Nature Biotechnology
21, 790 - 795 (2003)
Published online: 8 June 2003; | doi:10.1038/nbt834
Systematic discovery of analogous enzymes in thiamin
biosynthesisEnrique Morett1, 6, Jan O Korbel2, 3, 6, Emmanuvel Rajan1, Gloria Saab-Rincon1, Leticia Olvera1, Maricela Olvera1, Steffen Schmidt2, 3, 4, Berend Snel2, 5
& Peer Bork2, 31
Instituto de Biotecnología, Universidad
Nacional Autónoma de México, Av. Universidad 2001,
Cuernavaca, Morelos, 62210,
Mexico. 2
European Molecular Biology Laboratory,
Meyerhofstra e 1, 69117 Heidelberg,
Germany. 3
Max-Delbrück-Center for Molecular
Medicine, 13092 Berlin-Buch,
Germany. 4
University of Heidelberg, Department of
Parasitology, INF 324, 69120 Heidelberg,
Germany. 5
Present address: Nijmegen Centre for Molecular
Life Sciences, p/a CMBI, Toernooiveld 1, 6525 ED
Nijmegen, Netherlands. 6
These authors contributed equally to this work.
Correspondence should be addressed to Enrique Morett emorett@ibt.unam.mx or Peer Bork bork@embl-heidelberg.deIn 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.
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