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HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, official symbol HMGCR) is the rate-controlling enzyme (NADH-dependent, EC 1.1.1.88; NADPH-dependent, EC 1.1.1.34) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids.
HMG-CoA synthase: Acetoacetyl-CoA condenses with another Acetyl-CoA molecule to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). HMG-CoA reductase: HMG-CoA is reduced to mevalonate by NADPH. This is the rate limiting step in cholesterol synthesis, which is why this enzyme is a good target for pharmaceuticals . mevalonate-5-kinase
The following reaction involves the joining of acetyl-CoA and acetoacetyl-CoA to form HMG-CoA, a process catalyzed by HMG-CoA synthase. [8] In the final step of mevalonate biosynthesis, HMG-CoA reductase, an NADPH-dependent oxidoreductase, catalyzes the conversion of HMG-CoA into mevalonate, which is the primary regulatory point in this pathway.
This molecule is then reduced to mevalonate by the enzyme HMG-CoA reductase. Production of mevalonate is the rate-limiting and irreversible step in cholesterol synthesis and is the site of action for statins (a class of cholesterol-lowering drugs). [citation needed]
HMG-CoA is an intermediate in both cholesterol synthesis and ketogenesis. This reaction is overactivated in patients with diabetes mellitus type 1 if left untreated, due to prolonged insulin deficiency and the exhaustion of substrates for gluconeogenesis and the TCA cycle , notably oxaloacetate .
In molecular biology, the HMG-CoA reductase family is a family of enzymes which participate in the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. There are two distinct classes of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase enzymes: class I consists of eukaryotic and most archaeal enzymes EC ...
The primary goal was to inhibit the cholesterol biosynthesis in the body. Hence HMG-CoA reductase (HMGR) became a natural target. HMGR was found to be the rate-limiting enzyme in the cholesterol biosynthetic pathway. There is no build-up of potentially toxic precursors when HMGR is inhibited, because hydroxymethylglutarate is water-soluble and ...
The 3 substrates of this enzyme are (R)-mevalonate, CoA, and NADP +, whereas its 3 products are -3-hydroxy-3-methylglutaryl-CoA, NADPH, and H +. This enzyme belongs to the family of oxidoreductases , to be specific those acting on the CH-OH group of donor with NAD + or NADP + as acceptor.