Hydroxymethylglutaryl-CoA synthase

Last updated
3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (soluble)
Identifiers
SymbolHMGCS1
Alt. symbolsHMGCS
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
SymbolHMGCS2
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
PDB 1txt EBI.jpg
staphylococcus aureus 3-hydroxy-3-methylglutaryl-coa synthase
Identifiers
SymbolHMG_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
PDB 1txt EBI.jpg
staphylococcus aureus 3-hydroxy-3-methylglutaryl-coa synthase
Identifiers
SymbolHMG_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

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.

Contents

HMG-CoA synthase reaction HMG-CoA synthase.svg
HMG-CoA synthase reaction


acetyl-CoA + H2O + acetoacetyl-CoA (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. [1]

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. [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 Mevalonate pathway.png
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 Ketogenesis.svg
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]

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.

Related Research Articles

<span class="mw-page-title-main">Leucine</span> Chemical compound

Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO form under biological conditions), and a side chain isobutyl group, making it a non-polar aliphatic amino acid. It is essential in humans, meaning the body cannot synthesize it: it must be obtained from the diet. Human dietary sources are foods that contain protein, such as meats, dairy products, soy products, and beans and other legumes. It is encoded by the codons UUA, UUG, CUU, CUC, CUA, and CUG. Leucine is named after the Greek word for "white": λευκός (leukós, "white"), after its common appearance as a white powder, a property it shares with many other amino acids.

<span class="mw-page-title-main">Acetyl-CoA</span> Chemical compound

Acetyl-CoA is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle to be oxidized for energy production.

Juvenile hormones (JHs) are a group of acyclic sesquiterpenoids that regulate many aspects of insect physiology. The first discovery of a JH was by Vincent Wigglesworth. JHs regulate development, reproduction, diapause, and polyphenisms.

<span class="mw-page-title-main">Mevalonate pathway</span> Series of interconnected biochemical reactions

The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are used to make isoprenoids, a diverse class of over 30,000 biomolecules such as cholesterol, vitamin K, coenzyme Q10, and all steroid hormones.

<span class="mw-page-title-main">HMG-CoA reductase</span> Mammalian protein found in Homo sapiens

HMG-CoA reductase is the rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. HMGCR catalyzes the conversion of HMG-CoA to mevalonic acid, a necessary step in the biosynthesis of cholesterol. Normally in mammalian cells this enzyme is competitively suppressed so that its effect is controlled. This enzyme is the target of the widely available cholesterol-lowering drugs known collectively as the statins, which help treat dyslipidemia.

<span class="mw-page-title-main">HMG-CoA</span> Chemical compound

β-Hydroxy β-methylglutaryl-CoA (HMG-CoA), also known as 3-hydroxy-3-methylglutaryl coenzyme A, is an intermediate in the mevalonate and ketogenesis pathways. It is formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase. The research of Minor J. Coon and Bimal Kumar Bachhawat in the 1950s at University of Illinois led to its discovery.

Methylcrotonyl CoA carboxylase is a biotin-requiring enzyme located in the mitochondria. MCC uses bicarbonate as a carboxyl group source to catalyze the carboxylation of a carbon adjacent to a carbonyl group performing the fourth step in processing leucine, an essential amino acid.

<span class="mw-page-title-main">3-Hydroxy-3-methylglutaryl-CoA lyase</span> Class of enzymes

3-Hydroxy-3-methylglutaryl-CoA lyase is an enzyme (EC 4.1.3.4 that in human is encoded by the HMGCL gene located on chromosome 1. It is a key enzyme in ketogenesis. It is a ketogenic enzyme in the liver that catalyzes the formation of acetoacetate from HMG-CoA within the mitochondria. It also plays a prominent role in the catabolism of the amino acid leucine.

<span class="mw-page-title-main">Lanosterol synthase</span> Mammalian protein found in Homo sapiens

Lanosterol synthase (EC 5.4.99.7) is an oxidosqualene cyclase (OSC) enzyme that converts (S)-2,3-oxidosqualene to a protosterol cation and finally to lanosterol. Lanosterol is a key four-ringed intermediate in cholesterol biosynthesis. In humans, lanosterol synthase is encoded by the LSS gene.

<span class="mw-page-title-main">Acetoacetyl-CoA</span> Chemical compound

Acetoacetyl CoA is the precursor of HMG-CoA in the mevalonate pathway, which is essential for cholesterol biosynthesis. It also takes a similar role in the ketone bodies synthesis (ketogenesis) pathway of the liver. In the ketone bodies digestion pathway, it is no longer associated with having HMG-CoA as a product or as a reactant.

<span class="mw-page-title-main">Thiolase</span> Enzymes

Thiolases, also known as acetyl-coenzyme A acetyltransferases (ACAT), are enzymes which convert two units of acetyl-CoA to acetoacetyl CoA in the mevalonate pathway.

<span class="mw-page-title-main">Isovaleryl-CoA</span> Chemical compound

Isovaleryl-coenzyme A, also known as isovaleryl-CoA, is an intermediate in the metabolism of branched-chain amino acids.

<span class="mw-page-title-main">Methylcrotonyl-CoA</span> Chemical compound

3-Methylcrotonyl-CoA is an intermediate in the metabolism of leucine.

<span class="mw-page-title-main">3-Methylglutaconyl-CoA</span> Chemical compound

3-Methylglutaconyl-CoA (MG-CoA), also known as β-methylglutaconyl-CoA, is an intermediate in the metabolism of leucine. It is metabolized into HMG-CoA.

<span class="mw-page-title-main">Hydroxymethylglutaryl-CoA reductase (NADPH)</span>

In enzymology, a hydroxymethylglutaryl-CoA reductase (NADPH) (EC 1.1.1.34) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Isovaleryl-CoA dehydrogenase</span>

In enzymology, an isovaleryl-CoA dehydrogenase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">ATP citrate synthase</span> Class of enzymes

ATP citrate synthase (also ATP citrate lyase (ACLY)) is an enzyme that in animals represents an important step in fatty acid biosynthesis. By converting citrate to acetyl-CoA, the enzyme links carbohydrate metabolism, which yields citrate as an intermediate, with fatty acid biosynthesis, which consumes acetyl-CoA. In plants, ATP citrate lyase generates cytosolic acetyl-CoA precursors of thousands of specialized metabolites, including waxes, sterols, and polyketides.

<span class="mw-page-title-main">HMG-CoA reductase family</span>

In molecular biology, the HMG-CoA reductase family is a family of enzymes which participate in the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids.

<span class="mw-page-title-main">HMGCS2</span> Protein-coding gene in the species Homo sapiens

3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) is an enzyme in humans that is encoded by the HMGCS2 gene.

<i>beta</i>-Hydroxy <i>beta</i>-methylbutyryl-CoA Chemical compound

β-Hydroxy β-methylbutyryl-coenzyme A (HMB-CoA), also known as 3-hydroxyisovaleryl-CoA, is a metabolite of L-leucine that is produced in the human body. Its immediate precursors are β-hydroxy β-methylbutyric acid (HMB) and β-methylcrotonoyl-CoA (MC-CoA). It can be metabolized into HMB, MC-CoA, and HMG-CoA in humans.

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. Bibcode:2004PNAS..10116399B. 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 Molecular Biology. 15 (2): 187–95. doi:10.1111/j.1365-2583.2006.00627.x. PMID   16640729. S2CID   46317830.
  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