In molecular biology, hydroxymethylglutaryl-CoA synthase or HMG-CoA synthaseEC 2.3.3.10 is an enzyme which catalyzes the reaction in which acetyl-CoA condenses with acetoacetyl-CoA to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). This reaction comprises the second step in the mevalonate-dependent isoprenoidbiosynthesis pathway. 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. This results in shunting of excess acetyl-CoA into the ketone synthesis pathway via HMG-CoA, leading to the development of diabetic ketoacidosis.
The 3 substrates of this enzyme are acetyl-CoA, H2O, and acetoacetyl-CoA, whereas its two products are (S)-3-hydroxy-3-methylglutaryl-CoA and CoA.
In humans, the protein is encoded by the HMGCS1 gene on chromosome 5.
. . . Hydroxymethylglutaryl-CoA synthase . . .
This enzyme belongs to the family of transferases, specifically those acyltransferases that convert acyl groups into alkyl groups on transfer.
The systematic name of this enzyme class is acetyl-CoA:acetoacetyl-CoA C-acetyltransferase (thioester-hydrolysing, carboxymethyl-forming). Other names in common use include (S)-3-hydroxy-3-methylglutaryl-CoA acetoacetyl-CoA-lyase, (CoA-acetylating), 3-hydroxy-3-methylglutaryl CoA synthetase, 3-hydroxy-3-methylglutaryl coenzyme A synthase, 3-hydroxy-3-methylglutaryl coenzyme A synthetase, 3-hydroxy-3-methylglutaryl-CoA synthase, 3-hydroxy-3-methylglutaryl-coenzyme A synthase, beta-hydroxy-beta-methylglutaryl-CoA synthase, HMG-CoA synthase, acetoacetyl coenzyme A transacetase, hydroxymethylglutaryl coenzyme A synthase, and hydroxymethylglutaryl coenzyme A-condensing enzyme.
HMG-CoA synthase contains an important catalyticcysteine residue that acts as a nucleophile in the first step of the reaction: the acetylation of the enzyme by acetyl-CoA (its first substrate) to produce an acetyl-enzyme thioester, releasing the reducedcoenzyme A. The subsequent nucleophilic attack on acetoacetyl-CoA (its second substrate) leads to the formation of HMG-CoA.[1]
. . . Hydroxymethylglutaryl-CoA synthase . . .