Journal of Inherited Metabolic Disease

, Volume 36, Issue 3, pp 427–434 | Cite as

Metabolite proofreading, a neglected aspect of intermediary metabolism

  • Emile Van Schaftingen
  • Rim Rzem
  • Alexandre Marbaix
  • François Collard
  • Maria Veiga-da-Cunha
  • Carole L. Linster
Original Article


Enzymes of intermediary metabolism are less specific than what is usually assumed: they often act on metabolites that are not their ‘true’ substrate, making abnormal metabolites that may be deleterious if they accumulate. Some of these abnormal metabolites are reconverted to normal metabolites by repair enzymes, which play therefore a role akin to the proofreading activities of DNA polymerases and aminoacyl-tRNA synthetases. An illustrative example of such repair enzymes is L-2-hydroxyglutarate dehydrogenase, which eliminates a metabolite abnormally made by a Krebs cycle enzyme. Mutations in L-2-hydroxyglutarate dehydrogenase lead to L-2-hydroxyglutaric aciduria, a leukoencephalopathy. Other examples are the epimerase and the ATP-dependent dehydratase that repair hydrated forms of NADH and NADPH; ethylmalonyl-CoA decarboxylase, which eliminates an abnormal metabolite formed by acetyl-CoA carboxylase, an enzyme of fatty acid synthesis; L-pipecolate oxidase, which repairs a metabolite formed by a side activity of an enzyme of L-proline biosynthesis. Metabolite proofreading enzymes are likely quite common, but most of them are still unidentified. A defect in these enzymes may account for new metabolic disorders.



L-2-hydroxyglutarate dehydrogenase gene


D-2-hydroxyglutarate dehydrogenase gene



MVDC is Chercheur Qualifié of the Belgian FNRS. Alexandre Marbaix is supported by a FRIA fellowship. Work described in this review is supported by the Fonds National de la Recherche Scientifique (FNRS) and the Walloon region (Welbio) (EVS, RR, AM, FC, MVDC), and by the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement 276814 (CLL).

Conflict of interest



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Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Emile Van Schaftingen
    • 1
  • Rim Rzem
    • 1
  • Alexandre Marbaix
    • 1
  • François Collard
    • 1
  • Maria Veiga-da-Cunha
    • 1
  • Carole L. Linster
    • 2
  1. 1.Welbio and de Duve InstituteUniversité catholique de LouvainBrusselsBelgium
  2. 2.Luxembourg Centre for Systems BiomedicineUniversity of LuxembourgEsch-sur-AlzetteLuxembourg

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