Genotype to phenotype mapping still needs underpinning by research in metabolism and enzymology

The article ‘Evidence that the metabolite repair enzyme NAD(P)HX epimerase has a moonlighting function’ by Niehaus et al. published in this issue illustrates a number of the problems that still arise when attempting to translate genotypes to phenotypes, such as for interpreting mutant phenotypes or building genome-scale metabolic models. In this case, the mutation concerned appears to map to an enzyme in one of the little-known but essential metabolite repair pathways that have been discovered in recent years. However, the bioinformatic and experimental evidence presented suggests that the annotated enzyme activity of the mutated gene product, whilst correct, accounts neither for the phenotype nor for the chromosomal and transcriptional associations of the gene. The bioinformatic and metabolomic evidence presented points to an additional but important role for the gene product in pyridoxal phosphate homoeostasis, thus adding the enzyme to the expanding list of those with a ‘moonlighting function’.