title: Systematic discovery of analogous enzymes in thiamin biosynthesis.
abstract: In all genome-sequencing projects completed to date, a considerable number of 'gaps' have been found in the biochemical pathways of the respective species. In many instances, missing enzymes are displaced by analogs, functionally equivalent proteins that have evolved independently and lack sequence and structural similarity. Here we fill such gaps by analyzing anticorrelating occurrences of genes across species. Our approach, applied to the thiamin biosynthesis pathway comprising approximately 15 catalytic steps, predicts seven instances in which known enzymes have been displaced by analogous proteins. So far we have verified four predictions by genetic complementation, including three proteins for which there was no previous experimental evidence of a role in the thiamin biosynthesis pathway. For one hypothetical protein, biochemical characterization confirmed the predicted thiamin phosphate synthase (ThiE) activity. The results demonstrate the ability of our computational approach to predict specific functions without taking into account sequence similarity.
authors.affiliation: Instituto de Biotecnología, Universidad Nacional Autónoma de México, Av. Universidad 2001, Cuernavaca, Morelos, 62210, Mexico. emorett@ibt.unam.mx
authors.forename: Enrique
authors.initials: E
authors.lastname: Morett
authors.forename: Jan O
authors.initials: JO
authors.lastname: Korbel
authors.forename: Emmanuvel
authors.initials: E
authors.lastname: Rajan
authors.forename: Gloria
authors.initials: G
authors.lastname: Saab-Rincon
authors.forename: Leticia
authors.initials: L
authors.lastname: Olvera
authors.forename: Maricela
authors.initials: M
authors.lastname: Olvera
authors.forename: Steffen
authors.initials: S
authors.lastname: Schmidt
authors.forename: Berend
authors.initials: B
authors.lastname: Snel
authors.forename: Peer
authors.initials: P
authors.lastname: Bork
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000096:biosynthesis* / Q000737:chemistry* / Q000145:classification / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D004734:Energy Metabolism / Q000502:physiology*; D004926:Escherichia coli / Q000737:chemistry* / Q000145:classification / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D013831:Thiamine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D019883:Alkyl and Aryl Transferases; C435495:thiamin phosphate synthase; D013831:Thiamine