Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Summary

l-2-hydroxyglutaric aciduria is a metabolic disorder in which l-2-hydroxyglutarate accumulates as a result of a deficiency in FAD-linked l-2-hydroxyglutarate dehydrogenase, a mitochondrial enzyme converting l-2-hydroxyglutarate to α-ketoglutarate. The origin of the l-2-hydroxyglutarate, which accumulates in this disorder, is presently unknown. The oxidation–reduction potential of the 2-hydroxyglutarate/α-ketoglutarate couple is such that l-2-hydroxyglutarate could potentially be produced through the reduction of α-ketoglutarate by a NAD- or NADP-linked oxidoreductase. In fractions of rat liver cytosolic extracts that had been chromatographed on an anion exchanger we detected an enzyme reducing α-ketoglutarate in the presence of NADH. This enzyme co-purified with cytosolic l-malate dehydrogenase (cMDH) upon further chromatography on Blue Sepharose. Mitochondrial fractions also contained an NADH-linked, ‘α-ketoglutarate reductase’ which similarly co-purified with mitochondrial l-malate dehydrogenase (mMDH). Purified mMDH catalysed the reduction of α-ketoglutarate to l-2-hydroxyglutarate with a catalytic efficiency that was about 107-fold lower than that observed with oxaloacetate. For the cytosolic enzyme, this ratio amounted to 108, indicating that this enzyme is more specific. Both cMDH and mMDH are highly active in tissues and α-ketoglutarate is much more abundant than oxaloacetate and more concentrated in mitochondria than in the cytosol. As a result of this, the weak activity of mMDH on α-ketoglutarate is sufficient to account for the amount of l-2-hydroxyglutarate that is excreted by patients deficient in FAD-linked l-2-hydroxyglutarate dehydrogenase. The latter enzyme appears, therefore, to be responsible for a ‘metabolite repair’ phenomenon and to belong to the expanding class of ‘house-cleaning’ enzymes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Amar-Costesec A, Beaufay H, Wibo M, et al (1974) Analytical study of microsomes and isolated subcellular membranes from rat liver. II. Preparation and composition of the microsomal fraction. J Cell Biol 61: 201–212.

    Article  CAS  PubMed  Google Scholar 

  • Barth PG, Hoffmann GF, Jaeken J, et al. (1992) l-2-hydroxyglutaric acidemia: a novel inherited neurometabolic disease. Ann Neurol 32: 66–71.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Bertocci LA, Lujan BF (1999) Incorporation and utilization of [3-13C]lactate and [1,2-13C]acetate by rat skeletal muscle. J Appl Physiol 86: 2077–2089.

    CAS  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem 72: 245–248.

    Article  Google Scholar 

  • Buckel W, Miller SL (1987) Equilibrium constants of several reactions involved in the fermentation of glutamate. Eur J Biochem 164: 565–569.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Davies DD, Kun E (1957) Isolation and properties of malic dehydrogenase from ox-heart mitochondria. Biochem J 66: 307–316.

    CAS  PubMed  Google Scholar 

  • de Duve C, Pressman BC, Gianetto R, Wattiaux R, Appelmans F (1955) Tissue fractionation studies 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem J 60: 604–617.

    Google Scholar 

  • Delpierre G, Vanstapel F, Stroobant V, Van Schaftingen E (2000) Conversion of a synthetic fructosamine into its 3-phospho derivative in human erythrocytes. Biochem J 352: 835–839.

    Article  CAS  PubMed  Google Scholar 

  • Delpierre G, Collard F, Fortpied J, Van Schaftingen E (2002) Fructosamine 3-kinase is involved in an intracellular deglycation pathway in human erythrocytes. Biochem J 365: 801–808.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Galperin MY, Moroz OV, Wilson KS, Murzin AG (2006) House cleaning, a part of good housekeeping. Mol Microbiol 59: 5–19.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Hung HC, Kuo MW, Chang GG, Liu GY (2005) Characterization of the functional role of allosteric site residue Asp102 in the regulatory mechanism of human mitochondrial NAD(P)+-dependent malate dehydrogenase (malic enzyme). Biochem J 392: 39–45.

    Article  CAS  PubMed  Google Scholar 

  • Ljunggren B, Ratcheson RA, Siesjo BK (1974) Cerebral metabolic state following complete compression ischemia. Brain Res 73: 291–307.

    Article  CAS  PubMed  Google Scholar 

  • Lowenson JD, Kim E, Young SG, Clarke S (2001) Limited accumulation of damaged proteins in l-isoaspartyl (d-aspartyl) O-methyltransferase-deficient mice. J Biol Chem 276: 20695–20702.

    Article  CAS  PubMed  Google Scholar 

  • Moskovitz J (2005) Roles of methionine sulfoxide reductases in antioxidant defense, protein regulation and survival. Curr Pharm Des 11: 1451–1457.

    Article  CAS  PubMed  Google Scholar 

  • O’Donnell JM, Doumen C, LaNoue KF, et al (1998) Dehydrogenase regulation of metabolite oxidation and efflux from mitochondria in intact hearts. Am J Physiol 274: H467–476.

    PubMed  Google Scholar 

  • Reeves HC, Ajl SJ (1962) Alpha-hydroxyglutaric acid synthetase. J Bacteriol 84: 186–187.

    CAS  PubMed  Google Scholar 

  • Phillips SA, Thornalley PJ (1993) The formation of methylglyoxal from triose phosphates. Investigation using a specific assay for methylglyoxal. Eur J Biochem 212: 101–105.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Rzem R, Veiga-da-Cunha M, Noël 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 USA 101: 16849–16854.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Schatz L, Segal HL (1969) Reduction of alpha-ketoglutarate by homogeneous lactic dehydrogenase X of testicular tissue. J Biol Chem 244: 4393–4397.

    CAS  PubMed  Google Scholar 

  • Soboll S, Horst C, Hummerich H, Schumacher JP, Seitz HJ (1992) Mitochondrial metabolism in different thyroid states. Biochem J 281: 171–173.

    CAS  PubMed  Google Scholar 

  • Solow BT, White RH (1997) Absolute stereochemistry of 2-hydroxyglutaric acid present in methanopterin. Chirality 9: 678–680.

    Article  CAS  Google Scholar 

  • Topçu M, Jobard F, Halliez S, (2004) l-2-Hydroxyglutaric aciduria: identification of a mutant gene C14orf160, localized on chromosome 14q22.1. Hum Mol Genet 13: 2803–2811.

    Article  PubMed  Google Scholar 

  • Tsuzuki T, Egashira A, Igarashi H, et al (2001) Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase. Proc Natl Acad Sci USA 98: 11456–11461.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Weil-Malherbe H (1937) The oxidation of l(-)α-hydroxyglutaric acid in animal tissues. Biochem J 31: 2080–2094.

    CAS  PubMed  Google Scholar 

  • Williamson DH, Lund P, Krebs HA (1967) The redox state of free nicotinamide–adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochem J 103: 514–527.

    CAS  PubMed  Google Scholar 

  • Wiseman MS, McKay D, Crow KE, Hardman MJ (1991) Rat liver mitochondrial malate dehydrogenase: purification, kinetic properties, and role in ethanol metabolism. Arch Biochem Biophys 290: 191–196.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto A, Takagi H, Kitamura D, et al (1998) Deficiency in protein l-isoaspartyl methyltransferase results in a fatal progressive epilepsy. J Neurosci 18: 2063–2074.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. de Duve Institute, Laboratory of Physiological Chemistry, Université catholique de Louvain, Avenue Hippocrate 75, B-1200, Brussels, Belgium

    R. Rzem, E. Van Schaftingen & M. Veiga-da-Cunha

  2. Cliniques universitaires Saint-Luc, Laboratoire des Maladies métaboliques, Université catholique de Louvain, Brussels, Belgium

    M.-F. Vincent

Authors
  1. R. Rzem
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M.-F. Vincent
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Van Schaftingen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Veiga-da-Cunha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. Van Schaftingen.

Additional information

Communicating editor: Michael Gibson

Competing interests: None declared

References to electronic databases: l-2-Hydroxyglutaric aciduria: OMIM 236792

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rzem, R., Vincent, MF., Van Schaftingen, E. et al. l-2-Hydroxyglutaric aciduria, a defect of metabolite repair. J Inherit Metab Dis 30, 681–689 (2007). https://doi.org/10.1007/s10545-007-0487-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-007-0487-0

Keywords

Search

Navigation