title: Metabolite proofreading, a neglected aspect of intermediary metabolism.
abstract: 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.
authors.affiliation: Welbio and de Duve Institute, Université catholique de Louvain, Brussels, Belgium. emile.vanschaftingen@uclouvain.be
authors.forename: Emile
authors.initials: E
authors.lastname: Van Schaftingen
authors.forename: Rim
authors.initials: R
authors.lastname: Rzem
authors.forename: Alexandre
authors.initials: A
authors.lastname: Marbaix
authors.forename: François
authors.initials: F
authors.lastname: Collard
authors.forename: Maria
authors.initials: M
authors.lastname: Veiga-da-Cunha
authors.forename: Carole L
authors.initials: CL
authors.lastname: Linster
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism / Q000502:physiology; D000214:Acyl Coenzyme A / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000378:metabolism / Q000502:physiology; D000818:Animals; D004798:Enzymes / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D006836:Hydro-Lyases / Q000378:metabolism / Q000502:physiology; D053858:Metabolic Networks and Pathways / Q000235:genetics / Q000502:physiology; D008660:Metabolism / Q000235:genetics / Q000502:physiology*; D008661:Metabolism, Inborn Errors / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000214:Acyl Coenzyme A; D004798:Enzymes; C102829:ethylmalonyl-coenzyme A; D000429:Alcohol Oxidoreductases; C023858:2-hydroxyglutarate dehydrogenase; D006836:Hydro-Lyases; D000103:Acetyl-CoA Carboxylase