L-2-hydroxyglutarate dehydrogenase, mitochondrial is an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''L2HGDH''
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 ...
, also known as C14orf160, on
chromosome 14.
Function
This gene encodes L-2-hydroxyglutarate dehydrogenase, a
flavin adenine dinucleotide
In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which ma ...
(FAD)-dependent enzyme that oxidizes
L-2-hydroxyglutarate to alpha-ketoglutarate in a variety of mammalian tissues. Mutations in this gene cause
L-2-hydroxyglutaric aciduria
2-hydroxyglutaric aciduria is a rare neurometabolic disorder characterized by the significantly elevated levels of hydroxyglutaric acid in one's urine. It is either autosomal recessive or autosomal dominant.
Presentation
The signs/symptoms of this ...
, a rare autosomal recessive neurometabolic disorder resulting in moderate to severe mental retardation.
L2HGDH codes for a protein that is 50 kDa in size. The L2HGDH protein contains a mitochondrial-targeting
transit peptide and is localized to the
mitochondrial inner membrane inside
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 ...
inside the cell. The L2HGDH protein catalyzes the following reaction, and requires
flavin adenine dinucleotide
In biochemistry, flavin adenine dinucleotide (FAD) is a redox-active coenzyme associated with various proteins, which is involved with several enzymatic reactions in metabolism. A flavoprotein is a protein that contains a flavin group, which ma ...
(FAD) as a
co-factor:
(S)-2-hydroxyglutarate + acceptor = 2-oxoglutarate + reduced acceptor.
L-2-hydroxyglutarate is produced by
promiscuous action of
malate dehydrogenase
Malate dehydrogenase () (MDH) is an enzyme that reversibly catalyzes the oxidation of malate to oxaloacetate using the reduction of NAD+ to NADH. This reaction is part of many metabolic pathways, including the citric acid cycle. Other malate ...
on 2-oxoglutarate; the L2HGDH protein is thus an example of a
metabolite repair enzyme because it reconverts the useless damage product L-2-hydroxyglutarate back to 2-oxoglutarate.
Clinical significance
Mutations in the L2HGDH gene cause
L-2-hydroxyglutaric aciduria
2-hydroxyglutaric aciduria is a rare neurometabolic disorder characterized by the significantly elevated levels of hydroxyglutaric acid in one's urine. It is either autosomal recessive or autosomal dominant.
Presentation
The signs/symptoms of this ...
, a rare
autosomal recessive
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
neurometabolic disorder. Individuals with L2HGDH mutations present toxic accumulation of high concentration of
L-2-hydroxyglutaric acid in the
plasma and
cerebrospinal fluid
Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
. At least 70 disease-causing variants in the L2HGDH gene have been discovered in patients.
Patients with
L-2-hydroxyglutaric aciduria
2-hydroxyglutaric aciduria is a rare neurometabolic disorder characterized by the significantly elevated levels of hydroxyglutaric acid in one's urine. It is either autosomal recessive or autosomal dominant.
Presentation
The signs/symptoms of this ...
are associated with moderate to severe
mental retardation
Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...
,
psychomotor retardation
Psychomotor retardation involves a slowing down of thought and a reduction of physical movements in an individual. It can cause a visible slowing of physical and emotional reactions, including speech and affect.
Psychomotor retardation is most ...
,
cerebellar ataxia
Cerebellar ataxia is a form of ataxia originating in the cerebellum. Non-progressive congenital ataxia (NPCA) is a classical presentation of cerebral ataxias.
Cerebellar ataxia can occur as a result of many diseases and may present with symptoms ...
,
macrocephaly
Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a Heredity, familial genetic characteristic. People diagnosed with macrocephaly will receive further medical ...
, or
epilepsy
Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
.
L2HGDH has a role in mediating differentiation in T-cells via its activity on S-2HG.
Molecular interactions
KLK10
See also
*
D2HGDH
*
2-hydroxyglutarate synthase
*
2-hydroxyglutarate dehydrogenase
*
Hydroxyacid-oxoacid transhydrogenase
References
Further reading
*
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