Leveraging structure for enzyme function prediction: methods, opportunities, and challenges

•Of the >50 million protein sequences, <1% have experimentally determined functions.•Protein structures can provide clues to function, such as the substrates of enzymes.•Homology modeling and ligand docking algorithms can help infer function from structure.•Recent successes include discovery of novel metabolites, enzymes, and pathways.

The rapid growth of the number of protein sequences that can be inferred from sequenced genomes presents challenges for function assignment, because only a small fraction (currently <1%) has been experimentally characterized. Bioinformatics tools are commonly used to predict functions of uncharacterized proteins. Recently, there has been significant progress in using protein structures as an additional source of information to infer aspects of enzyme function, which is the focus of this review. Successful application of these approaches has led to the identification of novel metabolites, enzyme activities, and biochemical pathways. We discuss opportunities to elucidate systematically protein domains of unknown function, orphan enzyme activities, dead-end metabolites, and pathways in secondary metabolism.