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

Mol Syst Biol. 2012 May 8;8:581. doi: 10.1038/msb.2012.13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Mapping
  • Databases, Genetic
  • Enzymes / genetics*
  • Enzymes / metabolism
  • Humans
  • Metabolic Networks and Pathways
  • Metagenome / genetics*
  • Metagenomics / methods*
  • Models, Biological
  • Sequence Analysis, DNA
  • Systems Biology

Substances

  • Enzymes