NADP-DEPENDENT ENZYMES .2. EVOLUTION OF THE MONONUCLEOTIDE AND DINUCLEOTIDE BINDING DOMAINS

Nicotinamide adenine dinucleotides [NAD and NADP with both referred to as NAD(P)] are among the more diffuse redox cofactors, Despite their stereochemical similarity where the only difference is a phosphomonoes ter on the ribose near the adenine of NADP, they show different bioche mical reactivities with NAD behaving as an oxidant and NADP as a reduc tant. NAD(P)-dependent enzymes generally share a common open alpha/bet a fold with few exceptions only recently structurally characterized, T his study of the molecular evolution of the NAD(P) binding domains, po ssible given the large number of known molecular structures, addresses two main questions: 1) can a common fold exist in different biologica l systems (divergent evolution) and 2) does a relationship exist among similar biological systems that display different folds (convergent e volution)? Both the structures of mono- and dinucleotide binding domai ns have been classified by cluster analysis based on the similarity ev aluated by their main chain C alpha superposition. Moreover, the cofac tor conformations and the stereochemical characteristics of their pock ets have also been classified by analogous methods on the basis of the published tertiary structures. Two primary results appear: 1) the cla ssification of the mononucleotide binding domains is different from th at of the dinucleotide binding folds and 2) both divergent and converg ent evolutionary pathways can be hypothesized, the latter less frequen tly observed and less pronounced but nevertheless evident. The general ly accepted hypothesis that dinucleotide binding domains have evolved by gene duplication of primordial genes coding for the smaller mononuc leotide binding domains is acceptable but the two halves of the result ing dinucleotide binding domains are evolutionarly uncorrelated. The N H2-terminal mononucleotide binding domain is less variable than the CO OH-terminal half, probably because it involves the binding of the ADP moiety of NAD(P) invariant in all examined systems. There is evidence to postulate that evolutionary pathways for NAD(P)-dependent enzymes a re both divergent and convergent. In fact, nearly all combinations of similarity/dissimilarity in overall fold, cofactor conformation, and c ofactor binding pocket structural characteristics for each enzyme pair examined are possible, The NAD(P)-dependent enzymes apparently provid e a canonical example of an evolutionary principle that ''anything goe s.'' (C) 1997 Wiley-Liss, Inc.