New enzymes in search of a function: the elusive activity that links renalase to hypertension

Today, with over 1000 prokaryotic and eukaryotic genomes already completed and about 4000 under way, the number of experimentally uncharacterized proteins is increasing exponentially (1). Genomic and post-genomic analyses provide valuable tools in predicting properties, functions and activities of the resulting huge set of ‘unknown’ proteins, estimated to represent more than 50% of plant and animal gene products (1). The discovery of human renalase represents an instructive example of the application of such approaches, showing both the power of comparative genomics in identifying novel proteins playing target ‘orphan’ functions, and its major limitations in predicting the details of the molecular activity of the identified proteins. Renalase has been discovered by screening genomic databases for previously uncharacterized, kidney-expressed, secreted enzymes, predicted to possess catecholamine-degrading activity. To date, several observations have confirmed the involvement of renalase in blood pressure regulation, suggesting that it represents an important novel link between the excretory and the cardiovascular systems, with obvious therapeutic implications (2). When the protein was finally isolated in recombinant form, the predicted adoption of a p-hydroxybenzoate reductase-like fold and the presence of bound flavin adenine dinucleotide cofactor were confirmed (3,4). However, at variance with the expectations, renalase turned out to be devoid of amine-degrading activity and not to be secreted through the conventional secretory pathway (3,4). The study of the reactivity of the active-site of this putative oxidoreductase is now in progress at the light of its recently determined crystal structure, in order to ascertain its actual catalytic activity and the molecular mechanism of its physiological action. 1. Hanson AD, et al. Biochem J. 2009; 425: 1-11. 2. Xu J, et al. J Clin Invest. 2005; 115: 1275-80. 3. Pandini V, et al. Protein Expr Purif. 2010; 72: 244-53. 4. Milani M, et al. J Mol Biol. 2011; 411: 463-73.