Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent.
Alfred W. Alberts,Julie S. Chen,G Kuron,V Hunt,Jesse W. Huff,Carl H. Hoffman,John W. Rothrock,Lopez Maria B,Henry Joshua,Elbert E. Harris,Arthur A. Patchett,R L Monaghan,S Currie,E Stapley,George Albers-Schonberg,Otto D. Hensens,J Hirshfield,Karst Hoogsteen,Jerrold M. Liesch,James P. Springer +19 more
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It was shown that mevinolin was an orally active cholesterol-lowering agent in the dog and orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay.Abstract:
Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolini and its open acid form, mevinolinic acid, were determined by a combination of physical techniques. Mevinolin was shown to be 1,2,6,7,8,8a-hexahydro-beta, delta-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-hepatanoic acid delta-lactone. Mevinolin in the hydroxy-acid form, mevinolinic acid, is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]; its Ki of 0.6 nM can be compared to 1.4 nM for the hydroxy acid form of the previously described related inhibitor, ML-236B (compactin, 6-demethylmevinolin). In the rat, orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay (50% inhibitory dose = 46 microgram/kg). Furthermore, it was shown that mevinolin was an orally active cholesterol-lowering agent in the dog. Treatment of dogs for 3 weeks with mevinolin at 8 mg/kg per day resulted in a 29.3 +/- 2.5% lowering of plasma cholesterol.read more
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Fifty years of drug discovery from fungi
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Tomato hydroxymethylglutaryl-CoA reductase is required early in fruit development but not during ripening.
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Endothelial activation by aPL: a potential pathogenetic mechanism for the clinical manifestations of the syndrome.
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Relationship between mevalonate and mitogenesis in human fibroblasts stimulated with platelet-derived growth factor.
TL;DR: There is a critical time period, several h before S phase, when PDGF-stimulated cells require mevalonate in order for DNA synthesis to proceed at 24 h, and this critical period comprised the interval of approximately 10-20 h after PDGF addition and especially the early part of this interval.
References
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Ml-236a, ml-236b, and ml-236c, new inhibitors of cholesterogenesis produced by penicillium citrinum
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Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme a reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity
TL;DR: The experiments reported in this paper demonstrate that MG236A and ML-236B inhibit specifically 3-hydroxy-3-methylglutaryl (HMG)CoA reductase (EC 1 .I .1.34), the rate-limiting enzyme in cholesterol synthetic pathway, without affecting the rest of the enzymes involved in this pathway, and that the inhibition is competitive with respect to the substrate HMG-CoA.