Richard N. Armstrong of Vanderbilt University has earned one of this year’s Cope Senior Scholar Awards for his multidisciplinary research at the interface of chemistry and biology—including work in physical organic chemistry, mechanistic enzymology, structural biology, computational chemistry, and bioinformatics.
Armstrong’s many achievements in a professional career going back to the 1970s have included groundbreaking research on enzymes that detoxify foreign agents in mammals, the metabolism of small molecules by bacteria, and the structure and biology of proteins involved in leukotriene biosynthesis.
For example, he has played a leading role in mechanistic and structural characterization of enzymes involved in detoxification of xenobiotic compounds. These agents are not normally found inside an organism but make their way there via food, environmental exposure, and other sources. Such enzymes include glutathione (GSH) transferases, uridine diphosphate glucuronyltransferase, and epoxide hydrolase.
Highlights of the studies have included observing the active site of GSH’s thiolate anion, obtaining the first crystal structure of a GSH transferase with GSH bound to it, dissecting the role of specific residues in the enzyme’s mechanism, and determining the structure of a novel mitochondrial GSH transferase.
The work on GSH transferases “exemplifies Armstrong’s venturesome approach to research,” notes enzymologist Perry A. Frey of the University of Wisconsin, Madison.
Armstrong’s “chemical intuition, clever mechanistic experiments, and early embrace of structural biology” led to his group’s determination of the structures and detailed mechanisms of GSH transferases that play crucial roles in toxic electrophile breakdown, adds enzymologist John A. Gerlt of the University of Illinois, Urbana-Champaign.
Armstrong has also elucidated the detailed mechanisms of membrane proteins. In collaboration with a Karolinska Institute group, he used hydrogen-deuterium exchange mass spectrometry to study conformational transitions of membrane proteins in detergent micelles and two-dimensional crystals of lipid bilayers. And with collaborators at Stockholm University, he helped decipher the conformational dynamics of four individual catalytic intermediates in cytochrome c oxidase, a membrane protein involved in respiration. The latter study “remains the benchmark for H-D exchange mass spectrometry investigations of integral membrane proteins in both size and mechanistic complexity,” Gerlt says.
“Among Armstrong’s other noteworthy accomplishments, elucidation of how proteins confer resistance to the broad-spectrum antibiotic fosfomycin stands out,” says Donald Hilvert of the Swiss Federal Institute of Technology, Zurich, whose research interests include enzymology. “His work in this area has provided a window for understanding the enzymology of these fascinating metalloenzymes while opening up exciting opportunities for addressing the global problem of antimicrobial resistance.
“In short,” Hilvert continues, “Armstrong tackles topical problems having both academic and practical importance. His ability to combine the tools and thinking of organic chemistry and structural biology with enzymology is masterful. His research program is creative, chemically rigorous, and experimentally elegant.”
Armstrong, 65, was born in Boonville, Mo. He earned a bachelor’s degree in chemistry at Western Illinois University, Macomb, in 1970 and a Ph.D. in organic chemistry at Marquette University in 1975. After two postdoctoral years at the University of Chicago and a two-year fellowship at the National Institutes of Health, he joined the chemistry faculty at the University of Maryland, College Park, in 1980 and moved to Vanderbilt in 1995.