Squalestatin 1, a potent inhibitor of squalene synthase, which lowers serum cholesterol in vivo

Squalestatin 1 is a member of a novel family of fermentation products isolated from a previously unknown Phoma species (Coelomycetes). Squalestatin 1 is a potent, selective inhibitor of squalene synthase, a key enzyme in cholesterol biosynthesis; in vitro, 50% inhibition of enzyme activity is observ...

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Published in:The Journal of biological chemistry 1992-06, Vol.267 (17), p.11705-11708
Main Authors: BAXTER, A, FITZGERALD, B. J, WRIGHT, C, HUTSON, J. L, MCCARTHY, A. D, MOTTERAM, J. M, ROSS, B. C, SAPRA, M, SNOWDEN, M. A, WATSON, N. S, WILLIAMS, R. J
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Animals
Apolipoprotein A-I - metabolism
Apolipoproteins B - blood
Biological and medical sciences
biosynthesis
Bridged Bicyclo Compounds - pharmacology
Bridged Bicyclo Compounds, Heterocyclic
Callithrix
Cells, Cultured
cholesterol
Cholesterol - biosynthesis
Cholesterol - blood
Enzymes and enzyme inhibitors
Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors
Farnesyl-Diphosphate Farnesyltransferase - metabolism
Fundamental and applied biological sciences. Psychology
hepatocytes
inhibition
Liver - cytology
Liver - metabolism
Male
Phoma
Rats
squalestatin 1
Tricarboxylic Acids - pharmacology
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Summary:Squalestatin 1 is a member of a novel family of fermentation products isolated from a previously unknown Phoma species (Coelomycetes). Squalestatin 1 is a potent, selective inhibitor of squalene synthase, a key enzyme in cholesterol biosynthesis; in vitro, 50% inhibition of enzyme activity is observed at a concentration of 12 +/- 5 nM (range of 4-22 nM). Squalestatin 1 inhibits cholesterol biosynthesis from [14C]acetate by isolated rat hepatocytes (50% inhibition at 39 nM) and by rat liver in vivo. In marmosets, a species with a lipoprotein profile similar to that of man, squalestatin 1 lowers serum cholesterol by up to 75%. This compound will allow further investigation of the control of the sterol biosynthesis pathway and could also lead to the development of new therapies for elevated serum cholesterol.
ISSN:0021-9258
1083-351X
DOI:10.1016/s0021-9258(19)49754-8