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
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

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

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

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

HMG-CoA synthase occurs in eukaryotes, archaea and certain bacteria.[2]

Eukaryotes

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

The cytosolic form is the starting point of the mevalonate pathway, which leads to cholesterol and other sterolic and isoprenoid compounds).

Mevalonate pathway

Mitochondrial

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.

Ketogenesis

Bacteria

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

References

  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. 
2.3.1: other than amino-acyl groups
2.3.2: Aminoacyltransferases
2.3.3: converted into alkyl on transfer
  • B
  • enzm
  • 1.1
    • 2
    • 3
    • 4
    • 5
    • 6
    • 7
    • 8
    • 10
    • 11
    • 13
    • 14
    • 15-18
  • 2.1
    • 2
    • 3
    • 4
    • 5
    • 6
    • 7
      • 2.7.10
      • 11-12
    • 8
  • 3.1
      • 3.1.3.48
    • 2
    • 3
    • 4
      • 3.4.21
      • 22
      • 23
      • 24
    • 5
    • 6
    • 7
  • 4.1
    • 2
    • 3
    • 4
    • 5
    • 6
  • 5.1
    • 2
    • 3
    • 4
    • 99
  • 6.1-3
    • 4
    • 5-6
Synthesis
Malonyl-CoA synthesis
Fatty acid desaturases
Triacyl glycerol
Degradation
Acyl transport
General
Unsaturated
Odd chain
Other

M: MET

mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m

k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon

m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)

Metabolism: lipid metabolism – ketones/cholesterol synthesis enzymes/steroid metabolism
Mevalonate pathway
To HMG-CoA
Ketogenesis
To Mevalonic acid
To DMAPP
Geranyl-
To cholesterol
To lanosterol
7-Dehydrocholesterol path
Desmosterol path
To Bile acids
Steroidogenesis
To pregnenolone
To corticosteroids
To sex hormones
To androgens
To estrogens
Other/ungrouped

M: MET

mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m

k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon

m (A16/C10), i (k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)

M: END

anat/phys/devp/horm

noco (d)/cong/tumr, sysi/epon

proc, drug (A10/H1/H2/H3/H5)

This article incorporates text from the public domain Pfam and InterPro IPR013746 This article incorporates text from the public domain Pfam and InterPro IPR013528

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