α-Hydroxyglutaric acid (2-hydroxyglutaric acid) is an
alpha hydroxy acid
α-Hydroxy acids, or alpha hydroxy acids (AHAs), are a class of chemical compounds that consist of a carboxylic acid with a hydroxyl group substituent on the adjacent (alpha) carbon. Prominent examples are glycolic acid, lactic acid, mandelic ac ...
form of
glutaric acid
Glutaric acid is the organic compound with the formula C3H6(COOH)2 . Although the related "linear" dicarboxylic acids adipic and succinic acids are water-soluble only to a few percent at room temperature, the water-solubility of glutaric acid is ...
.
In biology
In humans the compound is formed by a
hydroxyacid-oxoacid transhydrogenase
In enzymology, a hydroxyacid-oxoacid transhydrogenase () is an enzyme that catalyzes the chemical reaction
:(S)-3-hydroxybutanoate + 2-oxoglutarate \rightleftharpoons acetoacetate + (R)-2-hydroxyglutarate
Thus, the two substrates of this enzym ...
whereas in bacteria is formed by a
2-hydroxyglutarate synthase. The compound can be converted to
α-ketoglutaric acid through the action of a
2-hydroxyglutarate dehydrogenase which, in humans, are two enzymes called
D2HGDH and
L2HGDH. Deficiency in either of these two enzymes lead to a disease known as
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 thi ...
.
D-2-hydroxyglutarate
Mutations in
isocitrate dehydrogenase
Isocitrate dehydrogenase (IDH) () and () is an enzyme that catalyzes the oxidative decarboxylation of isocitrate, producing alpha-ketoglutarate (α-ketoglutarate) and CO2. This is a two-step process, which involves oxidation of isocitrate (a s ...
(
IDH1
Isocitrate dehydrogenase 1 (NADP+), soluble is an enzyme that in humans is encoded by the ''IDH1'' gene on chromosome 2. Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two ...
and
IDH2
Isocitrate dehydrogenase ADP mitochondrial is an enzyme that in humans is encoded by the ''IDH2'' gene.
Isocitrate dehydrogenases are enzymes that catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two ...
), which frequently occur in
glioma
A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours.
Signs and symptoms
...
and
AML,
[
] produce
D-2-hydroxyglutarate from
alpha-ketoglutarate.
-2-hydroxyglutarate accumulates to very high concentrations which inhibits the function of enzymes that are dependent on alpha-ketoglutarate, including
histone lysine demethylases.
This leads to a hypermethylated state of DNA and histones,
which results in different gene expression that can activate
oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels. s and inactivate
tumor-suppressor genes. Studies have also shown that 2-hydroxyglutarate may be converted back to alpha-ketoglutarate either enzymatically or non-enzymatically.
Further studies are required to fully understand the dynamics between 2-hydroxyglutarate and alpha-ketoglutarate.
L-2-hydroxyglutarate
On the other hand, L-2-hydroxyglutarate is produced at high levels in low oxygen conditions, including cells of the immune system.
[ ]
References
{{DEFAULTSORT:Hydroxyglutaric acid, alpha-
Dicarboxylic acids
Alpha hydroxy acids