Abstract 1596 Damage is Inevitable and Repair is Essential - Also in Metabolism

A great majority of metabolic enzymes are nowadays genetically identified and gaps in metabolic pathways are becoming more exceptional. Metabolomic studies and protein database analyses indicate, however, that even in well-characterized organisms like yeast and humans, hundreds of putative enzymes of unknown function persist. Findings over the past 15 years suggest that a possibly significant fraction of these 'unknown' enzymes function as metabolite repair enzymes by acting on abnormal and potentially toxic metabolites that are constantly generated inside our cells by unwanted chemistry or enzyme promiscuity. NADHX and NADPHX for example are hydrated and redox inactive forms of the NADH and NADPH cofactors. We discovered a highly conserved metabolite repair system, composed of an epimerase (NAXE) and a dehydratase (NAXD), that converts NAD(P)HX back to the normal cofactors. We found that knocking out NAXD leads to high NADHX accumulation in cells, resulting in central metabolic perturbations, notably in de novo serine synthesis. The physiological importance of the NAD(P)HX repair system is now strikingly illustrated by a recently identified fatal neurometabolic condition that develops in young children deficient in this repair system. The concept of metabolite repair has triggered the discovery of many new, sometimes quite unexpected enzymatic reactions and helped to solve several other rare disease mechanisms. There are strong reasons to believe that more such discoveries are still to follow. Metabolomics has been and will continue to be a central tool for uncovering non-canonical metabolites and elucidating underground metabolism. Importantly, therapeutic approaches with promising results have already been tested in two human disorders of metabolite repair, highlighting once again how conceptual advances pushed by fundamental research can be translated within sometimes reasonable timeframes into enhanced patient care. The research at LCSB was supported by the Luxembourg National Research Fund (FNR), the JuniclairFoundation, and Lions Clubs Luxembourg. The research at MCRI was supported by the State Government of Victoria's Operational Infrastructure Support Program, the MitoFoundation, internal MCRI grants, and the Crane and Perkins families.