OXCT1

OXCT1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3DLX
Identifiers
Aliases	OXCT1, OXCT, SCOT, 3-oxoacid CoA-transferase 1
External IDs	OMIM: 601424; MGI: 1914291; HomoloGene: 377; GeneCards: OXCT1; OMA:OXCT1 - orthologs
Gene location (Human) Chr. Chromosome 5 (human) Band 5p13.1 Start 41,730,065 bp End 41,870,519 bp
Gene location (Mouse) Chr. Chromosome 15 (mouse) Band 15|15 A1 Start 4,055,865 bp End 4,184,826 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in myocardium of left ventricle right ventricle endothelial cell middle temporal gyrus cardiac muscle tissue of right atrium Achilles tendon orbitofrontal cortex Brodmann area 46 superior frontal gyrus postcentral gyrus Top expressed in epithelium of stomach myocardium of ventricle human kidney tunica media of zone of aorta medial dorsal nucleus lateral septal nucleus Rostral migratory stream lateral geniculate nucleus digastric muscle hair follicle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity protein homodimerization activity 3-oxoacid CoA-transferase activity CoA-transferase activity Cellular component mitochondrial matrix mitochondrion nucleoplasm Biological process response to nutrient response to activity heart development brain development ketone body catabolic process response to starvation response to hormone adipose tissue development ketone catabolic process positive regulation of insulin secretion involved in cellular response to glucose stimulus metabolism response to ethanol cellular ketone body metabolic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5019 67041 Ensembl ENSG00000083720 ENSMUSG00000022186 UniProt P55809 Q9D0K2 RefSeq (mRNA) NM_000436 NM_024188 RefSeq (protein) NP_000427 NP_001351228 NP_001351229 NP_001351230 NP_001351231 NP_001351232 NP_077150 Location (UCSC) Chr 5: 41.73 – 41.87 Mb Chr 15: 4.06 – 4.18 Mb PubMed search
Wikidata
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3-oxoacid CoA-transferase 1 (OXCT1) is an enzyme that in humans is encoded by the OXCT1 gene. It is also known as succinyl-CoA-3-oxaloacid CoA transferase (SCOT). Mutations in the OXCT1 gene are associated with succinyl-CoA:3-oxoacid CoA transferase deficiency. This gene encodes a member of the 3-oxoacid CoA-transferase gene family. The encoded protein is a homodimeric mitochondrial matrix enzyme that plays a central role in extrahepatic ketone body catabolism by catalyzing the reversible transfer of coenzyme A (CoA) from succinyl-CoA to acetoacetate.

Structure

Gene

The OXCT1 gene resides on chromosome 5 at the band 5p13. OXCT1 spans a length of over 100 kb and includes 17 exons.

Protein

The crystal structure of human OXCT1 reveals it to be a homodimer with two active sites. Each of its monomers contains N- and C-terminal domains that share an α/β structural fold characteristic of CoA transferase family I members. These terminal domains are joined by a linker region and form the enzyme's active site. Specifically, the conserved residue Glu344 within the active site is responsible for the enzyme's catalytic function by attacking the succinyl-CoA substrate, leading to the formation of the enzyme-CoA thioester intermediate.

Function

OXCT1 is a member of the CoA transferase family I, which is known to catalyze the transfer of CoA between carboxylic acid groups. In particular, OXCT1 catalyzes the first, rate-limiting step in ketolysis by transferring the CoA from succinyl-CoA to acetoacetate, giving acetoacetyl-CoA (AcAc-CoA). The product AcAc-CoA can then be converted by acetoacetyl-CoA thiolase into acetyl-CoA, which enters the citric acid cycle to generate energy for the cell. As a result, OXCT1 allows cells to utilize energy stored in ketone bodies synthesized by the liver during conditions of energy deficiency, such as low glucose levels. In addition, OXCT1 activity leads to the formation of Acetyl-CoA, which serves as a precursor for short-chain acyl-CoAs and lipids in the cytosol.

OXCT1 is found in the mitochondrial matrix of all tissues except the liver, though it is most abundantly expressed in heart, brain, and kidney tissue. Considering that liver cells function in ketogenesis and OXCT1 in ketolysis, OXCT1 may be absent from the liver to allow ketone body formation to proceed.

Clinical Significance

Metabolic disorders

SCOT deficiency is a rare autosomal recessive metabolic disorder that can lead to recurrent episodes of ketoacidosis and even permanent ketosis. Twenty-four mutations in the human OXCT1 gene have been identified and associated with SCOT deficiency: three nonsense mutations, two insertion mutations, and 19 missense mutations. These mutations alter OXCT1 form and thus function in various ways, and they determine what phenotypic complications a patient may present. For instance, several missense mutations that substitute bulkier or charged residues hinder proper folding of OXCT1, leading to more severe outcomes such as permanent acidosis.

OXCT1 has also been implicated diabetes. In a study by MacDonald et al., OXCT1 activity was shown to be lower by 92% in pancreatic islets of human patients with type 2 diabetes compared to those in healthy patients, though the cause is currently unknown.

Cancer

Since OXCT1 functions in metabolizing ketone bodies, it has been proposed to promote tumor growth by providing tumor cells with an additional energy source. Therefore, ketone inhibitors may prove effective in treating patients experiencing recurring and metastatic tumors. A proteomics study identified OXCT1 to be one of 16 proteins upregulated in carcinoma HepG2 cells treated with Platycodin D, an anti-cancer agent.

See also

• Succinyl-CoA:3-oxoacid CoA transferase deficiency

Further reading

• Pérez-Cerdá C, Merinero B, Sanz P, Jiménez A, Hernández C, García MJ, Ugarte M (1992). "A new case of succinyl-CoA: acetoacetate transferase deficiency". Journal of Inherited Metabolic Disease. 15 (3): 371–3. doi:10.1007/BF02435979. PMID 1405472. S2CID 13058612.
• Zołnierowicz S, Scisłowski PW, Swierczyński J, Zelewski L (1985). "Acetoacetate utilization by human placental mitochondria". Placenta. 5 (3): 271–6. doi:10.1016/S0143-4004(84)80037-5. PMID 6150478.
• Fukao T, Song XQ, Mitchell GA, Yamaguchi S, Sukegawa K, Orii T, Kondo N (October 1997). "Enzymes of ketone body utilization in human tissues: protein and messenger RNA levels of succinyl-coenzyme A (CoA):3-ketoacid CoA transferase and mitochondrial and cytosolic acetoacetyl-CoA thiolases". Pediatric Research. 42 (4): 498–502. doi:10.1203/00006450-199710000-00013. PMID 9380443.
• Song XQ, Fukao T, Watanabe H, Shintaku H, Hirayama K, Kassovska-Bratinova S, Kondo N, Mitchell GA (1998). "Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency: two pathogenic mutations, V133E and C456F, in Japanese siblings". Human Mutation. 12 (2): 83–8. doi:10.1002/(SICI)1098-1004(1998)12:2<83::AID-HUMU2>3.0.CO;2-P. PMID 9671268. S2CID 42111273.
• Tanaka H, Kohroki J, Iguchi N, Onishi M, Nishimune Y (January 2002). "Cloning and characterization of a human orthologue of testis-specific succinyl CoA: 3-oxo acid CoA transferase (Scot-t) cDNA". Molecular Human Reproduction. 8 (1): 16–23. doi:10.1093/molehr/8.1.16. PMID 11756565.
• Fukao T, Shintaku H, Kusubae R, Zhang GX, Nakamura K, Kondo M, Kondo N (December 2004). "Patients homozygous for the T435N mutation of succinyl-CoA:3-ketoacid CoA Transferase (SCOT) do not show permanent ketosis". Pediatric Research. 56 (6): 858–63. doi:10.1203/01.PDR.0000145297.90577.67. PMID 15496607.
• Fukao T, Sakurai S, Rolland MO, Zabot MT, Schulze A, Yamada K, Kondo N (November 2006). "A 6-bp deletion at the splice donor site of the first intron resulted in aberrant splicing using a cryptic splice site within exon 1 in a patient with succinyl-CoA: 3-Ketoacid CoA transferase (SCOT) deficiency". Molecular Genetics and Metabolism. 89 (3): 280–2. doi:10.1016/j.ymgme.2006.04.014. PMID 16765626.