PMID:19000819

Citation	Kalyanaraman, C, Imker, HJ, Fedorov, AA, Fedorov, EV, Glasner, ME, Babbitt, PC, Almo, SC, Gerlt, JA and Jacobson, MP (2008) Discovery of a dipeptide epimerase enzymatic function guided by homology modeling and virtual screening. Structure 16:1668-77
Abstract	We have developed a computational approach to aid the assignment of enzymatic function for uncharacterized proteins that uses homology modeling to predict the structure of the binding site and in silico docking to identify potential substrates. We apply this method to proteins in the functionally diverse enolase superfamily that are homologous to the characterized L-Ala-D/L-Glu epimerase from Bacillus subtilis. In particular, a protein from Thermotoga martima was predicted to have different substrate specificity, which suggests that it has a different, but as yet unknown, biological function. This prediction was experimentally confirmed, resulting in the assignment of epimerase activity for L-Ala-D/L-Phe, L-Ala-D/L-Tyr, and L-Ala-D/L-His, whereas the enzyme is annotated incorrectly in GenBank as muconate cycloisomerase. Subsequently, crystal structures of the enzyme were determined in complex with three substrates, showing close agreement with the computational models and revealing the structural basis for the observed substrate selectivity.
Links	PubMed PMC2714228 Online version:10.1016/j.str.2008.08.015
Keywords	Amino Acid Sequence; Bacillus subtilis/enzymology; Bacterial Proteins/chemistry; Bacterial Proteins/metabolism; Base Sequence; Crystallography, X-Ray; DNA Primers; Dipeptidases/chemistry; Dipeptidases/metabolism; Enzymes/chemistry; Enzymes/genetics; Enzymes/metabolism; Kinetics; Models, Molecular; Molecular Sequence Data; Phylogeny; Protein Conformation; Racemases and Epimerases/chemistry; Racemases and Epimerases/metabolism; Sequence Alignment; Sequence Homology, Amino Acid; Thermotoga maritima/enzymology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
THEMA:AEEP		GO:0016855: racemase and epimerase activity, acting on amino acids and derivatives	ECO:0000314:		F		Table 3 shows kinetic parameters evaluated for the enzyme for the epimerization of various dipeptides.	complete CACAO 10144
THEMA:AEEP	enables	GO:0016855: racemase and epimerase activity, acting on amino acids and derivatives	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete

References

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