4zcc | pdb_00004zcc
Renalase in complex with NADH
Structural highlights
Publication Abstract from PubMedDespite a lack of convincing in vitro evidence and a number of sound refutations, it is widely accepted that renalase is an enzyme unique to animals that catalyzes the oxidative degradation of catecholamines in blood in order to lower vascular tone. Very recently, we identified isomers of beta-NAD(P)H as substrates for renalase (Beaupre, B. A. et al. (2015) Biochemistry, 54, 795-806). These molecules carry the hydride equivalent on the 2 or 6 position of the nicotinamide base and presumably arise in nonspecific redox reactions of nicotinamide dinucleotides. Renalase serves to rapidly oxidize these isomers to form beta-NAD(P)(+) and then pass the electrons to dioxygen, forming H2O2. We have also shown that these substrate molecules are highly inhibitory to dehydrogenase enzymes and thus have proposed an intracellular metabolic role for this enzyme. Here, we identify a renalase from an organism without a circulatory system. This bacterial form of renalase has the same substrate specificity profile as that of human renalase but, in terms of binding constant (Kd), shows a marked preference for substrates derived from beta-NAD(+). 2-dihydroNAD(P) substrates reduce the enzyme with rate constants (kred) that greatly exceed those for 6-dihydroNAD(P) substrates. Taken together, kred/Kd values indicate a minimum 20-fold preference for 2DHNAD. We also offer the first structures of a renalase in complex with catalytically relevant ligands beta-NAD(+) and beta-NADH (the latter being an analogue of the substrate(s)). These structures show potential electrostatic repulsion interactions with the product and a unique binding orientation for the substrate nicotinamide base that is consistent with the identified activity. Bacterial Renalase: Structure and Kinetics of an Enzyme with 2- and 6-Dihydro-beta-NAD(P) Oxidase Activity from Pseudomonas phaseolicola.,Hoag MR, Roman J, Beaupre BA, Silvaggi NR, Moran GR Biochemistry. 2015 Jun 23;54(24):3791-802. doi: 10.1021/acs.biochem.5b00451. Epub, 2015 Jun 9. PMID:26016690[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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