Our new paper, published in PNAS, resolves a decades-long question about how MoaC constructs the core of molybdenum cofactor (Moco), a small molecule required for essential metabolic enzymes. By combining biochemical experiments, mass spectrometry, and X-ray crystallography, we captured short-lived reaction intermediates and discovered that MoaC temporarily forms a covalent bond with its substrate. This bond acts as a molecular tether, carrying and positioning a carbon atom during a complex molecular rearrangement. We term this previously unrecognized strategy “guiding covalent catalysis.” The findings reveal a new way enzymes can control complex chemistry and suggest that related mechanisms may operate in the biosynthesis of other essential cofactors.
Department of Biochemistry, Duke University School of Medicine
