TA-3037A, a new inhibitor of glutathione S-transferase, produced by actinomycetes. I. Production, isolation, physico-chemical properties and biological activities.

TA-3037A, a new inhibitor of glutathione S-transferase was discovered in the fermentation broth of Streptomyces sp. TA-3037. It was purified by chromatography followed by solvent extraction and then isolated as yellow needles. TA-3037A has the molecular formula of C16H11NO4. It was competitive with the substrate, and the inhibition constant (Ki) was 4.9 microM.

TA-3037A, a new inhibitor of glutathione S-transferase, produced by actinomycetes. II. Structure determination.

TA-3037A, a new inhibitor of glutathione S-transferase, has been isolated from the culture broth of Streptomyces sp. TA-3037. The structure of TA-3037A was defined as (Z)-3-benzylidene-3,4-dihydro-2-oxo-2H-1,4-benzoxazine-5-carboxylic acid by an analysis of spectral properties and chemical studies of TA-3037A and its derivatives.

Isolation and biosynthesis of 3 alpha-hydroxy-3,5-dihydromonacolin L.

3 alpha-Hydroxy-3,5-dihydromonacolin L acid (acid form), a new compound related to monacolin K (mevinolin), was isolated from the culture broth of a strain of Monascus ruber. The structure of the compound was determined by a combination of physical techniques. 4a,5-Dihydromonacolin L was converted to 3 alpha-hydroxy-3,5-dihydromonacolin L by a cell-free extract of M. ruber in the presence of molecular oxygen. The results demonstrate that the former is the direct precursor in the biosynthesis of the latter.

Biosynthesis of monacolins: conversion of monacolin L to monacolin J by a monooxygenase of Monascus ruber.

The microbial metabolites monacolins J and L are specific inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in cholesterol synthesis. The producing strain Monascus ruber M 4681 was found to convert exogenously added monacolin L to J. In this hydroxylation reaction 18O2 was incorporated into monacolin L, giving [18O]-monacolin J. The cell-free extracts of M. ruber quantitatively hydroxylated monacolin L to J, and molecular oxygen was required for the hydroxylation. The enzyme was located in the microsomal fraction and specific for NADPH. The enzyme activity was inhibited by metyrapone, carbon monoxide, sulfhydryl reagents and cytochrome c. The results indicate that monacolin L is the precursor of monacolin J, and that a monooxygenase is involved in this reaction.

Monacolin M, a new inhibitor of cholesterol biosynthesis.

Monacolin M, a new specific inhibitor of cholesterol biosynthesis structurally related to monacolin K (mevinolin), was isolated from cultures of a strain of Monascus ruber. The structure of monacolin M was determined to be beta-hydroxybutyryl ester of monacolin J by a combination of physical techniques. It was suggested that monacolin M is derived from monacolin J via a synthetic pathway distinct from that for the synthesis of monacolin K, alpha-methylbutyryl ester of monacolin J. The inhibitory effect of monacolin M on beta-hydroxy-beta-methylglutaryl-CoA reductase was slightly lower than that of monacolin K.

Microbial conversion of compactin (ML-236B) to ML-236A.

Approximately 1,600 fungal strains were tested for ability to convert compactin (ML-236B) to ML-236A and Emericella unguis IFO 8087 was found to be the most active. E. unguis converted ML-236B to ML-236A with a yield of over 90%.