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Mechanism of Controlling the Formation and Reactivities of Radicals in GTP 3’,8-cyclase in Molybdenum Cofactor Biosynthesis

Portrait of Prof. Kenichi (Ken) Yokoyama, guest speaker
Prof. Kenichi (Ken) Yokoyama
Associate Professor of Chemistry, Biochemistry, and Cell Biology
Duke University School of Medicine
iSTEM Building 2, Room 1218
Inorganic Seminar

Radical S-adenosyl-L-methionine (SAM) enzymes form a large superfamily with >700,000 unique gene sequences. These enzymes catalyze reductive cleavage of SAM to generate a highly reactive 5′-deoxyladenosyl radical and catalyze otherwise chemically challenging radical reactions. While a large number of reactions have been reported to be catalyzed by these enzymes, the molecular details of the mechanisms by which these enzymes control the formation and reactivities of free radical species remain largely unknown. My group has been tacking these questions by mechanistically characterizing the MoaA enzyme in the molybdenum cofactor (Moco) biosynthesis. Moco is a ubiquitous cofactor found in all kingdoms of life and essential for the lives of many organisms including humans and pathogenic bacteria. In humans, genetic mutations in Moco biosynthesis cause a fatal disease, Moco deficiency (MoCD). More than 50% of MoCD patients carry mutations in the moaA gene coding for a radical SAM enzyme MoaA. My group has discovered that MoaA catalyzes a unique 3′,8-cyclization of guanosine 5′-triphosphate (GTP) as the first step in the Moco biosynthesis. The 3′,8-cyclization of GTP was unprecedented in synthetic or biological reactions and is impossible without the MoaA catalysis. Therefore, my group has been studying the mechanism of MoaA catalysis by combining various approaches including enzymology, EPR, NMR, and theoretical studies. The results so far have provided insights into how MoaA controls the formation and reactivities of free radical species. The study has also elucidated the mechanism by which the MoCD-causing mutations inactivate MoaA.

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