Mechanisms of enzyme-catalyzed reactions, functional genomics, lignin deconstruction for biofuel production: the importance of chemistry in the evolution of new enzymatic activities
With the availability of complete sequences for the genomes of numerous eubacteria, archaea, and eukaryotes, parallel structure/function studies of enzymes derived from a common progenitor is the best strategy for elucidating structure/function relationships for enzyme-catalyzed reactions. This approach, “genomic enzymology”, allows an efficient and precise identification of essential structure/function relationships that are important in catalysis. It also allows an understanding of the strategies used by Nature to evolve "new" enzymes and, therefore, provides design principles for the in vitro design of novel enzymes that catalyzed unnatural reactions. Our studies are enhancing the ability to predict the functions of "unknown" proteins discovered in genome projects.
We are studying three superfamilies of enzymes that are derived from common ancestors that share the ubiquitous (β/α)8-barrel fold. The members of the enolase superfamily catalyze different overall reactions initiated by abstraction of the α-proton of a carboxylate anion to form an enediolate anion intermediate that must be stabilized by the active site. The members of the D-ribulose 1,5-bisphosphate carboxylase/oxygenase (RuBisCO) superfamily. The members of the orotidine 5'-monophosphate (OMP) decarboxylase suprafamily catalyze different reactions that do not share any mechanistic features; our discovery of this suprafamily supports the hypothesis that Nature is opportunistic and can both identify and utilize functionally versatile active site templates in the evolution of new enzymatic activities.
We also are discovering and characterizing novel enzymes involved in the degradation of lignin in plant biomass. The production of biofuels from plant biomass is limited by the access of degradative enzymes to the cellulose by lignin, a complex polymer of phenylpropanoid units. Identification and characterization of these enzymes will facilitate the design of new microbial species that can be used to improve the efficiency of biofuel production.
B.S., 1969, Michigan State University (Biochemistry)
A.M., 1970, Harvard University (Biochemistry and Molecular Biology)
Ph.D., 1974, Harvard University (Biochemistry and Molecular Biology)
Postdoc., 1974-75, National Institutes of Health
American Association for the Advancement of Science Fellow, 2007
Repligen Corporation Award in Chemistry of Biological Processes, 2003