Although catalyzing a rate-limiting step in cholesterol biosynthesis is the best known role of HMG-CoA reductase, the enzyme also participates in the production of a wide variety of other compounds. Some clinical benefits attributed to inhibitors of HMG-CoA reductase appear to be independent of any serum cholesterol-lowering effect. Van Doren et al. (1998) described a new cholesterol-independent role for the enzyme, in regulating a developmental process, primordial germ cell migration. Van Doren et al. (1998) concluded that the regulated expression of HMG-CoA reductase has a critical developmental function in providing spatial information to guide migrating primordial germ cells.
In humans, the HMG-CoA reductase reaction is rate-limiting for the biosynthesis of cholesterol and therefore constitutes a prime target of drugs that reduce serum cholesterol levels. Recent advances in genome sequencing that permitted comparison of 50 HMG-CoA reductase sequences has revealed two previously unsuspected classes of this enzyme (Bochar et al., 1999).
NCBI Summary:
HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis and is regulated via a negative feedback mechanism mediated by sterols and non-sterol metabolites derived from mevalonate, the product of the reaction catalyzed by reductase. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, an important determinant of atherosclerosis.
General function
Metabolism, Enzyme, Oxidoreductase
Comment
Cellular localization
Cytoplasmic
Comment
3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is anchored to the endoplasmic reticulum (ER) membrane by a hydrophobic NH2-terminal domain that contains seven apparent membrane-spanning regions and a single N-linked carbohydrate chain. The catalytic domain, which includes the COOH-terminal two-thirds of the protein, extends into the cytoplasm (Jingami et al., 1987).
Activities of enzymes involved in cholesterol metabolism were measured in ovaries of PMS-hCG-primed immature rats. Microsomal 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme in sterol synthesis, was low during the period of maximal steroid production and cholesteryl ester storage (Schuler et al., 1981).
Expression regulated by
LH, cholesterol, cAMP
Comment
Ovarian localization
Granulosa, Luteal cells
Comment
Golos and Strauss, 1988 and "Luteal cell 3-hydroxy-3-methylglutaryl coenzyme-A reductase activity and cholesterol metabolism throughout pregnancy in the rat" (Azhar et al., 1988).