With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Professor Tadhg Begley from Texas A&M University to investigate the enzymology of menaquinone biosynthesis in bacteria. Menaquinone is a membrane bound vitamin that plays a key role in bacterial energy generation and human blood clotting. Recently a new pathway was discovered for how this compound is produced in bacteria. The proposed research will focus on understanding the details of the new chemistry involved in this pathway. This research is significant because it will uncover new chemical reactions in bacteria that will enable the design of new antibiotics against pathogenic bacteria. In addition to new knowledge gained during the course of the menaquinone biosynthesis project, graduate students and a significant cadre of undergraduates will receive training in biological chemistry. The PI will also revise the textbook "The Organic Chemistry of Biological Pathways" and continue to participate in a workshop to mentor new faculty in organic and biological chemistry.
A new menaquinone biosynthetic pathway was recently discovered that uses two radical SAM enzymes (MqnE and MqnC) to assemble the napthoquinone moiety of the cofactor. Both of these enzymes involve radical addition reactions to aromatic rings. A set of experiments to elucidate the mechanisms of these two enzymes will be carried out. The physical organic chemistry-based approach will involve the synthesis and testing of substrate analogs to trap and characterize intermediates. Sequence analysis predicts the identity of the genes encoding the last two enzymes on the pathway. A set of undergraduate projects, to characterize these gene products will also be conducted. As menaquinone is an important cofactor in all living systems, understanding this widely distributed biosynthetic pathway is an element of the basic chemistry of life processes. In addition, in terms of long range scientific impact, this pathway has potential for antibiotic development because it is absent in most human intestinal bacteria and present in many pathogens.
