Abstract
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.
Highlights
From Glaxo Group Research Ltd., Greenford Road, Greenford, Middlesex UB6 OHE and SGlaxo Group Research Ltd., Park Road, Ware, Hertfordshire SG12 005, United Kingdom suitable for evaluation in uiuo
Is a potent, selective inhibitor of squalene synthase, a Materials-The isolation,characterization, and structural elucikey enzyme in cholesterol biosynthesis;in vitro, 50% dation of squalestatin 1 is described elsewhere
Squalestatin 1 inhibits cholesterol biosynthesis from [I4C]acetbayte isolated rat hepatocytes(50%inhibition at39 nM) and Sidebottom et al, 1992); the structure of this compound is shown in Fig. 1. [1-"CIAcetic acid, sodium salt, ["Clbicarbonate, [1,5-14C] citrate, [2-14C]farnesyl diphosphate (FPP),and RS-[5-3H]mevalonolactonweere from Amersham International
Summary
Is a potent, selective inhibitor of squalene synthase, a Materials-The isolation,characterization, and structural elucikey enzyme in cholesterol biosynthesis;in vitro, 50% dation of squalestatin 1 is described elsewhere (Dawson et al, 1992; inhibition of enzyme activity is observed at a concentration of 12 2 5 nM (range of 4-22 nM). Activity was measured using rat liver microsomes as enzyme source and a novel separation of substrates and products. This method is described in detail elsewhere (Tait, 1992),but briefly, after incubation of enzyme with [14C]FPP, threeaction mixture isabsorbed onto silica.
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