The OXCT1 gene resides on chromosome 5 at the band 5p13. OXCT1 spans a length of over 100 kb and includes 17 exons.[4]
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.[5]
Function
OXCT1 is a member of the CoA transferase family I, which is known to catalyze the transfer of CoA between carboxylic acid groups.[5][6] In particular, OXCT1 catalyzes the first, rate-limiting step in ketolysis by transferring the CoA from succinyl-CoA to acetoacetyl CoA. Acetoacetyl-CoA can then be converted by acetoacetyl-CoA thiolase into acetyl-CoA, which enters the citric acid cycle to generate energy for the cell.[5] 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.[7] In addition, OXCT1 activity leads to the formation of acetoacetate, which serves as a precursor for short-chain acyl-CoAs and lipids in the cytosol.[8]
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.[5][7] 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.[7]
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.[5]
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.[8]
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.[9] Interestingly, a proteomics study identified OXCT1 to be one of 16 proteins upregulated in carcinoma HepG2 cells treated with Platycodin D, an anti-cancer agent.[10]
↑Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y (July 2014). "Ketone body metabolism and its defects". Journal of Inherited Metabolic Disease. 37 (4): 541–51. doi:10.1007/s10545-014-9704-9. PMID24706027.
↑Fukao T, Mitchell GA, Song XQ, Nakamura H, Kassovska-Bratinova S, Orii KE, Wraith JE, Besley G, Wanders RJ, Niezen-Koning KE, Berry GT, Palmieri M, Kondo N (September 2000). "Succinyl-CoA:3-ketoacid CoA transferase (SCOT): cloning of the human SCOT gene, tertiary structural modeling of the human SCOT monomer, and characterization of three pathogenic mutations". Genomics. 68 (2): 144–51. doi:10.1006/geno.2000.6282. PMID10964512.
↑ 7.07.17.2Orii KE, Fukao T, Song XQ, Mitchell GA, Kondo N (July 2008). "Liver-specific silencing of the human gene encoding succinyl-CoA: 3-ketoacid CoA transferase". The Tohoku Journal of Experimental Medicine. 215 (3): 227–36. doi:10.1620/tjem.215.227. PMID18648183.
↑Lu JJ, Lu DZ, Chen YF, Dong YT, Zhang JR, Li T, Tang ZH, Yang Z (September 2015). "Proteomic analysis of hepatocellular carcinoma HepG2 cells treated with platycodin D". Chinese Journal of Natural Medicines. 13 (9): 673–9. doi:10.1016/S1875-5364(15)30065-0. PMID26412427.
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. PMID1405472.
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. PMID6150478.
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. PMID9380443.
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. PMID9671268.
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. PMID11756565.
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. PMID15496607.
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. PMID16765626.
