Dehydrogenase E1 and transketolase domain containing 1 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the DHTKD1
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. This gene encodes a component of a
mitochondria
A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
l 2-oxoglutarate-dehydrogenase-complex-like protein involved in the degradation pathways of several
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s, including
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...
. Mutations in this gene are associated with
2-aminoadipic 2-oxoadipic aciduria and
Charcot-Marie-Tooth Disease Type 2Q.
Structure
The DHTKD1 gene encodes a protein that has 919 amino acids, and is one of two
isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
within the 2-oxoglutarate-dehydrogenase complex.
Function
DHTKD1 is part of an OGDHc-like supercomplex that is responsible for a crucial step in the degradation pathways of L-lysine, L-hydroxylysine, and L-tryptophan. Specifically, this enzyme catalyzes the
decarboxylation
Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...
of
2-oxoadipate to
glutaryl-CoA.
There is a strong correlation between DHTKD1 expression levels and
ATP production, which signifies that DHTKD1 plays a critical role in energy production in mitochondria. Moreover, suppression of DHTKD1 results in decreased levels of
biogenesis
Spontaneous generation is a Superseded scientific theories, superseded scientific theory that held that living creatures could arise from abiotic component, non-living matter and that such processes were commonplace and regular. It was Hypoth ...
and increased levels of
reactive oxygen species
In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
(ROS) within the mitochondria. Globally, this impairs cell growth and enhances
cell apoptosis.
Clinical significance
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. The clinical presentation of this disease in inconsistent.
Mutations in this gene could also cause neurological abnormalities.
Indeed, one form of Charcot-Marie-Tooth (CMT) disease has been associated with DHTKD1, although the disease encompasses a wide spectrum of clinical neuropathies. Specifically, a heterogeneous nonsense mutation within the gene leads to decreased levels of DHTKD1 mRNA and proteins, and impaired ATP generation. This implicates this mutation as a causative agent for CMT-2 Disease.
References
Further reading
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