Biochemical and molecular approaches for production of pravastatin, a potent cholesterol-lowering drug.
The intensive search for inhibitors of cholesterol biosynthesis by screening culture broths has spanned more than 20 years here at Sankyo. Resulting from our efforts, ML-236B was discovered in Japan as the first potent and specific inhibitor of HMG-CoA reductase. This compound contributed-to the Nobel Prize-winning work of Goldstein and Brown in which they elucidated the mechanisms of the LDL receptor pathway. After the discovery of ML-236B, many attempts were performed to find other HMG-CoA reductase inhibitors, and some potent inhibitors including pravastatin have already been launched. HMG-CoA reductase inhibitors are in worldwide clinical use and play a pivotal role in the therapy of hyperlipidemic patients. Pravastatin is produced by a two-step fermentation, firstly ML-236B is produced by Penicillium citrinum followed by the hydroxylation of ML-236B by S. carbophilus to form pravastatin. Recent advances in the molecular characterization of the Cyt P-450sca-2 and their responsiveness to ML-236B and PB in bacterial cultures should help elucidate the underlying cellular and molecular mechanisms of ML-236BNa and PB induction. In an effort to increase the productivity of this fermentation process, new technologies have been developed, and the mechanism of hydroxylation has been extensively investigated.
Biomedical Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
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Serizawa
D000818:Animals; D005285:Fermentation; D006900:Hydroxylation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006949:Hyperlipidemias / Q000188:drug therapy; D008956:Models, Chemical; D010407:Penicillium / Q000378:metabolism; D017035:Pravastatin / Q000627:therapeutic use; D013302:Streptomyces / Q000378:metabolism; D013678:Technology, Pharmaceutical
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017035:Pravastatin