The number of proteins in the UniProt database (>89M sequences in Release 2017_08) is increasing with a doubling time of 2.5 yrs; however, ≥50% of the proteins have uncertain or unknown functions. Because sequence homology alone is not sufficient to assign in vitro activities and in vivo metabolic functions to uncharacterized enzymes, we are developing large-scale tools strategies to facilitate the prediction and subsequent experimental verification of their activities and functions. This lecture will highlight several examples of the use of these tools and strategies for discovery of novel enzymes and metabolic pathways: 1) a novel pathway for methionine salvage using metabolomics and transcriptomics, 2) a novel pathway for 4-hydroxyproline betaine catabolism using homology modeling and integrative pathway mapping, 3) large-scale assignment of functions to members of the proline racemase family guided by genome context, and 4) the use of solute binding proteins for microbial transport systems to guide the discovery of novel catabolic pathways. These approaches use sequence similarity networks (SSNs) for entire protein families and genome neighborhood networks (GNNs) for isofunctional groups in protein families to leverage the large amount of protein and nucleic sequence information now available; the lecture also will describe web servers for generation of SSNs (EFI-EST; and GNNs (EFI-GNT;


Professor Gerlt is the Program Director of the Enzyme Function Initiative (EFI) under the National Institute of General Medical Sciences involving 9 academic institutions in the US and Canada. He is a mechanistic enzymologist and an expert in structure-function studies of numerous metabolic enzymes. Prof Gerlt has made numerous significant contributions to the field of mechanistic enzymology and physical organic chemistry, and his seminal work on the enolase superfamily and the crotonase superfamily has established a new and important discipline of genomic enzymology. Prof Gerlt has won numerous awards and currently holds the Gutgsell Chair, a prestigious University Endowed Chair. He has published extensively in prestigious journals and is currently the Associate Editor for the ACS journal, Biochemistry, and is on the Editorial Board of several journals.