Novel insights into L-2-hydroxyglutaric aciduria: mass isotopomer studies reveal 2-oxoglutaric acid as the metabolic precursor of L-2-hydroxyglutaric acid.
Employing lymphoblasts derived from two non related patients with L-2-HG aciduria, we examined the origin of L-2-hydroxyglutaric acid (L-2-HG) through incubation with [(13)C6]glucose and [(2)H5]glutamic acid. Formation of labelled 2-ketoglutaric acid (2-KG), citric acid and L-2-HG was determined by GC-MS. The quantitative and qualitative isotopomer pattern following incubation with [(13)C6]glucose was identical for all end-products. Incubations with [(2)H5]glutamic acid as precursor revealed the formation of identical isotopomers for 2-KG and L-2-HG. Our data indicate that 2-KG is the metabolic precursor of L-2-HG, adding to previous studies which revealed that 2-KG is the metabolic precursor of D-2-HG. These data suggest that 2-KG has a pathophysiological role in combined D/L-2-HG aciduria.
Struys
E A
EA
VU University Medical Centre, Clinical Chemistry, Metabolic Unit, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. e.struys@vumc.nl
Gibson
K M
KM
Jakobs
C
C
D000429:Alcohol Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002247:Carbon Isotopes; D002460:Cell Line; D019343:Citric Acid / Q000378:metabolism; D003903:Deuterium; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D005977:Glutarates / Q000378:metabolism* / Q000652:urine; D006801:Humans; D007656:Ketoglutaric Acids / Q000378:metabolism*; D008214:Lymphocytes / Q000201:enzymology / Q000378:metabolism*; D008661:Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction
D002247:Carbon Isotopes; D005977:Glutarates; D007656:Ketoglutaric Acids; C019417:alpha-hydroxyglutarate; D019343:Citric Acid; D018698:Glutamic Acid; D003903:Deuterium; D000429:Alcohol Oxidoreductases; C506763:L2HGDH protein, human; D005947:Glucose