3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR)

3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) is the rate-limiting enzyme in the mevalonate pathway, responsible for the conversion of HMG-CoA to mevalonic acid, a precursor for cholesterol and other isoprenoids[1][8]. It is anchored in the membrane of the endoplasmic reticulum and contains a sterol-sensing domain and a catalytic domain[1][7][9]. HMGCR activity is a critical control point in cholesterol homeostasis and is tightly regulated at transcriptional, translational, and protein degradation levels[1][7]. It is the therapeutic target for statins, a major drug class for lowering blood cholesterol and treating and preventing cardiovascular disease[2][4][6][8]. HMGCR inhibition leads to decreased synthesis of cholesterol and increased expression of hepatic LDL receptors, which together produce substantial reductions in plasma LDL cholesterol and improve cardiovascular outcomes[4][6]. Statin efficacy and safety profiles are influenced by the enzyme's biochemical and structural properties, including its membrane association, multimeric structure, and regulatory mechanisms[5][7].

Other names

HMG-CoA reductaseHMGRHydroxymethylglutaryl-CoA reductase3-hydroxy-3-methylglutaryl coenzyme A reductase

Competitive inhibition of HMG-CoA reductase active site, preventing conversion of HMG-CoA to mevalonate (the rate-limiting step in cholesterol synthesis) Allosteric/conformational changes reducing enzyme activity