title: Prediction and identification of sequences coding for orphan enzymes using genomic and metagenomic neighbours.
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.
authors.affiliation: Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Takuji
authors.initials: T
authors.lastname: Yamada
authors.forename: Alison S
authors.initials: AS
authors.lastname: Waller
authors.forename: Jeroen
authors.initials: J
authors.lastname: Raes
authors.forename: Aleksej
authors.initials: A
authors.lastname: Zelezniak
authors.forename: Nadia
authors.initials: N
authors.lastname: Perchat
authors.forename: Alain
authors.initials: A
authors.lastname: Perret
authors.forename: Marcel
authors.initials: M
authors.lastname: Salanoubat
authors.forename: Kiran R
authors.initials: KR
authors.lastname: Patil
authors.forename: Jean
authors.initials: J
authors.lastname: Weissenbach
authors.forename: Peer
authors.initials: P
authors.lastname: Bork
mesh_terms: D002874:Chromosome Mapping; D030541:Databases, Genetic; D004798:Enzymes / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D053858:Metabolic Networks and Pathways; D054892:Metagenome / Q000235:genetics*; D056186:Metagenomics / Q000379:methods*; D008954:Models, Biological; D017422:Sequence Analysis, DNA; D049490:Systems Biology
chemical_list: D004798:Enzymes