HMG-CoA synthase

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3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (soluble)
Identifiers
Symbol HMGCS1
Alt. symbols HMGCS
Entrez 3157
HUGO 5007
OMIM 142940
RefSeq NM_002130
UniProt Q01581
Other data
EC number 2.3.3.10
Locus Chr. 5 p14-p13
3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (mitochondrial)
Identifiers
Symbol HMGCS2
Entrez 3158
HUGO 5008
OMIM 600234
RefSeq NM_005518
UniProt P54868
Other data
Locus Chr. 1 p13-p12
Hydroxymethylglutaryl-coenzyme A synthase N terminal
PDB 1txt EBI.jpg
staphylococcus aureus 3-hydroxy-3-methylglutaryl-coa synthase
Identifiers
Symbol HMG_CoA_synt_N
Pfam PF01154
Pfam clan CL0046
InterPro IPR013528
PROSITE PDOC00942
Hydroxymethylglutaryl-coenzyme A synthase C terminal
PDB 1txt EBI.jpg
staphylococcus aureus 3-hydroxy-3-methylglutaryl-coa synthase
Identifiers
Symbol HMG_CoA_synt_C
Pfam PF08540
Pfam clan CL0046
InterPro IPR013746
PROSITE PDOC00942

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]

  1. ^ 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. 
  2. ^ 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. 
  3. ^ 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. 
  4. ^ Goldstein J.L., Brown M.S. (1990) Regulation of the mevalonate pathway. Nature 343, 425-430
  5. ^ 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. 
  6. ^ 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