NO120830B - - Google Patents
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- NO120830B NO120830B NO15271964A NO15271964A NO120830B NO 120830 B NO120830 B NO 120830B NO 15271964 A NO15271964 A NO 15271964A NO 15271964 A NO15271964 A NO 15271964A NO 120830 B NO120830 B NO 120830B
- Authority
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- Norway
- Prior art keywords
- acid
- atcc
- thiamine
- medium
- brevibacterium ammoniagenes
- Prior art date
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- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 claims description 24
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 claims description 20
- 239000011721 thiamine Substances 0.000 claims description 19
- 235000019157 thiamine Nutrition 0.000 claims description 19
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 claims description 18
- 229960003495 thiamine Drugs 0.000 claims description 18
- 241000186145 Corynebacterium ammoniagenes Species 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 13
- 239000011713 pantothenic acid Substances 0.000 claims description 13
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 12
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 claims description 12
- 235000019161 pantothenic acid Nutrition 0.000 claims description 12
- 229940055726 pantothenic acid Drugs 0.000 claims description 12
- GRSZFWQUAKGDAV-UHFFFAOYSA-N Inosinic acid Natural products OC1C(O)C(COP(O)(O)=O)OC1N1C(NC=NC2=O)=C2N=C1 GRSZFWQUAKGDAV-UHFFFAOYSA-N 0.000 claims description 10
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 claims description 10
- 235000013902 inosinic acid Nutrition 0.000 claims description 10
- 244000005700 microbiome Species 0.000 claims description 10
- 235000015097 nutrients Nutrition 0.000 claims description 10
- RQFCJASXJCIDSX-UHFFFAOYSA-N 14C-Guanosin-5'-monophosphat Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(O)=O)C(O)C1O RQFCJASXJCIDSX-UHFFFAOYSA-N 0.000 claims description 8
- GRSZFWQUAKGDAV-KQYNXXCUSA-N IMP Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(NC=NC2=O)=C2N=C1 GRSZFWQUAKGDAV-KQYNXXCUSA-N 0.000 claims description 8
- 229950006790 adenosine phosphate Drugs 0.000 claims description 8
- RQFCJASXJCIDSX-UUOKFMHZSA-N guanosine 5'-monophosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O RQFCJASXJCIDSX-UUOKFMHZSA-N 0.000 claims description 8
- 235000013928 guanylic acid Nutrition 0.000 claims description 8
- 229960003767 alanine Drugs 0.000 claims description 7
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 claims description 6
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 claims description 6
- 229960002685 biotin Drugs 0.000 claims description 6
- 235000020958 biotin Nutrition 0.000 claims description 6
- 239000011616 biotin Substances 0.000 claims description 6
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000005516 coenzyme A Substances 0.000 claims description 6
- 229940093530 coenzyme a Drugs 0.000 claims description 6
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- DJWYOLJPSHDSAL-UHFFFAOYSA-N Pantethine Natural products OCC(C)(C)C(O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)C(O)C(C)(C)CO DJWYOLJPSHDSAL-UHFFFAOYSA-N 0.000 claims description 5
- 239000002773 nucleotide Substances 0.000 claims description 5
- DJWYOLJPSHDSAL-ROUUACIJSA-N pantethine Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)CO DJWYOLJPSHDSAL-ROUUACIJSA-N 0.000 claims description 5
- 229960000903 pantethine Drugs 0.000 claims description 5
- 235000008975 pantethine Nutrition 0.000 claims description 5
- 239000011581 pantethine Substances 0.000 claims description 5
- 239000002213 purine nucleotide Substances 0.000 claims description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000002777 nucleoside Substances 0.000 claims description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 3
- DCTLYFZHFGENCW-UUOKFMHZSA-N 5'-xanthylic acid Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(NC(=O)NC2=O)=C2N=C1 DCTLYFZHFGENCW-UUOKFMHZSA-N 0.000 claims 1
- -1 B-alanine Substances 0.000 claims 1
- 239000002609 medium Substances 0.000 description 36
- 238000000855 fermentation Methods 0.000 description 26
- 230000004151 fermentation Effects 0.000 description 26
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 20
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 11
- 229930024421 Adenine Natural products 0.000 description 11
- 229960000643 adenine Drugs 0.000 description 11
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 9
- 239000002054 inoculum Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 229940088594 vitamin Drugs 0.000 description 6
- 229930003231 vitamin Natural products 0.000 description 6
- 235000013343 vitamin Nutrition 0.000 description 6
- 239000011782 vitamin Substances 0.000 description 6
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 5
- 229960002079 calcium pantothenate Drugs 0.000 description 5
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012499 inoculation medium Substances 0.000 description 3
- 229940040511 liver extract Drugs 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000003722 vitamin derivatives Chemical class 0.000 description 3
- AEOBEOJCBAYXBA-UHFFFAOYSA-N A2P5P Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1OP(O)(O)=O AEOBEOJCBAYXBA-UHFFFAOYSA-N 0.000 description 2
- 241000251468 Actinopterygii Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- 239000001888 Peptone Substances 0.000 description 2
- 108010080698 Peptones Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940000635 beta-alanine Drugs 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 235000019319 peptone Nutrition 0.000 description 2
- IZRPKIZLIFYYKR-UHFFFAOYSA-N phenyltoloxamine Chemical compound CN(C)CCOC1=CC=CC=C1CC1=CC=CC=C1 IZRPKIZLIFYYKR-UHFFFAOYSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- 241000186146 Brevibacterium Species 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 239000010903 husk Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000013028 medium composition Substances 0.000 description 1
- 235000013379 molasses Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
- C12P19/26—Preparation of nitrogen-containing carbohydrates
- C12P19/28—N-glycosides
- C12P19/30—Nucleotides
-
- 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
- C12P19/26—Preparation of nitrogen-containing carbohydrates
- C12P19/28—N-glycosides
- C12P19/30—Nucleotides
- C12P19/32—Nucleotides having a condensed ring system containing a six-membered ring having two N-atoms in the same ring, e.g. purine nucleotides, nicotineamide-adenine dinucleotide
-
- 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
- C12P21/00—Preparation of peptides or proteins
Landscapes
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Seasonings (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
Fremgangsmåte til fremstilling av 5'-purin-nukleotider ved fermentering. Process for the production of 5'-purine nucleotides by fermentation.
Foreliggende oppfinnelse angår en fremgangsmåte til fremstilling av 5'-purin-nukleotidene 5'-inosinsyre ti det folgende kalt 5<»->IMP), 5'-guanylsyre (5,-GMP), 5'-adenylsyre (5'-AMP) og 5'-xantyl- The present invention relates to a method for the production of the 5'-purine nucleotides 5'-inosinic acid hereinafter called 5<»->IMP), 5'-guanylic acid (5,-GMP), 5'-adenylic acid (5'-AMP ) and 5'-xantyl-
syre (5'-XMP) og denne fremgangsmåte er kjennetegnet ved at Brevibacterium ammoniagenes ATCC 6871 eller ATCC 6872 eller adenin- eller guaninkrevende mutanter derav dyrkes i et næringsmedium inneholdende (l) fra 0.5 til 50 mikrogram per milliliter av pantotensyre, et pantotensyre-givende stoff, P-alanin, pantetin eller koenzym A, og (2) acid (5'-XMP) and this method is characterized in that Brevibacterium ammoniagenes ATCC 6871 or ATCC 6872 or adenine- or guanine-requiring mutants thereof are grown in a nutrient medium containing (l) from 0.5 to 50 micrograms per milliliter of pantothenic acid, a pantothenic acid-giving substance, β-alanine, pantethine or coenzyme A, and (2)
fra 0.1 til 10 mikrogram per milliliter av tiamin, tiaminhydrohalo-from 0.1 to 10 micrograms per milliliter of thiamine, thiamine hydrohalo-
genid eller et tiamin-givende stoff, idet næringsmediet også inne-genide or a thiamine-giving substance, as the nutrient medium also contains
holder biotin og en purinbase eller et nukleosid derav, inntil i alt vesentlig maksimal dannelse av det onskede 5,-nukleotid er oppnådd, holds biotin and a purine base or a nucleoside thereof, until essentially maximum formation of the desired 5,-nucleotide is achieved,
og ved at 5'-nukleotidet gjenvinnes fra næringsmediet.and in that the 5' nucleotide is recovered from the nutrient medium.
Fra belgisk patent nr. 621 122 er det kjent å tilsette pantotensyre og tiamin til næringsmediet ved dyrking av mikroorganismer tilhorende slekten Brevibacterium for fremstilling av 5'-nukleotider. Disse tilsetninger anvendes bare som næringsstoffer og er ikke -uunn-værlige i sammensetningen av mediet. Det må derfor sluttes at andre midler også kan benyttes. Det fremgår videre fra patentet at den samtidige tilstedeværelse av de nevnte vitaminstoffer ikke synes å være en betingelse. Ved utforelsen av foreliggende oppfinnelse er derimot den samtidig tilstedeværelse av nevnte vitaminer såvel som bruken av en spesiell mikroorganisme av arten Brevibacterium ammoniagenes av vesentlig betydning. Patentet anvender helt andre mikroorganismer enn de som anvendes i foreliggende oppfinnelse og patentet benytter også meget mindre mengder av pantotensyre og tiamin. Pro-duktutbytte i foreliggende oppfinnelse er meget storre enn det som oppnåes ved fremgangsmåten i det belgiske patent. I patentet oppnåes f.eks. bare 0.33 mg/ml GMP og 0.17-0.30 mg/ml AMP, mens utbyttet av disse forbindelser ved foreliggende fremgangsmåte henholdsvis er 3«9-4-9mg/ml og 6.5 mg/ml. Ved foreliggende oppfinnelse dannes således GMP og AMP i mengder som er 10 ganger storre enn de som frembringes ved det belgiske patentets fremgangsmåte. From Belgian patent no. 621 122, it is known to add pantothenic acid and thiamine to the nutrient medium when cultivating microorganisms belonging to the genus Brevibacterium for the production of 5'-nucleotides. These additives are only used as nutrients and are not indispensable in the composition of the medium. It must therefore be concluded that other means can also be used. It also appears from the patent that the simultaneous presence of the aforementioned vitamin substances does not appear to be a condition. In carrying out the present invention, on the other hand, the simultaneous presence of said vitamins as well as the use of a special microorganism of the species Brevibacterium ammoniagenes is of significant importance. The patent uses completely different microorganisms than those used in the present invention and the patent also uses much smaller amounts of pantothenic acid and thiamine. Product yield in the present invention is much greater than that achieved by the method in the Belgian patent. In the patent, e.g. only 0.33 mg/ml GMP and 0.17-0.30 mg/ml AMP, while the yield of these compounds by the present method is respectively 3,9-4-9mg/ml and 6.5 mg/ml. In the present invention, GMP and AMP are thus formed in amounts that are 10 times greater than those produced by the Belgian patent's method.
Da moderstammene ATCC nr. 6871 og 6872 krever biotin som vektsfaktor, krever naturligvis de fra disse stammer avledede mutanter også biotin for sin vekst. As the parent strains ATCC No. 6871 and 6872 require biotin as a weight factor, naturally the mutants derived from these strains also require biotin for their growth.
Som purinbase tilsettes en liten mengde adenin til den adenin-krevende mutant og en liten mengde guanin til den guaninkrevende mutant. Mengden som må tilsettes, varierer med stammene og dyrkningsbetingelsene, men utgjor normalt ca. l-200yu/ml beregnet som de respektive baser. As a purine base, a small amount of adenine is added to the adenine-requiring mutant and a small amount of guanine to the guanine-requiring mutant. The amount that must be added varies with the strains and cultivation conditions, but normally amounts to approx. l-200yu/ml calculated as the respective bases.
Ved de optimale tilsetningsméngder av hver base vil 5<*->lMP akkumuleres når det gjelder adenin-krevende mutant, og 5'- XM. P vil opp<-samles når det gjelder en guanin-krevende mutant. ;I fermenteringer hvor det anvendes moderstammer (ATCC nr. ;6871 eller 6872) må purinbase og/eller dennes nukleosid tilsettes som . prekursor, i en mengde på over 0.5 mg/ml. Hvis det tilsettes hypo.^can-tin og inosin vil ^'- IMP ansamle seg, mens 5<t_>GMP ansamles hvis guanin og guanosin tilsettes; og ved tilsetning av adenin og adenosin ansamles 5'-AMP. Det kan også benyttes naturmaterialer som i seg selv inneholder deres prekursorer. Eksempelvis er det mulig å tilsette ;fermenteringssuppe som er oppnådd fra en kultur av mikroorganismer som er i stand til å danne hypox.antin. ;Det benyttede grunnmedium inneholder en karbonkilde, en kilde for uorganisk nitrogen, uorganiske salter, en aminosyrekilde, og andre forbindelser som er nodvendige for veksten av den mikroorganisme som anvendes. Blant næringsbestanddelene er fosfater og magnesiumsalter viktige, og for å få gode utbytter er det nodvendig å tilsette begge disse, så det fåes en betydelig konsentrasjon av dem. Den mest foretrukne tilsetning utgjores av 0.6-1.5% KgHPO^, 0.6-1.5% KH2P0^og 0.6-15.% MgS0^.7H20, og tilsetningen bor skje slik at det oppnås nesten innbyrdes lik konsentrasjon av disse tre salter. Kt naturlig forekommende næringsmedium som inneholder pantotensyre og tiamin eller de foran nevnte beslektede stoffer er vel egnet for bruk i den foreliggende oppfinnelse. ;Blant naturmaterialer som inneholder pantotensyre og som kan nyttes i den foreliggende oppfinnelse kan det nevnes kjottekstrakt, leverekstrakt, risklid, melasse, opplost fiskemateriale og lignende. ;Blant brukbare naturmaterialer som inneholder tiamin kan ;nevnes risskall og -klid, gjærekstrakt, leverekstrakt, og lignende. ;Ved anvendelse av de adenin- eller guanin-krevende mutanter av Brevibacterium ammoniagenes utfores dyrkningen i et medium som inneholder en liten mengde av adenin respektivt av guanin, for dannelse av vedkommende 5'-purin-nukleotid. ;Selve fermenteringsmetoden er praktisk talt som for andre metoder. Temperaturen er 25-38°C; den optimale er ca. 30°C. Normalt er rysting av lukkede fermenteringsbeholdere fordelaktig, og submers fermentering er fordelaktig i tanker og åpne kar. Dyrkningstiden er 24-168 timer, og mengden av 5'-purin-nukleotid når sitt maksimum i lopet av 72-120 timer. ;De folgende eksempler belyser oppfinnelsen. Mediets sammensetning er i eksemplene angitt som den % av hver bestanddel som er opplost i vann, beregnet på det totale volum. ;Eksempel 1;Brevibacterium ammoniagenes ATCC nr. 6872 dyrkes etter autoklavering (15 minutter ved 120°C) i 24 timer i et podemedium som inneholder 2% glukose, 1.0% casaminosyrer (fri for vitamin) 0.1% KgHPO^, 0.03% MgS0^.7H20, 0.3% NaCl, 0.01% FeS0^.7H20 og 30/ug/liter biotin, (pH 7«3)j°g inokuleres i en mengde av 10% (volum) i fermenteringsmediet. Porsjoner på JO ml av mediene helles i en 250 ml erlenmeyer-kolbe,.og benyttes etter autoklavering (ved 120°C i 15 minutter). Det anvendes et fermenteringsmedium som har den nedenfor angitte sammensetning, og fermenteringen utfores ved 30°C under omroring. ;Fermenteringsmediets sammensetning: 10% glukose, 1% K2HP0^, 1% KH2P04, 1% MgS04.7H20, 0.01% CaCl2.2H20, 30/ug/liter biotin, 3 mg/ ml hypooc.antin, Ca-pantotenat i forskjellige konsentrasjoner. pH-verdien reguleres med 5n NaOH til 8.0 for behandling i autoklav (ved ;.120°C i 15 minutter). Etter steriliseringen tilsettes det til mediet 0.6% sterilisert urea og tiamin.HC1, i forskjellige konsentrasjoner. Den mengde 5'-inosinsyre (Na-salt) som har samlet seg i dyrkningsvæsken etter 96 timers forlop er angitt i den folgende tabell I. ; Eksempel 2;Dyrkningen utfores med samme stamme og samme dyrkningsbe-tingelser som i eksempel 1, men under tilsetning av B-alanin i forskjellige konsentrasjoner, istedenfor kalsiumpantoténat. Den mengde 5'-inosinsyre (Nansalt) som har dannet seg i lopet av 120 timer er angitt i den nedenstående tabell II. ; Eksempel 3;Det ble anvendt samme mikroorganismestamme som i eksempel;1 og samme podemedium, bare med den forskjell at det var tilsatt 1.5% pepton istedenfor 1.0% casaminosyrer. Det ble benyttet et fermenteringsmedium hvortil det var tilsatt passende mengder av B-alanin, pantetin, koenzym A samt gjærekstrakt, kjottekstrakt, leverekstrakt og opplost fiskemateriale inneholdende slike forbindelser istedenfor kalsiumpantotenat, samt l^ug/ml tiamin. Ellers er dyrkningsbetingelsene som i eksempel 1. Den nedenstående tabell III angir den mengde 5'-inosinsyre (Na-salt) som har samlet seg i fermenteringsmediet etter 120 timers foriop. ; Eksempel 4;Det benyttes Brevibacterium ammoniagenes ATCC nr. 6871. Det anvendes samme pode- respektivt fermenteringsmedium som i eksempel 3>og fermenteringen foregår med tilsatt pantotensyre (eller B-alanin) og tiamin i forskjellige konsentrasjoner. Ellers er fermen-teringsprosessen lik-* den i eksempel 1. Den folgende tabell IV angir hvor meget 5'-inosinsyre (Na-salt) det har samlet seg etter 96 timers fermentering. At the optimal addition amounts of each base, 5<*->1MP will accumulate in the case of the adenine-requiring mutant, and 5'-XM. P will accumulate in the case of a guanine-requiring mutant. In fermentations where mother strains are used (ATCC no. 6871 or 6872) purine base and/or its nucleoside must be added as . precursor, in an amount of more than 0.5 mg/ml. If hypo.^can-tin and inosine are added, ^'- IMP will accumulate, while 5<t_>GMP will accumulate if guanine and guanosine are added; and when adenine and adenosine are added, 5'-AMP accumulates. Natural materials that themselves contain their precursors can also be used. For example, it is possible to add fermentation broth obtained from a culture of microorganisms capable of forming hypox.antin. The basic medium used contains a carbon source, a source of inorganic nitrogen, inorganic salts, an amino acid source, and other compounds that are necessary for the growth of the microorganism used. Among the nutrients, phosphates and magnesium salts are important, and to get good yields it is necessary to add both of these, so that a significant concentration of them is obtained. The most preferred addition consists of 0.6-1.5% KgHPO^, 0.6-1.5% KH2P0^ and 0.6-15.% MgS0^.7H20, and the addition should be made so that an almost mutually equal concentration of these three salts is achieved. A naturally occurring nutrient medium containing pantothenic acid and thiamine or the above-mentioned related substances is well suited for use in the present invention. Among natural materials which contain pantothenic acid and which can be used in the present invention, mention may be made of meat extract, liver extract, rice bran, molasses, dissolved fish material and the like. Among usable natural materials containing thiamine can be mentioned rice husk and bran, yeast extract, liver extract, and the like. When using the adenine- or guanine-requiring mutants of Brevibacterium ammoniagenes, cultivation is carried out in a medium containing a small amount of adenine or guanine, respectively, for the formation of the relevant 5'-purine nucleotide. ;The fermentation method itself is practically the same as for other methods. The temperature is 25-38°C; the optimum is approx. 30°C. Normally, shaking closed fermentation vessels is beneficial, and submersible fermentation is beneficial in tanks and open vessels. The cultivation time is 24-168 hours, and the amount of 5'-purine nucleotide reaches its maximum in the course of 72-120 hours. The following examples illustrate the invention. The composition of the medium is given in the examples as the % of each component that is dissolved in water, calculated on the total volume. ;Example 1;Brevibacterium ammoniagenes ATCC No. 6872 is grown after autoclaving (15 minutes at 120°C) for 24 hours in an inoculum medium containing 2% glucose, 1.0% casamino acids (vitamin free) 0.1% KgHPO^, 0.03% MgSO^ .7H2O, 0.3% NaCl, 0.01% FeS0^.7H2O and 30 µg/liter biotin, (pH 7-3)j°g are inoculated in an amount of 10% (volume) in the fermentation medium. Portions of JO ml of the media are poured into a 250 ml Erlenmeyer flask and used after autoclaving (at 120°C for 15 minutes). A fermentation medium is used which has the composition stated below, and the fermentation is carried out at 30°C with stirring. ;Fermentation medium composition: 10% glucose, 1% K2HP0^, 1% KH2P04, 1% MgS04.7H20, 0.01% CaCl2.2H20, 30/ug/liter biotin, 3 mg/ml hypooc.antin, Ca-pantothenate in various concentrations . The pH value is adjusted with 5n NaOH to 8.0 for treatment in an autoclave (at ;.120°C for 15 minutes). After sterilization, 0.6% sterilized urea and thiamin.HC1, in different concentrations, are added to the medium. The amount of 5'-inosinic acid (Na salt) which has accumulated in the culture liquid after 96 hours is indicated in the following table I.; Example 2: The cultivation is carried out with the same strain and the same cultivation conditions as in example 1, but with the addition of B-alanine in different concentrations, instead of calcium pantothenate. The amount of 5'-inosinic acid (Nansalt) that has formed over the course of 120 hours is indicated in Table II below. ; Example 3: The same microorganism strain as in example 1 and the same inoculum medium were used, only with the difference that 1.5% peptone was added instead of 1.0% casamino acids. A fermentation medium was used to which were added suitable amounts of B-alanine, pantethine, coenzyme A as well as yeast extract, meat extract, liver extract and dissolved fish material containing such compounds instead of calcium pantothenate, as well as l^ug/ml thiamine. Otherwise, the cultivation conditions are as in example 1. Table III below indicates the amount of 5'-inosic acid (Na salt) which has accumulated in the fermentation medium after 120 hours of incubation. ; Example 4: Brevibacterium ammoniagenes ATCC No. 6871 is used. The same inoculum and fermentation medium is used as in example 3> and the fermentation takes place with added pantothenic acid (or B-alanine) and thiamine in different concentrations. Otherwise, the fermentation process is similar to that in example 1. The following table IV indicates how much 5'-inosinic acid (Na salt) has accumulated after 96 hours of fermentation.
Eksempel 5 Example 5
Brevibacterium ammoniagenes nr. 7208 ATCC nr. I5187 (adenin-krevende mutant av ATCC nr. 6872) blir anvendt. Det medium som fås ved å tilsette 5C<y>ug/ml adenin til det i eksempel 1 beskrevne medium benyttes som podemedium, og det medium som fås ved tilsetning av 5C<y>ug/ml adenin til det i eksempel 1 beskrevne fermenteringsmedium anvendes som fermenteringsmedium. Stammen dyrkes under tilsetning av passende mengder av kalsiumpantotenat (eller 8-alanin) og tiamin til fermenteringsmediet. Ellers er dyrkningsbetingelsene som i eksempel 1. Den folgende tabell V angir hvor meget 5<1->inosinsyre (Na-salt) det har dannet seg etter 120 timers dyrkning. Brevibacterium ammoniagenes No. 7208 ATCC No. I5187 (adenine-requiring mutant of ATCC No. 6872) is used. The medium obtained by adding 5C<y>ug/ml adenine to the medium described in example 1 is used as inoculation medium, and the medium obtained by adding 5C<y>ug/ml adenine to the fermentation medium described in example 1 is used as fermentation medium. The strain is grown while adding appropriate amounts of calcium pantothenate (or 8-alanine) and thiamine to the fermentation medium. Otherwise, the cultivation conditions are as in example 1. The following table V indicates how much 5<1->inosic acid (Na salt) has formed after 120 hours of cultivation.
1 Eksempel 6 1 Example 6
Det anvendes Brevibacterium ammoniagenes nr. 7309 ATCC nr. 15312 (adenin-krevende mutant av ATCC nr. 6872) samt det i eksempel 5 beskrevne pode- respektive fermenteringsmedium, til hvilke det er tilsatt 5/ug/ml adenin. Mediet blir dyrket uten tilsetning respektivt med tilsetning av 10<y>ug/ml kalsiumpantotenat og l<y>ug/ml tiamin. Ellers er dyrkningsbetingelsene som i eksempel 1. Etter 96 timers dyrkning finnes det bare spor av 5'-inosinsyre i det tilfelle hvor intet vitamin var tilsatt, men 6.3 mg/ml i det tilfelle hvor begge vitaminer var blitt tilsatt. Brevibacterium ammoniagenes No. 7309 ATCC No. 15312 (adenine-requiring mutant of ATCC No. 6872) is used as well as the inoculum and respective fermentation medium described in Example 5, to which 5 µg/ml of adenine has been added. The medium is cultured without addition, respectively with the addition of 10<y>ug/ml calcium pantothenate and 1<y>ug/ml thiamine. Otherwise, the cultivation conditions are as in example 1. After 96 hours of cultivation, there are only traces of 5'-inosinic acid in the case where no vitamin was added, but 6.3 mg/ml in the case where both vitamins had been added.
F. ksempel 7-Example 7-
Det benyttes samme stamme og kulturmedium som i eksempel 6, samt et fermenteringsmedium til hvilket det er tilsatt B-alanin, pantetin, koenzym A, og naturmaterialer som inneholder B-alanin og koenzym A istedenfor kalsiumpantotenat. Kilers er dyrkningsbetingelsene de samme som i eksempel 1. Folgende tabell VI angir mengden av 5'-inosinsyre (Na-salt) som har samlet seg etter 120 timers dyrkning. The same strain and culture medium as in example 6 are used, as well as a fermentation medium to which B-alanine, pantethine, coenzyme A, and natural materials containing B-alanine and coenzyme A have been added instead of calcium pantothenate. Kilers, the cultivation conditions are the same as in example 1. The following table VI indicates the amount of 5'-inosinic acid (Na salt) which has accumulated after 120 hours of cultivation.
Eksempel 8 Example 8
Det benyttes Brevibacterium ammoniagenes 7320 ATCC nr. 15190 (adenin-krevende mutant av ATCC nr. 6871), og forovrig er dyrkningsbetingelsene som i eksempel 5«Etter 9-6 timers dyrkning har det samlet seg 4-2 mg/ml 5'-inosinsyre (Na-salt). i det medium som var fått ved å tilsette 5/ug/ml P-alanin og l^ug/ml tiamin til fermenteringsmediet. I medium som er fritt for begge vitaminene dannes det derimot bare spor av 5'-inosinsyre. Brevibacterium ammoniagenes 7320 ATCC no. 15190 (adenine-requiring mutant of ATCC no. 6871) is used, and otherwise the cultivation conditions are as in example 5 "After 9-6 hours of cultivation, 4-2 mg/ml 5'-inosic acid has accumulated (Na salt). in the medium obtained by adding 5 µg/ml β-alanine and 1 µg/ml thiamine to the fermentation medium. In medium that is free of both vitamins, on the other hand, only traces of 5'-inosinic acid are formed.
Eksempel 9Example 9
Det anvendes samme stamme og podemedium som i eksempel 1, samt benyttes det medium som fås ved å tilsette 0.3% pepton til fer-ment eringsmediet i eksempel 1, uten at hypoxantin er tilstede. Det tilsettes pantotensyre eller en beslektet forbindelse i forskjellige konsentrasjoner samt tiamin. Tilsetningen av guanin under veskten utfores på en slik måte at det forefinnes 2 mg/ml guanin etter 72 timers dyrkning. Ellers er dyrkningsbetingelsene som i eksempel 1. Den folgende tabell VII angir mengden av 5'-guanylsyre (Na-salt) i væsken etter 96 timers dyrkning. The same strain and inoculum medium as in example 1 are used, and the medium obtained by adding 0.3% peptone to the fermentation medium in example 1 is used, without hypoxanthine being present. Pantothenic acid or a related compound is added in different concentrations as well as thiamine. The addition of guanine during growth is carried out in such a way that 2 mg/ml guanine is present after 72 hours of cultivation. Otherwise, the cultivation conditions are as in example 1. The following table VII indicates the amount of 5'-guanylic acid (Na salt) in the liquid after 96 hours of cultivation.
Eksempel 10 Example 10
Det anvendes samme stamme og podemedium som i eksempel 1, samt et fermenteringsmedium som angitt i eksempel 9, til hvilket det er blitt tilsatt 5^\ ig/ m± pantotensyre og lyug/ml tiamin.HC1. Adenin tilsettes på en slik måte at det fås 2.5 mg/ml adenin etter dyrkning i 48 timer. Ellers er dyrkningsbetingelsene som i eksempel 1. Etter 96 timer har det i dyrkningsvæsken samlet seg 6.5 mg/ml adenylsyre. Hvis enten pantotensyre eller tiamin utelates, dannes det bare lite av 5'-adenylsyre. The same strain and inoculum medium as in example 1 are used, as well as a fermentation medium as stated in example 9, to which 5 µg/m ± pantothenic acid and lyug/ml thiamine.HC1 have been added. Adenine is added in such a way that 2.5 mg/ml adenine is obtained after cultivation for 48 hours. Otherwise, the culture conditions are the same as in example 1. After 96 hours, 6.5 mg/ml adenylic acid has accumulated in the culture liquid. If either pantothenic acid or thiamine is omitted, little 5'-adenylic acid is formed.
Eksempel 11Example 11
Det anvendes Brevibacterium ammoniagenes ATCC nr. 6871. Det benyttes det i eksempel 9 beskrevne pode- respektive fermenteringsmedium, og. guanin eller adenin tilsettes på en slik måte at det oppnås 2.0 mg/ml guanin eller adenin etter 48 timers dyrkning. Ellers er dyrkningsbetingelsene som i eksempel 1. I tilfelle av at guanin er blitt tilsatt, fås det etter 96 timer 4-8 mg/ml 5'-guanylsyre (Na-salt) i dyrkningsvæsken, og hvis adenin er blitt tilsatt, fås det 5.1 mg/ml 5'-adenylsyre. Hvis enten pantotensyre eller tiamin utelates, dannes det bare lite av 5'-guanylsyre respektive 5'-adenylsyre. Brevibacterium ammoniagenes ATCC no. 6871 is used. The inoculum and fermentation medium described in example 9 are used, and. guanine or adenine is added in such a way that 2.0 mg/ml guanine or adenine is obtained after 48 hours of cultivation. Otherwise, the culture conditions are as in example 1. If guanine has been added, after 96 hours 4-8 mg/ml 5'-guanylic acid (Na salt) is obtained in the culture liquid, and if adenine has been added, 5.1 mg/ml 5'-adenylic acid. If either pantothenic acid or thiamine is omitted, little is formed of 5'-guanylic acid or 5'-adenylic acid, respectively.
Eksempel 12Example 12
Det benyttés Brevibacterium ammoniagenes nr. 62221 ATCC 15138 (guanin-krevende mutant)-. Det benyttede podemedium er et som er fått ved å tilsette 10^ug/ml guanin til det i eksempel 1 beskrevne podemedium. Videre anvendes det i eksempel 1 beskrevne fermenteringsmedium, til hvilket det er blitt tilsatt 15/ug/ml guanin istedenfor hypoxantin, og pantotensyre (eller pantetin, koenzym A) og tiamin.HC1 i forskjellige konsentrasjoner. Ellers ligner dyrkningsbetingelsene de i eksempel 1 anvendte. Den folgende tabell VIII angir den mengde 5''-xantylsyre (Na-salt) som er dannet etter 120 timers dyrkning. Brevibacterium ammoniagenes no. 62221 ATCC 15138 (guanine-requiring mutant) was used. The inoculation medium used is one obtained by adding 10 µg/ml guanine to the inoculation medium described in example 1. Furthermore, the fermentation medium described in example 1 is used, to which 15 µg/ml guanine has been added instead of hypoxanthine, and pantothenic acid (or pantethine, coenzyme A) and thiamine.HC1 in different concentrations. Otherwise, the cultivation conditions are similar to those used in example 1. The following table VIII indicates the amount of 5''-xanthylic acid (Na salt) formed after 120 hours of cultivation.
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DE (2) | DE1445977A1 (en) |
DK (1) | DK105061C (en) |
ES (1) | ES298480A1 (en) |
GB (1) | GB1060428A (en) |
NL (1) | NL6403828A (en) |
NO (1) | NO120830B (en) |
SE (1) | SE316184B (en) |
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DE1445977A1 (en) | 1969-03-06 |
DE1695345A1 (en) | 1972-04-20 |
NL6403828A (en) | 1964-10-12 |
SE316184B (en) | 1969-10-20 |
DE1695345B2 (en) | 1977-05-18 |
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ES298480A1 (en) | 1964-09-01 |
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