This research award in the Inorganic, Bioinorganic, and Organometallic Chemistry program of the CHE division and in the Molecular and Cellular Biosciences Division supports work by Professor James Larrabee at Middlebury College to carry out fundamental studies on metallohydrolase enzymes using magnetic circular dichroism spectroscopy. Four enzymes that are in the study are methionine aminopeptidase metallo beta-lactamase, glycerophosphodiesterase, and phosphotriesterase; these enzymes all share the common active site structural motif of two metal ions bridged by carboxylate and water (or hydroxide) ligands. These enzymes are studied in the cobalt(II) form. This approach provides an especially strong magnetic circular dichroism signal that is used to monitor changes in the metal environment as inhibitors are bound to the enzymes. These changes are used to gain insight into the enzyme mechanisms, which are expected to be similar because of the structural similarities of the enzyme active sites.
This research study at Middlebury College is conducted by undergraduate research assistants as collaborators. This type of research experience encourages undergraduates to pursue careers in science and to further their science education by attending graduate school. This research award is supporting a total of nine undergraduate research assistants.
Understanding how enzymes function is generally important to science; however, a better understanding of these four enzymes has potential benefit to society. Methionine aminopeptidase has been identified as the target enzyme of anti-angiogenesis drugs; therefore, inhibitors are drug candidates to treat solid tumor cancers, arterial sclerosis, and rheumatoid arthritis. Metallo beta-lactamase hydrolyzes beta-lactams, a process which is the major cause of bacterial resistance to beta-lactam therapy. The esterases hydrolyze a number of organophosphates and have potential in bioremediation of organophosphate pesticide contamination and detoxification of organophosphate nerve agents.
