The Gordon Hammes Lecture Award is sponsored jointly by Biochemistry and the ACS Division of Biological Chemistry. The objective is to recognize and honor a single individual whose scientific contributions have had a major impact on research at the interface of chemistry and biology.
“I am delighted with the committee’s selection of John Gerlt as the 2017 Gordon Hammes lecturer. He is a visionary scientist whose impact on our understanding of protein function cannot be overstated,” says Alanna Schepartz, Editor-in-Chief of Biochemistry.
Craig Townsend, Chair of the ACS Division of Biological Chemistry, says “John is a great choice. I am pleased to offer my congratulations to him as the 2017 recipient of the Hammes Lectureship and thank him on the behalf of all of us for his service to the wider biological chemistry community. Apart from the excellent science honored by his selection, John has contributed over many years by organizing meetings and symposia, serving as an Associate Editor of Biochemistry, and as a founder of the Enzyme Function Initiative.”
Gerlt will present the Gordon Hammes lecture at a session in his honor at the 254th ACS National Meeting & Exposition in Washington, D.C., in August 2017. Biochemistry and the ACS Division of Biological Chemistry encourage you to attend the session and will provide more details on the date and time when they become available.
Interview With 2017 Gordon Hammes Lecture Award-Winner John Gerlt
How did you choose to pursue this field of research?
I was a graduate student in Frank Westheimer’s laboratory where I was exposed to both organic chemistry and enzymology. I learned about “problem-oriented” science—choose an interesting and important problem and do/learn what it takes to solve the problem. And, that is what I’ve tried to do throughout my career.
Thirty years ago, I was involved in the accidental discovery of the first functionally diverse enzyme superfamily—David Neidhart, George Kenyon, Greg Petsko, and I recognized that mandelate racemase and muconate lactonizing enzyme are structural homologues but catalyze different reactions that share enolate anion intermediates. Our focus was the mechanism of the mandelate racemase-catalyzed reaction, but we immediately realized a much large context for our work. Indeed, both enzymes are members of the functionally diverse enolase superfamily that now includes at least 60,000 members in the UniProt database. At the time we thought we should be able to understand how new catalytic functions evolve, as genome sequencing became routine we realized that the problem was not trivial. The functions of many (most?) of the members of the enolase superfamily are unknown (50% of the proteins in the sequence databases have unknown, uncertain, or incorrect functional annotations). Sine that time, my research focus has been figuring out how to assign functions to uncharacterized enzymes discovered in genome projects, with frequent diversions provided by the mechanisms of “interesting” enzymes discovered along the way.
What are you working on now?
I have learned the importance of multi-disciplinary science and working with world-class experts in complementary disciplines. I now am collaborating with John Cronan at The University of Illinois, a microbiologist, Steve Almo at Albert Einstein College of Medicine, a structural enzymologist, and Matt Jacobson, Andrej Sali, and Brian Shoichet at University of California, San Francisco, computational enzymologists. We are working together to devise strategies for predicting the functions of uncharacterized enzymes discovered in microbial genome projects. We are using the solute binding proteins (SBPs) for transport systems to guide the discovery of novel enzymes in novel catabolic pathways. The ligand specificity of the SBP anchors the identity of the substrate for the first enzyme in the pathway and the proximity of the gene encoding the SBP to those for the pathway enzymes facilitates prediction of the pathway. Of course, the predictions have to be verified both in vitro and in vivo (experimental enzymology and microbiology)! In the course of this work, we have developed community-accessible “genomic enzymology” web servers to generate sequence similarity networks for analysis of sequence-function relationships in protein families and genome neighborhood networks to identify genome context.
What do you anticipate working on in the future?
Given the difficulty of the problem of assigning in vitro enzymatic activities and in vivo metabolic functions to uncharacterized enzymes, I plan to continue working on the functional assignment challenge. We continue to discover novel enzymatic reactions with novel mechanisms in novel pathways. Nature keeps providing scientific “amusement” that keeps the interest level high!
What is important in training the next generation of researchers?
I appreciate the importance of encouraging students and postdocs to pursue their own interests. Frank Westheimer often told us that “the best science is done by young scientists.” Old scientists “know too much” to do innovative science because they are often hindered by old ideas.
And, from my own experiences and their rewards, I am convinced that progress often is best achieved by multi-disciplinary teams. So, I believe that providing students and postdocs with that environment is important for them in both the short and long term.
Recent Articles by John A. Gerlt in ACS Publications Journals:
A General Strategy for the Discovery of Metabolic Pathways: d-Threitol, l-Threitol, and Erythritol Utilization in Mycobacterium smegmatis
J. Am. Chem. Soc., 2015, 137 (46), pp 14570–14573
Rate and Equilibrium Constants for an Enzyme Conformational Change during Catalysis by Orotidine 5′-Monophosphate Decarboxylase
Biochemistry, 2015, 54 (29), pp 4555–4564
A Unique cis-3-Hydroxy-l-proline Dehydratase in the Enolase Superfamily
J. Am. Chem. Soc., 2015, 137 (4), pp 1388–1391
Experimental Strategies for Functional Annotation and Metabolism Discovery: Targeted Screening of Solute Binding Proteins and Unbiased Panning of Metabolomes
Biochemistry, 2015, 54 (3), pp 909–931
Enzyme Architecture: Deconstruction of the Enzyme-Activating Phosphodianion Interactions of Orotidine 5′-Monophosphate Decarboxylase
J. Am. Chem. Soc., 2014, 136 (28), pp 10156–10165
Identification of the in Vivo Function of the High-Efficiency d-Mannonate Dehydratase in Caulobacter crescentus NA1000 from the Enolase Superfamily
Biochemistry, 2014, 53 (25), pp 4087–4089