Ml-236a, ml-236b, and ml-236c, new inhibitors of cholesterogenesis produced by penicillium citrinum
01 Dec 1976-The Journal of Antibiotics (JAPAN ANTIBIOTICS RESEARCH ASSOCIATION)-Vol. 29, Iss: 12, pp 1346-1348
About: This article is published in The Journal of Antibiotics.The article was published on 1976-12-01 and is currently open access. It has received 903 citations till now. The article focuses on the topics: Penicillium citrinum.
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TL;DR: Recent studies indicate that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response.
Abstract: ▪ Abstract Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the over...
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TL;DR: 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.
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TL;DR: The structure of compactin, a metabolite isolated from cultures of Penicillium brevicompactum, has been determined by a combination of spectroscopic, chemical, and X-ray crystallographic methods.
Abstract: The structure of compactin (I){7-[1,2,6,7,8,8a-hexahydro-2-methyl-8-(2-methylbutyryloxy)naphthyl]-3-hydroxyheptan-5-olide}, a metabolite isolated from cultures of Penicillium brevicompactum, has been determined by a combination of spectroscopic, chemical, and X-ray crystallographic methods.
325 citations
TL;DR: In inhibition by citrinin of cholesterol and ergosterol synthesis and its hypocholesterolemic activity in rats, the inhibition of endogenous cholesterol synthesis could lead to a lowering of its level in the plasma.
Abstract: A compound active against sterol biosynthesis was isolated from the culture filtrate of the fungus Prthium ultimum IAM 6073 and identified as citrinin which had been isolated as an antibiotic.') The sequence of reactions by which cholesterol is formed from acetyl-CoA is one of the most complex biosynthetic pathways in eukaryotic cells. In every vertebrate species so far studied, potent activity in cholesterol synthesis can be detected in the liver which seems to be the sole organ supplying plasma cholesterol. Because of the importance of the plasma cholesterol level in atherosclerosis, several approaches have been made to control it by decreasing cholesterol synthesis in the liver.2~4) The inhibition of endogenous cholesterol synthesis could lead to a lowering of its level in the plasma. This communication describes inhibition by citrinin of cholesterol and ergosterol synthesis and its hypocholesterolemic activity in rats. The enzymatic synthesis of cholesterol was assayed by measuring the radioactive nonsaponifiable products derived from 14C-acetate in a rat liver enzyme system by the method of KNAUSS et al.5) Culture filtrates of microorganisms including fungi, bacteria, and actinomycetes were tested for inhibitory activity in this assay system, and Pvthium ultimum was selected as one of the producers of an inhibitor. The fungus was cultured aerobically in a medium containing 2.0% glucose, 2% peptone and 0.3 % corn steep liquor in a 30-liter fermentor for 4 days. The culture filtrate was adjusted to pH 2, and the active compound was extracted with benzene. The extract was concentrated in vacuo, resulting in the formation of yellowish crystals of the active compound. The compound was recrystallized from hot chloroform. Calcd.: C 62.39, H 5.64, O 31.97 Found: C 62.39, H 5.58, O 32.03 The chemical structure of 4,6-dihydro-8-hydroxy-3,4, 5-trimethyl 6 oxo3 H-2-benzopyran-7 carboxylic acid was suggested by n.m.r. spectrum. The identity with citrinin was proven by comparison with authentic samples (kindly supplied by Dr. S. UDAGAWA, National Institute of Hygienic Science, Tokyo). As shown in Fig. 1, citrinin strongly inhibited cholesterol synthesis from 14C-acetate. The concentration at which cholesterol synthesis was inhibited by 50 % was about 8.5 mcg/ml (3.4 x 10-5M). Under the same conditions, 14C-acetate incorporation into fatty acid fraction was also reduced by citrinin but to a lesser extent. The concentration of the inhibitor required for 50 inhibition of fatty acid synthesis was approximately 50 mcg/ml. Citrinin was also inhibitory in the sterol synthesizing system of the yeast Saccharomyces cerevisiae in which 14C-acetate incorporation into nonsaponifiable lipids was determined as described by KAWAGUCHI (Fig. 1).e) At a concentration of 100 mcg/ml, the inhibitor reduced the sterol synthesis by approximately 50%. For studies of hypocholesterolemic effect of
101 citations
TL;DR: In the present work the rat liver enzyme system of Bucher and McGarrahan was fractionated with ammonium sulfate, and the cofactor requirements for the conversion of acetate to sterols by this system were determined.
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TL;DR: Great inhibition of liver cholesterogenesis was evident with HMG administration to rats fed cholesterol in the diet than with rats fed only cholesterol, indicating an additive inhibitory effect of HMG.
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TL;DR: A series of arylalkyl hydrogen succinates and glutarates was synthesized and assayed for inhibition of yeast β -hydroxy- β - methylglutaryl coenzyme A reductase, finding the following compounds to be particularly active as inhibitors.
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