Seminar

Damage is inevitable and repair is essential – also in metabolism

Carole Linster, PhD

One of the revelations of the genomic revolution is that thousands of proteins encoded by sequenced genomes remain without identified function. Protein database analyses show that, even in extensively studied organisms like Saccharomyces cerevisiae and humans, about 30% of the proteome is still poorly understood at the functional level. More particularly, we estimated that around 600 yeast genes and 2000 human genes encode enzymes to which no clear molecular and/or biological role has been assigned yet. Recent findings suggest that a possibly significant fraction of these enzymes of unknown function are involved in a process called metabolite repair. Abnormal metabolites are constantly generated inside the cell by unwanted chemical reactions or by enzymatic side reactions; they are useless at best and toxic at worst. Metabolite repair enzymes clear the metabolite pool of these non-canonical metabolites. Their physiological importance is well illustrated through implication in disease processes. L-2-hydroxyglutaric aciduria for example, a severe human neurometabolic disorder, is caused by a deficiency in a metabolite repair enzyme. The latter normally prevents accumulation of a toxic side product formed by a TCA cycle enzyme. A series of other metabolite repair enzymes have been identified in mammals, but also in plants, invertebrates and microbes. I will describe how we combined comparative genomics, traditional biochemical and mass spectrometry-based approaches to contribute to these enzyme function discoveries and the study of their physiological relevance. While DNA and protein damage control have been extensively studied for many years, metabolite damage and repair has been neglected for a long time and is just starting to get more attention in the metabolic biochemistry field. In addition to rare disease research, metabolic modeling as well as metabolic engineering and synthetic biology efforts will certainly benefit from these recent fundamental developments.