Menaquinone biosynthesis via the futalosine pathway

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In humans and other mammals, menaquinone is an essential vitamin (vitamin K) involved in blood clotting and bone formation. Vitamin K deficiency leads to prolonged blood clotting times and hemorrhaging. With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Tadhg Begley from Texas A&M University (TAMU) to study how vitamin K is biochemically synthesized. The reaction will be tracked over time in order to determine the unique chemical mechanisms of two enzymes involved in the biosynthetic pathway. The resulting basic scientific knowledge may help in the design and discovery of new antibiotics targeting several human pathogens. In addition to the scientific goals, Dr. Begley will help to increase the participation of students from diverse backgrounds by mentoring a student and faculty member at Prairie View A&M University. Dr. Begley also provides research opportunities to undergraduates and engages with the community through the annual Texas A&M University Chemistry open house. The research studies focus on the complete mechanistic characterization of aminofutalosine synthase (MqnE). This enzyme is unusual in incorporating an adenosyl radical into the reaction product rather than using it to abstract a hydrogen atom. The studies determine the conformation of the bound captodative radical by Electron Paramagnetic Resonance and the trapping of radical intermediates. The mechanism of MqnE serves as a model system for radical S-adenosyl-l-methionine (SAM) enzymes that generate a substrate radical by radical addition rather than by hydrogen atom abstraction. MqnC catalyzes a spirocyclization reaction and is also a radical SAM enzyme. MqnD catalyzes the formation of the dihydro-napthoquinone moiety of menaquinone. Reaction product characterization differentiates the two proposed mechanisms for this reaction. This research will characterize all of the enzymes required for the biosynthesis of menaquinone via the futalosine-dependent pathway, and will develop of new, generally useful, strategies for studying enzyme-mediated radical additions to benzene rings. The broader impacts include the mentoring of students and faculty members at Prairie View A&M University, the development of a set of biological experiments for the TAMU Chemistry open house, the training of two undergraduates/year in biological chemistry research, and the organization of the international conference on biological cofactors.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.