In molecular biology, HMG-CoA synthase EC 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). It is the second reaction in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA is an intermediate in both cholesterol synthesis and ketogenesis. This reaction is over-activated 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.
HMG-CoA synthase reaction
Mechanism [edit]
HMG-CoA synthase contains an important catalytic cysteine 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 reduced coenzyme A. The subsequent nucleophilic attack on acetoacetyl-CoA (its second substrate) leads to the formation of HMG-CoA.[1]
Species distribution [edit]
HMG-CoA synthase occurs in eukaryotes, archaea and certain bacteria.[2]
Eukaryotes [edit]
In vertebrates, there are two different isozymes of the enzyme (cytosolic and mitochondrial); in humans the cytosolic form has only 60.6% amino acid identity with the mitochondrial form of the enzyme. HMG-CoA is also found in other eukaryotes such as insects, plants and fungi.[3]
Cytosolic [edit]
The cytosolic form is the starting point of the mevalonate pathway, which leads to cholesterol and other sterolic and isoprenoid compounds).
Mitochondrial [edit]
The mitochondrial form is responsible for the biosynthesis of ketone bodies. The gene for the mitochondrial form of the enzyme has three sterol regulatory elements in the 5' flanking region.[4] These elements are responsible for decreased transcription of the message responsible for enzyme synthesis when dietary cholesterol is high in animals: the same is observed for 3-hydroxy-3-methylglutaryl-CoA and the low density lipoprotein receptor.
Bacteria [edit]
In bacteria, isoprenoid precursors are generally synthesised via an alternative, non-mevalonate pathway, however a number of Gram-positive pathogens utilise a mevalonate pathway involving HMG-CoA synthase that is parallel to that found in eukaryotes.[5][6]
External links [edit]
References [edit]
- ^ Theisen MJ, Misra I, Saadat D, Campobasso N, Miziorko HM, Harrison DH (November 2004). "3-hydroxy-3-methylglutaryl-CoA synthase intermediate complex observed in "real-time"". Proc. Natl. Acad. Sci. U.S.A. 101 (47): 16442–7. doi:10.1073/pnas.0405809101. PMC 534525. PMID 15498869.
- ^ Bahnson BJ (November 2004). "An atomic-resolution mechanism of 3-hydroxy-3-methylglutaryl-CoA synthase". Proc. Natl. Acad. Sci. U.S.A. 101 (47): 16399–400. doi:10.1073/pnas.0407418101. PMC 534547. PMID 15546978.
- ^ Bearfield JC, Keeling CI, Young S, Blomquist GJ, Tittiger C (April 2006). "Isolation, endocrine regulation and mRNA distribution of the 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMG-S) gene from the pine engraver, Ips pini (Coleoptera: Scolytidae)". Insect Mol. Biol. 15 (2): 187–95. doi:10.1111/j.1365-2583.2006.00627.x. PMID 16640729.
- ^ Goldstein J.L., Brown M.S. (1990) Regulation of the mevalonate pathway. Nature 343, 425-430
- ^ Steussy CN, Robison AD, Tetrick AM, Knight JT, Rodwell VW, Stauffacher CV, Sutherlin AL (December 2006). "A structural limitation on enzyme activity: the case of HMG-CoA synthase". Biochemistry 45 (48): 14407–14. doi:10.1021/bi061505q. PMID 17128980.
- ^ Steussy CN, Vartia AA, Burgner JW, Sutherlin A, Rodwell VW, Stauffacher CV (November 2005). "X-ray crystal structures of HMG-CoA synthase from Enterococcus faecalis and a complex with its second substrate/inhibitor acetoacetyl-CoA". Biochemistry 44 (43): 14256–67. doi:10.1021/bi051487x. PMID 16245942.
This article incorporates text from the public domain Pfam and InterPro IPR013746 This article incorporates text from the public domain Pfam and InterPro IPR013528
