Looking in New Directions for Origins and Cryptic Mechanisms of Enzyme Catalysis

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Project Summary: This project is focused on understanding the physical and mechanistic properties of enzymes that underlie their exquisite function. In recent years, protein motions have been implicated as essential to achieve an extremely rapid catalysis of bond cleavage events at enzyme active sites. Methodology for the spatial and temporal resolution of such protein motions has been developed using enzyme prototypes that catalyze hydrogen and methyl transfer reactions. These studies are now being extended to the TIM barrel family of enzymes that represent 10% of known enzyme structures and catalyze 5 out of 7 known EC classes. With this knowledge in hand, new approaches arise for protein redesign, de novo design and drug targeting. A second emerging area in biological catalysis concerns the post-translational modification of peptides that have been synthesized at the ribosome. A combination of structural and biochemical probes is addressing the enigmatic pathway that produces the bacterial cofactor and vitamin, pyrroloquinoline quinone. As the result of a number of recent breakthrough observations, each of the catalysts within the pathway is now amenable for detailed mechanistic study. These enzymes have little or no precedence in humans, making the PQQ pathway a possible new target for antibiotic development.