Scheduled Seminars on 11/2/2010

MICHAEL GALPERIN at 11:00  Edit  Reschedule  Delete

Analogous enzymes revisited: Twelve years after
Twelve years ago we have undertaken a systematic study of the metabolic reactions that could be catalyzed by distinct classes of enzymes. In the course of that study we identified 105 Enzyme Commission nomenclature (EC) nodes represented by two or more enzyme forms without detectable sequence similarity to each other (PMID: 9724324). For 34 EC nodes, independent evolutionary origin of those enzyme forms has been substantiated (or inferred) by showing (or predicting) that the respective isozymes had distinct structural folds. These data confirmed that presence of alternative enzyme forms was a rule, rather than an exception, and stimulated search for additional enzyme forms.
In the past 12 years, efforts to close the remaining holes in microbial pathways led to the discovery of new enzyme forms, some of them duplicating the functions of previously known enzymes. In addition, structural genomics greatly improved structural coverage of microbial proteomes, making it possible to reexamine and further expand the original list of analogous enzymes. I will present the results of a recent re-analysis of the analogous enzymes (PMID: 20433725) that identified 185 EC nodes with truly analogous enzymes (non-homologous isofunctional enzymes, NISE), of which only 77 were from the original 1998 list. Among the 28 discarded nodes, the majority were the enzymes that came from the same SCOP superfamily but whose structures showed RMSD of at least 3.0 A. In several other cases, enzymes acting on non-identical substrates had been erroneously assigned to the same EC node. Structural assignments of the NISEs showed overrepresentation of proteins with the TIM-barrel fold and the nucleotide-binding Rossmann fold. From the functional perspective, the set of NISE was enriched in hydrolases, particularly carbohydrate hydrolases, and in enzymes involved in defense against oxidative stress. It appeared that at least some of the NISEs had been recruited relatively recently from enzyme families that were active against related substrates and were sufficiently flexible to accommodate changes in substrate specificity.

Joint work with Marina Omelchenko, Yuri Wolf, and Eugene Koonin


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