Selective inhibition of cholesterol synthesis by cell-free preparations of rat liver by using inhibitors of cytoplasmic acetoacetyl-coenzyme A thiolase.
Cytoplasmic acetoacetyl-CoA thiolase (acetyl-CoA C-acetyltransferase, EC 2.3.1.9) was partially purified from rat liver. The enzyme was irreversibly inactivated by 4-bromocrotonyl-CoA, but-3-ynoyl-CoA, pent-3-ynoyl-CoA and dec-3-ynoyl-CoA. In the case of the alk-3-ynoyl-CoA esters the potency as alkylating agents of acetoacetyl-CoA thiolase decreased with increased chain length of the alk-3-ynoyl moiety. Advantage was taken of the specific action of alk-3-ynoyl-CoA esters on acetoacetyl-CoA thiolase to show that in a postmitochondrial fraction from rat liver they are effective inhibitors of cholesterol synthesis from sodium [2-14C]acetate under conditions when mevalonate conversion into cholesterol and fatty acid synthesis are unafffected. Short-chain alk-3-ynoic acids have little effect on sterol synthesis, although dec-3-ynoic acid is an effective inhibitor owing to its conversion into the CoA ester by the microsomal fatty acyl-CoA synthetase.
D000085:Acetates / Q000378:metabolism; D000101:Acetyl-CoA C-Acetyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000477:Alkylating Agents; D000818:Animals; D001665:Binding Sites; D002784:Cholesterol / Q000096:biosynthesis*; D003066:Coenzyme A Ligases / Q000032:analysis; D003600:Cytosol; D007527:Isoenzymes; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D051381:Rats
D000085:Acetates; D000477:Alkylating Agents; D007527:Isoenzymes; D002784:Cholesterol; D000123:Acetyltransferases; D000101:Acetyl-CoA C-Acetyltransferase; D003066:Coenzyme A Ligases