Prediction and identification of sequences coding for orphan enzymes using genomic and metagenomic neighbours.

Molecular Systems Biology
Takuji YamadaPeer Bork

Abstract

Despite the current wealth of sequencing data, one-third of all biochemically characterized metabolic enzymes lack a corresponding gene or protein sequence, and as such can be considered orphan enzymes. They represent a major gap between our molecular and biochemical knowledge, and consequently are not amenable to modern systemic analyses. As 555 of these orphan enzymes have metabolic pathway neighbours, we developed a global framework that utilizes the pathway and (meta)genomic neighbour information to assign candidate sequences to orphan enzymes. For 131 orphan enzymes (37% of those for which (meta)genomic neighbours are available), we associate sequences to them using scoring parameters with an estimated accuracy of 70%, implying functional annotation of 16,345 gene sequences in numerous (meta)genomes. As a case in point, two of these candidate sequences were experimentally validated to encode the predicted activity. In addition, we augmented the currently available genome-scale metabolic models with these new sequence-function associations and were able to expand the models by on average 8%, with a considerable change in the flux connectivity patterns and improved essentiality prediction.

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Citations

May 16, 2014·PloS One·Alexander G ShearerChristine D Rhee
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Feb 23, 2019·Nature Protocols·Laurent HeirendtRonan M T Fleming

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Methods Mentioned

BETA
phylogenetic profiles
gene knock-out
gene-knockout
gene neighbourhood
PCR

Software Mentioned

SMASHcommunity
Celera assembler
FCA
Arachne
ILOG CPLEX Optimizer
Model Seed
HMMER3

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