D-2-Hydroxyglutaric acid

D-2-Hydroxyglutaric acid Description

D-2-Hydroxyglutaric acid is a biochemical hallmark of the inherited neurometabolic disorder D-2-hydroxyglutaric aciduria. D-2-hydroxyglutaric aciduria (caused by loss of D2HGDH or gain of function of IDH) is rare, with symptoms including cancer, macrocephaly, cardiomyopathy, mental retardation, hypotonia, and cortical blindness. An elevated urine level of D-2-hydroxyglutarate has been reported patient with spondyloenchondrodysplasia (OMIM 271550 ). D-2-hydroxyglutarate can be converted to α-ketoglutaric acid through the action of 2-hydroxyglutarate dehydrogenase (D2HGDH). Additionally, the enzyme D-3-phosphoglycerate dehydrogenase (PHGDH) can catalyze the NADH-dependent reduction of α-ketoglutarate (AKG) to D-2-hydroxyglutarate (D-2HG). Nyhan et al. (1995) described 3 female patients, 2 of them sibs, who were found to have excess accumliation of D-2-hydroxyglutaric acid in the urine. The phenotype was quite variable, even among the sibs, but included mental retardation, macrocephaly with cerebral atrophy, hypotonia, seizures, and involuntary movements. One of the patients developed severe intermittent vomiting and was given a pyloromyotomy. The electroencephalogram demonstrated hypsarrhythmia. There was an increased concentration of protein in cerebrospinal fluid, an unusual finding in inborn errors of metabolism (OMIM 600721 ). D-2-Hydroxyglutaric acid is also considered to be an oncometabolite (or cancer-causing metabolite). It can be produced via gain-of-function mutations in the cytosolic and mitochondrial isoforms of isocitrate dehydrogenase (IDH). IDH is part of TCA cycle and this compound is generated in high abundance when IDH is mutated. D-2-hydroxyglutarate is sufficiently similar in structure to 2-oxogluratate (2OG) that it is able to inhibit a range of 2OG-dependent dioxygenases, including histone lysine demethylases (KDMs) and members of the ten-eleven translocation (TET) family of 5-methylcytosine (5mC) hydroxylases. This inhibitory effect leads to alterations in the hypoxia induced factor (HIF)-mediated hypoxic response and alterations in gene expression through global epigenetic remodeling. The net effect is that D-2-hydroxyglutarate causes a cascading effect that leads genetic perturbations and malignant transformation. Structure

Synonyms

Chemical Formlia

C₅H₈O₅ Average Molecliar Weight

148.114 Monoisotopic Molecliar Weight

148.037173366 IUPAC Name

(2R)-2-hydroxypentanedioic acid Traditional Name

D-2-hydroxyglutaric acid CAS Registry Number

2889-31-8 SMILES

InChI Identifier

InChI Key

HWXBTNAVRSUOJR-GSVOUGTGSA-N Chemical Taxonomy Description

This compound belongs to the class of chemical entities known as short-chain hydroxy acids and derivatives. These are hydroxy acids with an alkyl chain the contains less than 6 carbon atoms. Kingdom

Chemical entities Super Class

Organic compounds Class

Organic acids and derivatives Sub Class

Hydroxy acids and derivatives Direct Parent

Short-chain hydroxy acids and derivatives Alternative Parents

Substituents

Molecliar Framework

Aliphatic acyclic compounds External Descriptors

Ontology Status

Detected and Quantified Origin

Biofunction

Application

Not Available Cellliar locations

Physical Properties State

Solid Experimental Properties

Predicted Properties

Spectra Spectra

Predicted LC-MS/MS Spectrum – 10V, PositiveNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 20V, PositiveNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 40V, PositiveNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 10V, NegativeNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 20V, NegativeNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 40V, NegativeNot Available

Biological Properties Cellliar Locations

Biofluid Locations

Tissue Location

Pathways

Normal Concentrations