Application of Actinomycetes in the Production of Pravastatin, a novel cholesterol-lowering agent (in Japanese with English abstract)

抄録

Pravastatin is a tissue-selective inhibitor of HMG-CoA reductase, a key enzyme in cholesterol biosynthesis. This compound was obtained by the microbial hydroxylation of mevastatin(ML-236B). Pravastatin was primarily discovered in the urine of dog as a minor active metabolite of mevastatin. Various fungi were tested for their transformation capability to find some Zygomycetes Mucor hiemalis converted mevastatin mainly to pravastatin. These fungi, however, were found to not tolerate increase in the amount of mevastatin added to the culture broth. Amycolata autotrophica of actinomycetes, the isolates from the soil sample collected in Australia, were found to have strong transformation activity with by-product in spite of its tolerance to the substrate. After further energetic screening for fresh isolates of actinomycetes, Streptomyces carbophilus was discovered as a potent converter with a limited amount of by-product. S. carbophilus was also tolerable to a higher amount of mevastatin in the culture broth. In this way, Streptomyces carbophilus having capability of industrial- scale production of pravastatin were isolated from soil sample collected in Australia. The hydroxylation of mevastatin to pravastatin in Streptomyces carbophilus was catalyzed by a cytochrome P-450sca monooxygenase system. The P-450sca system had turned out to exist in the soluble fraction and to be composed of only two components, P-450sca and flavoprotein. Therefore, a novel character of P-450sca system in prokaryote was suggested.