The effect of substrates and competitive inhibitors on the phosphatase-dependent activation of hepatic hydroxymethylglutaryl CoA reductase.
Previous studies have demonstrated that the in vitro activation of microsomal hepatic hydroxymethylglutaryl (HMG) CoA reductase by dephosphorylation is inhibited by HMG CoA or NADPH, the substrates of HMG CoA reductase (13). In the present study the effect of three competitive inhibitors of HMG CoA reductase on the activation of HMG CoA reductase was investigated. Adenosine-2'-monophospho-5'-diphosphoribose, a competitive inhibitor for the NADPH binding site, blocked the phosphatase-mediated activation of HMG CoA reductase. By contrast, neither compactin nor mevinolin, competitive inhibitors for the HMG CoA binding site, altered the activation of HMG CoA reductase. Moreover, the HMG CoA-mediated inhibition of the activation of HMG CoA reductase was not blocked even by very high concentrations of either compactin or mevinolin. These observations suggest that HMG CoA can bind to two sites on HMG CoA reductase. One site of HMG CoA binding serves as a catalytic site and is competitively blocked by compactin or mevinolin, and the second binding site is an allosteric site to which only HMG CoA is capable of binding. The binding of HMG CoA to this second site inhibits the activation of HMG CoA reductase by phosphatases.
D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin / Q000031:analogs & derivatives; D008862:Microsomes, Liver / Q000201:enzymology*; D009281:Naphthalenes / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D051381:Rats
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009281:Naphthalenes; C020857:phosphoadenosine diphosphoribose; C012258:mevastatin; D000246:Adenosine Diphosphate Ribose; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D010744:Phosphoric Monoester Hydrolases