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Journal of Inherited Metabolic Disease

, Volume 32, Issue 2, pp 135–142 | Cite as

l-2-Hydroxyglutaric aciduria, a disorder of metabolite repair

  • E. Van Schaftingen
  • R. Rzem
  • M. Veiga-da-Cunha
Ssiem Symposium 2008

Summary

The neurometabolic disorder l-2-hydroxyglutaric aciduria is caused by mutations in a gene present on chromosome 14q22.1 and encoding l-2-hydroxyglutarate dehydrogenase. This FAD-linked mitochondrial enzyme catalyses the irreversible conversion of l-2-hydroxyglutarate to alpha-ketoglutarate. The formation of l-2-hydroxyglutarate results from a side-activity of mitochondrial l-malate dehydrogenase, the enzyme that interconverts oxaloacetate and l-malate, but which also catalyses, very slowly, the NADH-dependent conversion of alpha-ketoglutarate to l-2-hydroxyglutarate. l-2-Hydroxyglutarate has no known physiological function in eukaryotes and most prokaryotes. Its accumulation is toxic to the mammalian brain, causing a leukoencephalopathy and increasing the susceptibility to develop tumours. l-2-Hydroxyglutaric aciduria appears to be the first disease of ‘metabolite repair’.

Keywords

Saccharopine Neurometabolic Disorder Dicarboxylic Aciduria Pyruvate Carboxylase Deficiency Riboflavin Supplement 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviation

LHGDG

l-2-hydroxyglutarate dehydrogenase gene

Notes

Acknowledgements

Work in the authors’ laboratory is supported by the Interuniversity Attraction Pole Programme, Belgian Science Policy (network P6/05), the Fonds de la Recherche Scientifique Médicale, the Actions de Recherche Concertées of the French Community of Belgium, and by a grant of Asco industries. M.V.D.C. is Chercheur Qualifié of the Fonds National de la Recherche Scientifique.

References

  1. Acheson SA, Kirkman HN, Wolfenden R (1988) Equilibrium of 5,6-hydration of NADH and mechanism of ATP-dependent dehydration. Biochemistry 27: 7371–7375. doi:10.1021/bi00419a030.PubMedCrossRefGoogle Scholar
  2. Achouri Y, Noël G, Vertommen D, Rider MH, Veiga-Da-Cunha M, Van Schaftingen E (2004) Identification of a dehydrogenase acting on d-2-hydroxyglutarate. Biochem J 381: 35–42. doi:10.1042/BJ20031933.PubMedCrossRefGoogle Scholar
  3. Barbot C, Fineza I, Diogo L, et al (1997) l-2-Hydroxyglutaric aciduria: clinical, biochemical and magnetic resonance imaging in six Portuguese pediatric patients. Brain Dev 19: 268–273. doi:10.1016/S0387-7604(97)00574-3.PubMedCrossRefGoogle Scholar
  4. Barth PG, Hoffmann GF, Jaeken J, et al (1993) l-2-Hydroxyglutaric acidaemia: clinical and biochemical findings in 12 patients and preliminary report on l-2-hydroxyacid dehydrogenase. J Inherit Metab Dis 16: 753–761. doi:10.1007/BF00711907.PubMedCrossRefGoogle Scholar
  5. Buckel W, Miller SL (1987) Equilibrium constants of several reactions involved in the fermentation of glutamate. Eur J Biochem 164: 565–569. doi:10.1111/j.1432-1033.1987.tb11164.x.PubMedCrossRefGoogle Scholar
  6. Chen E, Nyhan WL, Jakobs C, et al (1996) l-2-Hydroxyglutaric aciduria: neuropathological correlations and first report of severe neurodegenerative disease and neonatal death. J Inherit Metab Dis 19: 335–343. doi:10.1007/BF01799264.PubMedCrossRefGoogle Scholar
  7. Clarke S (2003) Aging as war between chemical and biochemical processes: protein methylation and the recognition of age-damaged proteins for repair. Ageing Res Rev 2: 263–285. doi:10.1016/S1568-1637(03)00011-4.PubMedCrossRefGoogle Scholar
  8. da Silva CG, Bueno AR, Schuck PF, et al (2003) l-2-Hydroxyglutaric acid inhibits mitochondrial creatine kinase activity from cerebellum of developing rats. Int J Dev Neurosci 21: 217–224. doi:10.1016/S0736-5748(03)00035-2.PubMedCrossRefGoogle Scholar
  9. Delpierre G, Rider MH, Collard F, et al (2000) Identification, cloning, and heterologous expression of a mammalian fructosamine-3-kinase. Diabetes 49: 1627–1634. doi:10.2337/diabetes.49.10.1627.PubMedCrossRefGoogle Scholar
  10. Duran M, Kamerling JP, Bakker HD, van Gennip AH, Wadman SK (1980) l-2-Hydroxyglutaric aciduria: an inborn error of metabolism? J Inherit Metab Dis 3: 109–112. doi:10.1007/BF02312543.PubMedCrossRefGoogle Scholar
  11. Galperin MY, Moroz OV, Wilson KS, Murzin AG (2006) House cleaning, a part of good housekeeping. Mol Microbiol 59: 5–19. doi:10.1111/j.1365-2958.2005.04950.x.PubMedCrossRefGoogle Scholar
  12. Graupner M, Xu H, White RH (2000) Identification of an archaeal 2-hydroxy acid dehydrogenase catalyzing reactions involved in coenzyme biosynthesis in methanoarchaea. J Bacteriol 182: 3688–3692. doi:10.1128/JB.182.13.3688-3692.2000.PubMedCrossRefGoogle Scholar
  13. Haliloglu G, Jobard F, Oguz KK, et al (2008) l-2-Hydroxyglutaric aciduria and brain tumors in children with mutations in the L2HGDH gene: Neuroimaging Findings. Neuropediatrics 39: 119–122. doi:10.1055/s-2008-1081217.PubMedCrossRefGoogle Scholar
  14. Jansen GA, Wanders RJ (1993) l-2-Hydroxyglutarate dehydrogenase: identification of a novel enzyme activity in rat and human liver. Implications for l-2-hydroxyglutaric acidemia. Biochim Biophys Acta 1225: 53–56.PubMedGoogle Scholar
  15. Junqueira D, Brusque AM, Porciúncula LO, et al (2003) Effects of l-2-hydroxyglutaric acid on various parameters of the glutamatergic system in cerebral cortex of rats. Metab Brain Dis 18: 233–243. doi:10.1023/A:1025559200816.PubMedCrossRefGoogle Scholar
  16. Kalliri E, Mulrooney SB, Hausinger RP (2008) Identification of Escherichia coli YgaF as an l-2-hydroxyglutarate oxidase. J Bacteriol 190: 3793–3798. doi:10.1128/JB.01977-07.PubMedCrossRefGoogle Scholar
  17. Kamoun P, Richard V, Rabier D, Saudubray JM (2002) Plasma lysine concentration and availability of 2-ketoglutarate in liver mitochondria. J Inherit Metab Dis 25: 1–6. doi:10.1023/A:1015195009330.PubMedCrossRefGoogle Scholar
  18. Kardon T, Noël G, Vertommen D, Van Schaftingen E (2006) Identification of the gene encoding hydroxyacid-oxoacid transhydrogenase, an enzyme that metabolizes 4-hydroxybutyrate. FEBS Lett 580: 2347–2350. doi:10.1016/j.febslet.2006.02.082.PubMedCrossRefGoogle Scholar
  19. Kaufman EE, Nelson T, Fales HM, Levin DM (1988) Isolation and characterization of a hydroxyacid-oxoacid transhydrogenase from rat kidney mitochondria. J Biol Chem 263: 16872–16879.PubMedGoogle Scholar
  20. Kölker S, Sauer SW, Hoffmann GF, et al (2008) Pathogenesis of CNS involvement in disorders of amino and organic acid metabolism. J Inherit Metab Dis 31: 194–204.Google Scholar
  21. Latini A, Scussiato K, Rosa RB, et al (2003) Induction of oxidative stress by l-2-hydroxyglutaric acid in rat brain. JNeurosci Res 74: 103–110. doi:10.1002/jnr.10735.PubMedCrossRefGoogle Scholar
  22. Lindahl G, Lindstedt G, Lindstedt S (1967) Metabolism of 2-amino-5-hydroxyadipic acid in the rat. Arch Biochem Biophys 119: 347–352. doi:10.1016/0003-9861(67)90463-8.PubMedCrossRefGoogle Scholar
  23. Maliekal P, Vertommen D, Delpierre G, Van Schaftingen E (2006) Identification of the sequence encoding N-acetylneuraminate-9-phosphate phosphatase. Glycobiology 16: 165–172. doi:10.1093/glycob/cwj050.PubMedCrossRefGoogle Scholar
  24. Molenaar D, van der Rest ME, Petrović S (1998) Biochemical and genetic characterization of the membrane-associated malate dehydrogenase (acceptor) from Corynebacterium glutamicum. Eur J Biochem 254: 395–403. doi:10.1046/j.1432-1327.1998.2540395.x.PubMedCrossRefGoogle Scholar
  25. Moroni I, Bugiani M, D’Incerti L, et al (2004) l-2-Hydroxyglutaric aciduria and brain malignant tumors: a predisposing condition? Neurology 62: 1882–1884.PubMedGoogle Scholar
  26. Moskovitz J (2005) Roles of methionine sulfoxide reductases in antioxidant defense, protein regulation and survival. CurrPharm Des 11: 1451–1457. doi:10.2174/1381612053507846.PubMedCrossRefGoogle Scholar
  27. Oppenheimer NJ, Kaplan NO (1974) Glyceraldehyde-3-phosphate dehydrogenase catalyzed hydration of the 5-6 double bond of reduced beta-nicotinamide adenine dinucleotide (betaNADH). Formation of beta-6-hydroxy-1,4,5,6-tetrahydronicotinamide adenine dinucleotide. Biochemistry 13: 4685–4694. doi:10.1021/bi00720a002.PubMedCrossRefGoogle Scholar
  28. Ozişik PA, Akalan N, Palaoğlu S, Topçu M. (2002) Medulloblastoma in a child with the metabolic disease l-2-hydroxyglutaric aciduria. Pediatr Neurosurg 37: 22–26. doi:10.1159/000065097.PubMedCrossRefGoogle Scholar
  29. Richard JP (1991) Kinetic parameters for the elimination reaction catalyzed by triosephosphate isomerase and an estimation of the reaction’s physiological significance. Biochemistry 30: 4581–4585. doi:10.1021/bi00232a031.PubMedCrossRefGoogle Scholar
  30. Rzem R, Veiga-da-Cunha M, Noel G, et al (2004) A gene encoding a putative FAD-dependent l-2-hydroxyglutarate dehydrogenase is mutated in l-2-hydroxyglutaric aciduria, Proc Natl Acad Sci U S A 101: 16849–16854. doi:10.1073/pnas.0404840101.PubMedCrossRefGoogle Scholar
  31. Rzem R, Van Schaftingen E, Veiga-da-Cunha M (2006) The gene mutated in l-2-hydroxyglutaric aciduria encodes l-2-hydroxyglutarate dehydrogenase. Biochimie 88: 113–116. doi:10.1016/j.biochi.2005.06.005.PubMedCrossRefGoogle Scholar
  32. Rzem R, Vincent MF, Van Schaftingen E, Veiga-da-Cunha M (2007) l-2-hydroxyglutaric aciduria, a defect of metabolite repair. J Inherit Metab Dis 30: 681–689. doi:10.1007/s10545-007-0487-0.PubMedCrossRefGoogle Scholar
  33. Samuraki M, Komai K, Hasegawa Y, et al (2008) A successfully treated adult patient with l-2-hydroxyglutaric aciduria. Neurology 70: 1051–1052. doi:10.1212/01.wnl.0000287141.90944.95.PubMedCrossRefGoogle Scholar
  34. Sass JO, Jobard F, Topçu M, et al (2008) l-2-Hydroxyglutaric aciduria: Identification of ten novel mutations in the L2HGDH gene. J Inherit Metab Dis. doi:10.1007/s10545-008-0855-4.
  35. Schatz L, Segal HL (1969) Reduction of alpha-ketoglutarate by homogeneous lactic dehydrogenase X of testicular tissue. J Biol Chem 244: 4393–4397.PubMedGoogle Scholar
  36. Sedgwick B, Bates PA, Paik J, Jacobs SC, Lindahl T (2007) Repair of alkylated DNA: recent advances. DNA Repair (Amst) 6: 429–442. doi:10.1016/j.dnarep.2006.10.005.CrossRefGoogle Scholar
  37. Struys EA, Verhoeven NM, Roos B, Jakobs C (2003) Disease-related metabolites in culture medium of fibroblasts from patients with d-2-hydroxyglutaric aciduria, l-2-hydroxyglutaric aciduria, and combined D/L-2-hydroxyglutaric aciduria. Clin Chem 49: 1133–1138. doi:10.1373/49.7.1133.PubMedCrossRefGoogle Scholar
  38. Struys EA, Verhoeven NM, Brunengraber H, Jakobs C (2004) Investigations by mass isotopomer analysis of the formation of d-2-hydroxyglutarate by cultured lymphoblasts from two patients with d-2-hydroxyglutaric aciduria. FEBS Lett 557: 115–120. doi:10.1016/S0014-5793(03)01459-5.PubMedCrossRefGoogle Scholar
  39. Struys EA, Salomons GS, Achouri Y et al (2005a) Mutations in the d-2-hydroxyglutarate dehydrogenase gene cause d-2-hydroxyglutaric aciduria. Am J Hum Genet 76: 358–360. doi:10.1086/427890.PubMedCrossRefGoogle Scholar
  40. Struys EA, Korman SH, Salomons GS et al (2005b) Mutations in phenotypically mild d-2-hydroxyglutaric aciduria. Ann Neurol 58: 626–630. doi:10.1002/ana.20559.PubMedCrossRefGoogle Scholar
  41. Struys EA, Gibson KM, Jakobs C (2007) Novel insights into l-2-hydroxyglutaric aciduria: mass isotopomer studies reveal 2-oxoglutaric acid as the metabolic precursor of l-2-hydroxyglutaric acid. J Inherit Metab Dis 30: 690–693. doi:10.1007/s10545-007-0697-5.PubMedCrossRefGoogle Scholar
  42. Topçu M, Jobard F, Halliez S, et al (2004) l-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum Mol Genet 13: 2803–2811. doi:10.1093/hmg/ddh300.PubMedCrossRefGoogle Scholar
  43. Topçu M, Aydin OF, Yalcinkaya C (2005) l-2-Hydroxyglutaric aciduria: a report of 29 patients. Turk J Pediatr 47: 1–7.PubMedGoogle Scholar
  44. van Beelen P, Stassen AP, Bosch JW, Vogels GD, Guijt W, Haasnoot CA (1984) Elucidation of the structure of methanopterin, a coenzyme from Methanobacterium thermoautotrophicum, using two-dimensional nuclear-magnetic-resonance techniques. Eur J Biochem 138: 563–571. doi:10.1111/j.1432-1033.1984.tb07951.x.PubMedCrossRefGoogle Scholar
  45. Veiga da-Cunha M, Jacquemin P, Delpierre G, et al (2006) Increased protein glycation in fructosamine 3-kinase-deficient mice. Biochem J 399: 257–264.PubMedCrossRefGoogle Scholar
  46. Vilarinho L, Cardoso ML, Gaspar P, et al (2005) Novel L2HGDH mutations in 21 patients with l-2-hydroxyglutaric aciduria of Portuguese origin. Hum Mutat 26: 395–396. doi:10.1002/humu.9373.PubMedCrossRefGoogle Scholar
  47. Wanders RJ, Vilarinho L, Hartung HP, et al (1997) l-2-Hydroxyglutaric aciduria: normal l-2-hydroxyglutarate dehydrogenase activity in liver from two new patients. JInherit Metab Dis 20: 725–726. doi:10.1023/A:1005355316599.PubMedCrossRefGoogle Scholar
  48. Weil-Malherbe H (1937) The oxidation of l(−)α-hydroxyglutaric acid in animal tissues. Biochem J 31: 2080–2094.PubMedGoogle Scholar
  49. Wright SK, Viola RE (2001) Alteration of the specificity of malate dehydrogenase by chemical modulation of an active site arginine. J Biol Chem 276: 31151–31155. doi:10.1074/jbc.M100892200.PubMedCrossRefGoogle Scholar
  50. Yilmaz K (2008) Riboflavin treatment in a case with l-2-hydroxyglutaric aciduria. Eur J Paediatr Neurol. doi:10.1016/j.ejpn.2008.01.003.

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • E. Van Schaftingen
    • 1
    • 2
  • R. Rzem
    • 1
  • M. Veiga-da-Cunha
    • 1
  1. 1.de Duve InstituteUniversité catholique de LouvainBrusselsBelgium
  2. 2.BrusselsBelgium

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