HMGCS2

3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial) is an enzyme in humans that is encoded by the HMGCS2 gene.^[5]

HMGCS2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2WYA
Identifiers
Aliases	HMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2
External IDs	OMIM: 600234; MGI: 101939; HomoloGene: 38066; GeneCards: HMGCS2; OMA:HMGCS2 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1p12 Start 119,748,002 bp[1] End 119,768,905 bp[1]
Gene location (Mouse) Chr. Chromosome 3 (mouse)[2] Band 3 F2.2|3 42.74 cM Start 98,187,751 bp[2] End 98,218,054 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right lobe of liver mucosa of transverse colon jejunal mucosa rectum mucosa of sigmoid colon duodenum renal medulla human kidney thoracic diaphragm apex of heart Top expressed in left lobe of liver lumbar spinal ganglion Stroma of ovary migratory enteric neural crest cell retinal pigment epithelium duodenum gastrula tunica media of zone of aorta vestibular sensory epithelium sexually immature organism More reference expression data BioGPS n/a
Gene ontology Molecular function transferase activity catalytic activity hydroxymethylglutaryl-CoA synthase activity Cellular component mitochondrion mitochondrial matrix Biological process steroid metabolic process sterol biosynthetic process lipid metabolism cholesterol metabolic process isoprenoid biosynthetic process cholesterol biosynthetic process metabolism steroid biosynthetic process ketone body biosynthetic process regulation of lipid metabolic process acetyl-CoA metabolic process farnesyl diphosphate biosynthetic process, mevalonate pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3158 15360 Ensembl ENSG00000134240 ENSMUSG00000027875 UniProt P54868 P54869 RefSeq (mRNA) NM_001166107 NM_005518 NM_008256 RefSeq (protein) NP_001159579 NP_005509 NP_032282 Location (UCSC) Chr 1: 119.75 – 119.77 Mb Chr 3: 98.19 – 98.22 Mb PubMed search [3] [4]
Wikidata
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The protein encoded by this gene belongs to the HMG-CoA synthase family. It is a mitochondrial enzyme that catalyzes the second and rate-limiting reaction of ketogenesis, a metabolic pathway that provides lipid-derived energy for various organs during times of carbohydrate deprivation, such as fasting, by addition of a third acetyl group to acetoacetyl-CoA, producing HMG-CoA.^[6]

Alternatively spliced transcript variants encoding different isoforms have been found for this gene.^[5]

Clinical significance

Mutations in this gene are associated with mitochondrial HMG-CoA synthase deficiency (also known as HMGCS2D), affecting ketone body synthesis.^[7] Affected patients are unable to perform ketogenesis during starvation and times of higher energy need such as fever and vigorous exercise. Commonly found is damage to heart muscles and the brain, along with hypoglycemia (not always present)^[8] and elevated blood fatty acid concentration. The mortality rate is 20%.^[9] Urine organic acid analysis can be used to detect likely cases, which can be further confirmed using DNA sequencing.^[10]

Occurrence

HMGCS2 deficiency is a rare disorder in humans, with fewer than 20 patients reported worldwide^[9] HMGCS2 is not found in cetaceans, elephantids, or Old World fruit bats. Fruit bats are known to be very sensitive to starvation, similar to humans with HMGCS2D. The other two groups seem to have evolved other means of coping with starvation.^[11]