and thereby generating AOH can be performed, for example, by mixing a suspension containing microorganisms prepared in advance and a solution containing AHX.
  • the step of reacting AHX with a microorganism to thereby generate AOH includes, for example, contacting AHX with a microorganism to thereby generate AOH, or contacting AHX with a microorganism, thereby converting AHX to AOH. It can also be referred to as a process of converting into
  • Microorganisms can be cultured under general culture conditions for microorganisms.
  • the culture can be performed, for example, under conditions of pH 6 to 8, temperature 25 to 42 ° C. for 6 to 24 hours.
  • the culture can be performed, for example, by shaking with aeration.
  • As a culture medium for culturing microorganisms various media containing nutrient components such as carbon sources, nitrogen sources, inorganic salts, vitamins and minerals used for microorganism culture can be used. Examples of the medium suitable for bacteria such as Burkholderia include TSB medium, YM medium, and the like. It is preferable to use a microorganism in the late logarithmic growth phase.
  • the cultured microorganisms can be collected from the medium by centrifugation or the like and used for the reaction with AHX. Microorganisms washed after collection may be used for the reaction with AHX.
  • the solvent for performing the reaction between AHX and the microorganism is preferably a buffer solution.
  • a buffer solution for example, phosphate buffered saline (PBS) can be used.
  • the AHX concentration in the reaction solution can be arbitrarily set.
  • the AOH generation efficiency can be kept high for a long time.
  • the AOH produced by the reaction can be recovered, for example, by centrifuging the reaction solution to separate the cells, and collecting and concentrating the supernatant.
  • the recovered supernatant may be subjected to a heat treatment or the like.
  • the recovered AOH may be further purified and crystallized.
  • the medium used has the composition shown in Table 1.
  • PBS phosphate buffered saline
  • a 10 ⁇ PBS solution having the composition shown in Table 2 was diluted 10-fold with distilled water.
  • Each platinum strain was inoculated in 5 ml of TSB medium dispensed into a test tube, and cultured with shaking at 30 ° C. and 180 rpm, and this was used as a preculture solution.
  • 1% of the preculture was inoculated into a 500 ml Erlenmeyer flask into which 100 ml of TSB medium was dispensed, and cultured at 30 ° C. for 6 hours at 180 rpm.
  • 1 ml of the obtained culture broth was centrifuged at 11000 rpm for 5 minutes to collect bacteria.
  • 1 ml of PBS was added and washed by centrifugation at 11000 rpm for 5 minutes.
  • a certain amount of the washed cells was suspended in 900 ⁇ l of PBS, and 100 ⁇ l of 0.7 mg / ml AHX in PBS was added to the suspension to prepare a reaction solution having an AHX concentration of 70 ⁇ g / ml.
  • the reaction solution was transferred to a round bottom Spitz and reacted at 30 ° C. for 24 hours. After a predetermined time, the reaction solution was centrifuged to separate the cells, and the supernatant was collected and heat-treated at 98 ° C. for 5 minutes.
  • the AHX and AOH concentrations in the reaction supernatant were analyzed by HPLC.
  • HPLC analysis conditions were as follows: Column: Develosil C30-UG-5 (Nomura Chemical Co., Ltd.), mobile phase: water + 0.02% TFA, temperature: room temperature, flow rate: 0.8 ml / min, wavelength: 254 nm, injection: 20 ⁇ l It was. The retention times of AHX and AOH were 25.2 minutes and 26.6 minutes, respectively. The results are shown in Table 3. It should be noted that, under the HPLC analysis conditions of this example, separation from impurities may be insufficient, and therefore the AOH concentration may be apparently measured higher than it actually is.
  • any bacteria used had the ability to produce AOH using AHX as a substrate.
  • the CH-1 strain, Burkholderia cepacia and Burkholderia fungorum all converted AHX in the medium into AOH and had a conversion efficiency of 100%.
  • Test Example 2 Comparison of AOH production activity
  • CH-1 Burkholderia cepacia
  • Burkholderia fungorum AOH generation activity up to 6 hours after the start of the reaction was examined.
  • the reaction conditions were the same as in Test Example 1 except that the reaction time was a predetermined time.
  • the AHX and AOH concentrations in the reaction solution were analyzed by HPLC in the same manner as in Test Example 1 at a predetermined time. The results are shown in FIG. 1 (CH-1 strain), FIG. 2 (Burkholderia cepacia), and FIG. 3 (Burkholderia fungorum).
  • the CHOH strain had the highest AOH production activity.
  • Test Example 3 Examination of reaction inhibition by products
  • the reaction was conducted for 96 hours under the same conditions as in Test Example 1, except that the initial concentration of AHX in the reaction solution was 2 mg / ml and the bacterial cell concentration was 3 times that of Test Example 1. It was.
  • the AHX concentration and AOH concentration in the reaction solution were measured by HPLC in the same manner as in Test Example 1 at a predetermined time. The results are shown in FIG.
  • the AHX concentration was similarly 2 mg / ml, and AOH was produced at 30 ° C. using 0.5 U of xanthine oxidase (from buttermilk, Oriental Yeast Co., Ltd.).
  • the AHX concentration and AOH concentration in the reaction solution Measurements were made. The results are shown in FIG.
  • Test Example 4 AOH decomposition reaction evaluation
  • the reaction was carried out in the same manner as in Test Example 1 except that the bacterial cell concentration in the reaction solution was twice that of Test Example 1 and AOH was used as the substrate instead of AHX.
  • the concentration of AOH in the reaction solution was measured by HPLC as in Test Example 1. The results are shown in FIG. Suspending AOH with the CH-1 strain did not reduce the AOH concentration. It was confirmed that the AOH degradation activity of the CH-1 strain was extremely weak.
  • Test Example 5 AOH yield evaluation
  • concentration of cells in the reaction solution was 3 times the amount of Test Example 1 and the initial concentration of AHX and the reaction temperature were as shown in Table 4.
  • the reaction was carried out for 8 hours. After the reaction, the reaction solution was centrifuged to separate the cells, and a supernatant was obtained. The supernatant was heat treated at 98 ° C. for 5 minutes, concentrated to 1/7 volume with a rotary evaporator, and allowed to stand at 4 ° C. for 3 days to form a precipitate.
  • AOH can be produced with high efficiency by a method using microorganisms such as CH-1 strain (microbe method).
  • XOD method XOD method
  • reaction inhibition due to the produced AOH is less likely to occur, so that the substrate concentration in the medium can be increased by about 60 times. It was possible.
  • the amount of the reaction solution used can be reduced to about 1/45 of that in the case of the XOD method by the microbial method.
  • the microbial method could produce AOH at a significantly lower cost than the XOD method.
  • Test Example 6 AOH production activity of various microorganisms
  • AOH production activity was examined using various microorganisms and CH-1 strains shown in Table 5 below. Collect strains that have been cultured in advance according to the type of various microorganisms, suspend a certain amount of cells in PBS, add AHX solution to an AHX concentration of 70 ⁇ g / ml, and The reaction was performed for 24 hours. After a predetermined time, the reaction solution was centrifuged to separate the cells, and the supernatant was collected and heat-treated at 98 ° C. for 5 minutes. The AHX and AOH concentrations in the supernatant of the reaction solution were measured by the same method as in Test Example 1. The results are shown in Table 5. It was confirmed that all the microorganisms have an activity to generate AOH from AHX.
  • Each of the above strains was inoculated into 5 mL of TSB medium dispensed into a test tube, cultured with shaking at 30 ° C. and 180 rpm, and this was used as a preculture solution. 1% of the preculture was inoculated into TSB medium and cultured at 30 ° C. for 8 hours at 180 rpm. The resulting culture solution (1 ml) was collected by centrifugation.
  • Test Example 8 Using the above 10 strains and the CH-1 strain, the reaction with AHX was carried out under the same conditions as in Test Example 7, except that the reaction time was 2.5 hours. The AHX concentration in the supernatant of the reaction solution was analyzed by HPLC in the same manner as in Test Example 1. The results are shown in Table 10. All strains had higher AOH production activity than the CH-1 strain.
  • Test Example 9 Among the strains used in Test Example 8, 7 strains having high AOH production activity were reacted with AHX under the same conditions as in Test Example 7 except that the reaction time was 0.5 hour or 1 hour. The AHX concentration in the supernatant of the reaction solution was analyzed by HPLC in the same manner as in Test Example 1. The results are shown in Table 11.
  • Test Example 10 (Test Example 10) Among the strains used in Test Example 9, four strains with higher AOH production activity were tested except that the AHX concentration in the reaction solution was 2 mg / ml and the reaction time was 1 hour, 2 hours or 4 hours. Reaction with AHX was carried out under the same conditions as in Example 7. AHX and AOH concentrations in the reaction solution were measured by HPLC in the same manner as in Test Example 1. The results are shown in Table 12 and FIGS.

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Abstract

La présente invention concerne un procédé de production de 2-aza-8-oxohypoxanthine, comprenant les étapes qui consistent : à faire réagir de la 2-azahypoxanthine avec un micro-organisme pour produire de la 2-aza-8-oxohypoxanthine ; et à isoler la 2-aza-8-oxohypoxanthine d'une solution de réaction.
PCT/JP2016/054182 2015-02-23 2016-02-12 Procédé de production de 2-aza-8-oxohypoxanthine Ceased WO2016136508A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020246468A1 (fr) * 2019-06-06 2020-12-10 ビタミンＣ６０バイオリサーチ株式会社 Activateur cellulaire de cellule animale

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JP2010527579A (ja) * 2006-09-11 2010-08-19 レール・リキード−ソシエテ・アノニム・プール・レテュード・エ・レクスプロワタシオン・デ・プロセデ・ジョルジュ・クロード 発酵の生産性および経済性を増大させるための溶存酸素プロフィール
JP2011103899A (ja) * 2003-06-05 2011-06-02 Ajinomoto Co Inc 目的物質の製造法
WO2012105495A1 (fr) * 2011-01-31 2012-08-09 旭化成ケミカルズ株式会社 Phénylpyruvate réductase et procédé pour fabriquer de l'acide phényl-lactique et de l'acide 4-hydroxy-phényl-lactique optiquement actifs en utilisant la même enzyme
WO2012147750A1 (fr) * 2011-04-27 2012-11-01 国立大学法人静岡大学 Dérivé d'imidazole

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011103899A (ja) * 2003-06-05 2011-06-02 Ajinomoto Co Inc 目的物質の製造法
JP2010527579A (ja) * 2006-09-11 2010-08-19 レール・リキード−ソシエテ・アノニム・プール・レテュード・エ・レクスプロワタシオン・デ・プロセデ・ジョルジュ・クロード 発酵の生産性および経済性を増大させるための溶存酸素プロフィール
WO2012105495A1 (fr) * 2011-01-31 2012-08-09 旭化成ケミカルズ株式会社 Phénylpyruvate réductase et procédé pour fabriquer de l'acide phényl-lactique et de l'acide 4-hydroxy-phényl-lactique optiquement actifs en utilisant la même enzyme
WO2012147750A1 (fr) * 2011-04-27 2012-11-01 国立大学法人静岡大学 Dérivé d'imidazole

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WO2020246468A1 (fr) * 2019-06-06 2020-12-10 ビタミンＣ６０バイオリサーチ株式会社 Activateur cellulaire de cellule animale
JPWO2020246468A1 (fr) * 2019-06-06 2020-12-10
CN112955116A (zh) * 2019-06-06 2021-06-11 维生素C60生化学研究公司 动物细胞的细胞活化剂
KR20220003051A (ko) * 2019-06-06 2022-01-07 비타민 씨60 바이오리서치 가부시키가이샤 동물 세포의 세포 부활제
JP7341438B2 (ja) 2019-06-06 2023-09-11 ビタミンＣ６０バイオリサーチ株式会社 動物細胞の細胞賦活剤
CN112955116B (zh) * 2019-06-06 2023-10-27 维生素C60生化学研究公司 动物细胞的细胞活化剂
KR102715941B1 (ko) 2019-06-06 2024-10-15 비타민 씨60 바이오리서치 가부시키가이샤 동물 세포의 세포 부활제

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