Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing oxygen-containing organic compound
Reexamination Certificate
1999-12-29
2001-10-23
Prats, Francisco (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing oxygen-containing organic compound
C424S121000, C424S200100, C435S125000, C435S169000, C435S252100, C435S253500, C544S292000, C549S292000, C560S119000, C560S188000, C560S256000
Reexamination Certificate
active
06306629
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is related to a new microorganism
Streptomyces exfoliatus
YJ-118 and a method for producing pravastatin sodium represented in formula I by using this microorganism which shows a strong tolerance to ML-236B and a high hydroxylation activity of ML-236B to pravastatin.
2. Description of the Prior Art
An elevated plasma cholesterol level has long been recognized as a major risk factor for atherosclertic disease, and specifically for coronary heart disease. It was expected that plasma cholesterol could be reduced as a result of inhibition of cholesterol biosynthesis because more than 70% of the total input of body cholesterol is derived from de novo synthesis in humans. In 1975, ML-236B, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co A) reductase, a rate-limiting enzyme in the biosynthesis of cholesterol, was discovered in the culture broth of Penicillin citrium. After thorough screening of hundreds of microbial products as well as chemically or biologically modified derivatives of ML-236B, pravastatin sodium was chosen as a candidate for development, because of its stronger and more tissue-selective activity than the prototype compound.
Pravastatin has been produced by two-step fermentation: first, biosynthesis of ML-236B and second, bioconversion of this compound to pravastatin sodium. Lactone and carboxylate of ML-236B are represented in formula II-a and formula II-b, respectively.
wherein, R is H or Na.
It was reported that
Streptomyces roseochromogenus
NRRL-1233
, Streptomyces roseochromogenus
IFO-3363
, Streptomyces roseochromogenus
IFO-3411 (U.S. Pat. No. 4,346,227) and
Streptomyces carbophilus
SANK-62585 (Ferm BP-1145),
Streptomyces halstedii
IFO-3199 (JP No. Pyung 4-349034) transformed ML-236B to pravastatin. These bacteria, however, cannot tolerate a relatively high amount of ML-236B in the culture broth because of antibacterial activity of the substrate, and show low productivity of pravastatin.
SUMMARY OF THE INVENTION
The present inventors investigated to find out a new microorganism which is tolerable to higher amount of ML-236B and also has strong transformation activity. Finally, they found a new microorganism.
Streptomyces exfoliatus
YJ-118.
REFERENCES:
patent: 5153124 (1992-10-01), Furuya et al.
patent: 5332574 (1994-07-01), Sugawara et al.
Kim Ji-Yoon
Lee Joo-Kyung
Lee Sang-Choon
Park Joo-Woong
Seo Dong-Jin
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Prats Francisco
Srivastava K. C.
Yungjin Pharmaceutical Ind. Co., Ltd.
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