DHTKD1
Description
The DHTKD1 (dehydrogenase E1 and transketolase domain containing 1) is a protein-coding gene located on chromosome 10.
DHTKD1 is a protein encoded by the DHTKD1 gene. It is a component of a mitochondrial 2-oxoglutarate-dehydrogenase-complex-like protein involved in the degradation pathways of several amino acids, including lysine. Mutations in this gene are associated with 2-aminoadipic 2-oxoadipic aciduria and Charcot-Marie-Tooth Disease Type 2Q. DHTKD1 has 919 amino acids and is one of two isoforms within the 2-oxoglutarate-dehydrogenase complex. DHTKD1 is part of an OGDHc-like supercomplex responsible for a crucial step in the degradation pathways of L-lysine, L-hydroxylysine, and L-tryptophan. This enzyme catalyzes the decarboxylation of 2-oxoadipate to glutaryl-CoA. DHTKD1 expression levels are strongly correlated with ATP production, signifying its critical role in energy production in mitochondria. Suppression of DHTKD1 results in decreased biogenesis and increased levels of reactive oxygen species (ROS) within the mitochondria, impairing cell growth and enhancing cell apoptosis. Mutations in the DHTKD1 gene are associated with alpha-aminoadipic and alpha-ketoadipic aciduria, an autosomal recessive inborn error of lysine, hydroxylysine, and tryptophan degradation. Only a handful of mutations have been observed in patients, including three missense mutations, two nonsense mutations, two splice donor mutations, one duplication, and one deletion and insertion. Two missense mutations are the most common cause of the deficiency.
DHTKD1 is a component of the 2-oxoadipate dehydrogenase complex (OADHC), which plays a critical role in the breakdown of L-lysine, L-hydroxylysine and L-tryptophan. Specifically, DHTKD1 catalyzes the first step in the conversion of 2-oxoadipate to glutaryl-CoA and CO2. This reaction is irreversible and involves the decarboxylation of 2-oxoadipate using thiamine diphosphate (ThDP) as a cofactor. The decarboxylated acyl intermediate is then transferred to the oxidized dihydrolipoyl group on the E2 enzyme (dihydrolipoyllysine-residue succinyltransferase or DLST). While DHTKD1 can also catalyze the decarboxylation of 2-oxoglutarate in vitro, it does so at a much slower rate than 2-oxoadipate. DHTKD1 is responsible for the last step of the breakdown of L-lysine, L-hydroxylysine and L-tryptophan, with 2-oxoadipate as the common product.
DHTKD1 is also known as AAKAD, AMOXAD, CMT2Q, E1a, OADC-E1, OADH-E1.
