HMGCS2

Protein-coding gene in the species Homo sapiens
HMGCS2
Available structures
PDBOrtholog search: PDBe RCSB
List of PDB id codes

2WYA

Identifiers
AliasesHMGCS2, 3-hydroxy-3-methylglutaryl-CoA synthase 2
External IDsOMIM: 600234; MGI: 101939; HomoloGene: 38066; GeneCards: HMGCS2; OMA:HMGCS2 - orthologs
Gene location (Human)
Chromosome 1 (human)
Chr.Chromosome 1 (human)[1]
Chromosome 1 (human)
Genomic location for HMGCS2
Genomic location for HMGCS2
Band1p12Start119,748,002 bp[1]
End119,768,905 bp[1]
Gene location (Mouse)
Chromosome 3 (mouse)
Chr.Chromosome 3 (mouse)[2]
Chromosome 3 (mouse)
Genomic location for HMGCS2
Genomic location for HMGCS2
Band3 F2.2|3 42.74 cMStart98,187,751 bp[2]
End98,218,054 bp[2]
RNA expression pattern
Bgee
HumanMouse (ortholog)
Top expressed in
  • right lobe of liver

  • jejunal mucosa

  • rectum

  • duodenum

  • renal medulla

  • kidney

  • thoracic diaphragm

  • mucosa of urinary bladder

  • body of stomach

  • kidney tubule
Top expressed in
  • left lobe of liver

  • retinal pigment epithelium

  • duodenum

  • sexually immature organism

  • testicle

  • uterus

  • seminiferous tubule

  • stria vascularis

  • left colon

  • carotid body
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
SpeciesHumanMouse
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 MbChr 3: 98.19 – 98.22 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

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 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]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000134240 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027875 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: 3-hydroxy-3-methylglutaryl-CoA synthase 2 (mitochondrial)".
  6. ^ Drabbe S, Pelzer A, Slenter D, Willighagen E (February 2023). "Disorders in ketone body synthesis (Homo sapiens)". Wiki Pathways.
  7. ^ Aledo R, Mir C, Dalton RN, Turner C, Pié J, Hegardt FG, et al. (February 2006). "Refining the diagnosis of mitochondrial HMG-CoA synthase deficiency". Journal of Inherited Metabolic Disease. 29 (1): 207–211. doi:10.1007/s10545-006-0214-2. PMID 16601895. S2CID 24866271.
  8. ^ Conlon, TA; Fitzsimons, PE; Borovickova, I; Kirby, F; Murphy, S; Knerr, I; Crushell, E (September 2020). "Hypoglycemia is not a defining feature of metabolic crisis in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: Further evidence of specific biochemical markers which may aid diagnosis". JIMD Reports. 55 (1): 26–31. doi:10.1002/jmd2.12146. PMC 7463059. PMID 32905056.
  9. ^ 丹, 马; 丹, 俞 (11 November 2018). "线粒体3-羟基3-甲基戊二酰辅酶A合成酶缺乏症1例并文献复习" [Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase deficiency: a case report and literature review]. Chinese Journal of Contemporary Pediatrics (in Chinese). 20 (11): 930–933. doi:10.7499/j.issn.1008-8830.2018.11.010. ISSN 1008-8830. PMC 7389032. PMID 30477625.
  10. ^ Conlon, TA; Fitzsimons, PE; Borovickova, I; Kirby, F; Murphy, S; Knerr, I; Crushell, E (September 2020). "Hypoglycemia is not a defining feature of metabolic crisis in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: Further evidence of specific biochemical markers which may aid diagnosis". JIMD Reports. 55 (1): 26–31. doi:10.1002/jmd2.12146. PMC 7463059. PMID 32905056.
  11. ^ Jebb D, Hiller M (October 2018). "Recurrent loss of HMGCS2 shows that ketogenesis is not essential for the evolution of large mammalian brains". eLife. 7: e38906. doi:10.7554/eLife.38906. PMC 6191284. PMID 30322448.

External links

  • Overview of all the structural information available in the PDB for UniProt: P54868 (Human Hydroxymethylglutaryl-CoA synthase, mitochondrial) at the PDBe-KB.


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2.3.1: other than amino-acyl groups2.3.2: Aminoacyltransferases2.3.3: converted into alkyl on transfer
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