Cytosolic modulators of activities of microsomal enzymes of cholesterol biosynthesis. Effects of Acyl-CoA inhibition and cytosolic Z-protein.
Physiological concentrations of long-chain fatty acyl-CoAs have now been shown to inhibit microsomal methyl sterol oxidase. Acyl-CoA inhibition of hydroxymethylglutaryl-CoA reductase as well as methyl sterol oxidase can be either prevented or reversed by the addition of purified Z-protein (fatty acid-binding protein). Concomitantly, Z-protein addition decreases the extent of binding of radioactively labeled oleoyl-CoA to microsomal membranes. Free heme also inhibits hydroxymethylglutaryl-CoA reductase, and Z-protein reverses the extent of observed inhibition by binding heme analogous to the effect observed with acyl-CoAs. Similarly, Z-protein reverses substrate inhibition of acyl-CoA:cholesterol acyltransferase at high concentrations of acyl-CoA substrate. All these observations are consistent with the suggestion that, by binding acyl-CoAs and other enzyme effectors such as free heme, Z-protein modulates the effects of fluctuations of concentrations of major cellular metabolites. Furthermore, because the concentration of Z-protein is very low in rapidly growing hepatomas, such tumors may be very poorly buffered against the effects of acyl-CoAs, free fatty acids, heme and other effectors that may vary markedly by either altered metabolism or release of metabolites from necrotic tumor tissue.
D000214:Acyl Coenzyme A / Q000494:pharmacology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis*; D003600:Cytosol / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D002785:Sterol O-Acyltransferase / Q000378:metabolism
D000214:Acyl Coenzyme A; D002352:Carrier Proteins; D050556:Fatty Acid-Binding Proteins; D002784:Cholesterol; D006899:Mixed Function Oxygenases; D006903:Hydroxymethylglutaryl CoA Reductases; C027532:methylsterol monooxygenase; D002785:Sterol O-Acyltransferase