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.
Serizawa
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Biomedical Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan.
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