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F-244 specifically inhibits 3-hydroxy-3-methylglutaryl coenzyme A synthase. 1987

H Tomoda, and H Kumagai, and H Tanaka, and S Omura
Kitasato Institute, Tokyo, Japan.

A beta-lactone isolated from Scopulariopsis sp. shows a potent inhibition of cholesterogenesis. The structure of this beta-lactone, termed F-244, is 3,5,7-trimethyl-12-hydroxy-13-hydroxymethyl-2,4-tetradecadiendioic acid 12,14-lactone. The inhibition site of F-244 in cholesterol synthesis was studied. The growth of Vero cells was inhibited at 6.25-12.5 micrograms/ml of F-244. The inhibition of growth was overcome by the addition of mevalonate to the culture medium, but not by the addition of acetate. In a rat liver enzyme system, the incorporations of [14C]acetate and [14C]acetyl-CoA into digitonin-precipitable sterol were 50% inhibited by 0.58 microgram/ml of F-244. The incorporation of [14C]mevalonate was not affected. Studies on the effects of F-244 on the three enzymes involved in mevalonate biosynthesis demonstrated that the drug specifically inhibits HMG-CoA synthase with IC50 value of 0.065 microgram/ml. The effect of analogs of F-244 on HMG-CoA synthase was also investigated.

UI MeSH Term Description Entries
D007652 Oxo-Acid-Lyases Enzymes that catalyze the cleavage of a carbon-carbon bond of a 3-hydroxy acid. (Dorland, 28th ed) EC 4.1.3. Ketoacid-Lyases,Ketoacid Lyases,Oxo Acid Lyases
D007783 Lactones Cyclic esters of hydroxy carboxylic acids, containing a 1-oxacycloalkan-2-one structure. Large cyclic lactones of over a dozen atoms are MACROLIDES. Lactone
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008148 Lovastatin A fungal metabolite isolated from cultures of Aspergillus terreus. The compound is a potent anticholesteremic agent. It inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase (HYDROXYMETHYLGLUTARYL COA REDUCTASES), which is the rate-limiting enzyme in cholesterol biosynthesis. It also stimulates the production of low-density lipoprotein receptors in the liver. Lovastatin, 1 alpha-Isomer,Mevinolin,6-Methylcompactin,Lovastatin, (1 alpha(S*))-Isomer,MK-803,Mevacor,Monacolin K,1 alpha-Isomer Lovastatin,6 Methylcompactin,Lovastatin, 1 alpha Isomer,MK 803,MK803,alpha-Isomer Lovastatin, 1
D008798 Mevalonic Acid A dihydroxy monocarboxylic acid and precursor in the biosynthetic pathway known as the mevalonate pathway, which produces terpenes and steroids that are vital for diverse cellular functions. Mevalonate,Acid, Mevalonic
D002240 Carbohydrate Sequence The sequence of carbohydrates within POLYSACCHARIDES; GLYCOPROTEINS; and GLYCOLIPIDS. Carbohydrate Sequences,Sequence, Carbohydrate,Sequences, Carbohydrate
D002460 Cell Line Established cell cultures that have the potential to propagate indefinitely. Cell Lines,Line, Cell,Lines, Cell
D005231 Fatty Acids, Unsaturated FATTY ACIDS in which the carbon chain contains one or more double or triple carbon-carbon bonds. Fatty Acids, Polyunsaturated,Polyunsaturated Fatty Acid,Unsaturated Fatty Acid,Polyunsaturated Fatty Acids,Acid, Polyunsaturated Fatty,Acid, Unsaturated Fatty,Acids, Polyunsaturated Fatty,Acids, Unsaturated Fatty,Fatty Acid, Polyunsaturated,Fatty Acid, Unsaturated,Unsaturated Fatty Acids
D006904 Hydroxymethylglutaryl-CoA Synthase An enzyme that catalyzes the synthesis of hydroxymethylglutaryl-CoA from acetyl-CoA and acetoacetyl-CoA. This is a key enzyme in steroid biosynthesis. This enzyme was formerly listed as EC 4.1.3.5. HMG CoA Synthase,3-hydroxy-3-methylglutaryl-coenzyme A synthase,HMG-CoA synthase,3 hydroxy 3 methylglutaryl coenzyme A synthase,A synthase, 3-hydroxy-3-methylglutaryl-coenzyme,CoA Synthase, HMG,Hydroxymethylglutaryl CoA Synthase,Synthase, HMG CoA,Synthase, Hydroxymethylglutaryl-CoA,synthase, 3-hydroxy-3-methylglutaryl-coenzyme A,synthase, HMG-CoA
D000085 Acetates Derivatives of ACETIC ACID. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the carboxymethane structure. Acetate,Acetic Acid Esters,Acetic Acids,Acids, Acetic,Esters, Acetic Acid

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