平特五不中

Abstract:

Enzymes are structurally dynamic molecules that play essential roles in many processes related to human health and disease. Despite the recognition for many years that enzyme structural transitions (conformational changes) are integral to the biochemical function and regulation of enzymes, the precise relationships between enzyme conformation and function are often incompletely understood. A better understanding of the structural dynamic mechanisms of enzyme function could inform applications in drug development, synthetic biology, or the engineering of enzymes with new functions. My group has been interested in the conformational dynamic properties of enzymes in several contexts that are relevant to human health and disease. First, we have investigated the lanthipeptide synthetase enzymes that install multiple thioether macrocycles into genetically encoded peptide antibiotics. Despite their relaxed substrate specificity, these enzymes often manage to install sets of thioether rings with precise control over the regio- and stereoselectivity of the macrocyclization. By making innovative use of a suite of mass spectrometry-based approaches, my group has begun to untangle the complex relationships between structural dynamics, conformational changes, and biochemical function in lanthipeptide synthetases. We are currently expanding this pioneering work on lanthipeptide synthetases to investigate the conformational dynamic properties of other natural product biosynthetic enzymes, and to develop and adapt additional biophysical measurements with improved spatial and temporal resolution. Second, in collaboration with the Auclair group, we have again turned to mass spectrometry to investigate the structural basis of allosteric regulation in cytochrome P450 enzymes, which play an essential role in drug metabolism in humans. The data show that P450 enzymes are conformational chameleons, whose structure and function are determined in part by the identity and location of the bound ligand. Future work will shift to investigating the reductase enzyme that regulates P450 activity through dynamic protein-protein interactions. Cumulatively, these and other efforts by my group have illustrated the unique ability of biological mass spectrometry to reveal previously intractable mechanistic information on conformationally dynamic enzymes of relevance to human health and disease.

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Bio:

Christopher J. Thibodeaux is a native of Louisiana (USA), where he graduated valedictorian with bachelor's degrees in Biochemistry, Botany, and Chemistry from Louisiana State University. He then entered graduate school in the lab of Hung-wen Liu at the University of Texas, Austin, where his Ph.D. focused on elucidating the chemical and kinetic mechanisms of enzyme catalysis. Following graduation, he completed postdoctoral stints in the labs of Taekjip Ha and Wilfred van der Donk at the University of Illinois, Urbana-Champaign, where he studied biomolecular single molecule fluorescence spectroscopy and peptide natural product biosynthesis, respectively. In 2016, he began his independent career in at 平特五不中, where he is currently an Assistant Professor in the Department of Chemistry and the Associate Director of the 平特五不中 Centre de Recherche en Biologie Structurale. His research is broadly aimed at combatting the problem of antimicrobial resistance by understanding the detailed molecular mechanisms of enzymes that synthesize structurally complex antimicrobial compounds, discovering novel antimicrobial compounds by genome mining, and by investigating the molecular mechanisms of bacterial virulence. In his spare time, he enjoys the outdoors, cooking and eating spicy food, large family gatherings, watching (American) football and baseball, and spending time with his wife and three daughters.

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