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 Coenzyme A (CoA, SHCoA, CoASH) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a subs ...

(CoA) from succinyl-CoA to

acetoacetate Acetoacetic acid (also acetoacetate and diacetic acid) is the organic compound with the formula CHCOCHCOOH. It is the simplest beta-keto acid, and like other members of this class, it is unstable. The methyl and ethyl esters, which are quite stab ...

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 An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

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 In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...

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 Acetyl-CoA (acetyl coenzyme A) 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 (Krebs cycle) to be oxidized for ...

, 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 Ketosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Physiological ketosis is a normal response to low glucose availability, such as low-carbohydrate diets or fasting, that provides an additional ...

. 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 The pancreas is an Organ (anatomy), organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine ...

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.