Hydroxymethylglutaryl-CoA synthase

In biochemistry, hydroxymethylglutaryl-CoA synthase or 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). This reaction comprises the second step in the mevalonate-dependent isoprenoid biosynthesis 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.

3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (soluble)
Identifiers
Symbol	HMGCS1
Alt. symbols	HMGCS
NCBI gene	3157
HGNC	5007
OMIM	142940
RefSeq	NM_002130
UniProt	Q01581
Other data
EC number	2.3.3.10
Locus	Chr. 5 p14-p13
Search for Structures Swiss-model Domains InterPro

3-hydroxy-3-methylglutaryl-Coenzyme A synthase 2 (mitochondrial)
Identifiers
Symbol	HMGCS2
NCBI gene	3158
HGNC	5008
OMIM	600234
RefSeq	NM_005518
UniProt	P54868
Other data
Locus	Chr. 1 p13-p12
Search for Structures Swiss-model Domains InterPro

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
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

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
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

HMG-CoA synthase reaction

acetyl-CoA + H₂O + acetoacetyl-CoA $\rightleftharpoons$ (S)-3-hydroxy-3-methylglutaryl-CoA + CoA

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.

Classification

This enzyme belongs to the family of transferases, specifically those acyltransferases that convert acyl groups into alkyl groups on transfer.

Nomenclature

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.

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.

Biological role

This enzyme participates in 3 metabolic pathways: synthesis and degradation of ketone bodies, valine, leucine and isoleucine degradation, and butanoate metabolism.

Species distribution

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

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.

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. 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.

Structural studies

As of late 2007, 4 structures have been solved for this class of enzymes, with PDB accession codes 1XPK, 1XPL, 1XPM, and 2P8U.

External links

• HMG-CoA+synthase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

References

• RUDNEY H (1957). "The biosynthesis of beta-hydroxy-beta-methylglutaric acid". J. Biol. Chem. 227 (1): 363–77. doi:10.1016/S0021-9258(18)70822-3. PMID 13449080.

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

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