SPRING 2019 SEMINAR SERIES
Dr. Ken Yokoyama
Radical mechanisms in cofactor biosynthesis and human inheritable disease
My group has been working on radical SAM enzymes that catalyze critical steps in the backbone construction of natural products and cofactors. In this seminar, I will focus on the biosynthesis of molybdenum cofactor (Moco). Moco is an organometallic cofactor essential for all kingdoms of life, plays central roles in various biological processes, and must be biosynthesized de novo. In humans, Moco biosynthesis is vital for the healthy development of the brain, and genetic mutations in biosynthetic genes cause a fatal disease, Moco deficiency. During Moco biosynthesis, the characteristic pyranopterin ring is constructed by a complex rearrangement of guanosine 5´-triphosphate (GTP) into cyclic pyranopterin (cPMP) through the action of two enzymes, MoaA and MoaC. Conventionally, MoaA, a radical SAM enzyme, was considered to catalyze the majority of this transformation, with MoaC playing little or no role in the pyranopterin formation. However, the data from our lab have revealed a distinct scenario, where MoaC is responsible for the majority of the transformation by converting an unusual cyclic nucleoside, 3´,8-cyclo-7,8-dihydro-guanosine 5’-triphosphate (3´,8-cH2GTP), to cPMP. In this seminar, I will present our discovery of 3´,8-cH2GTP and mechanistic and structural characterizations of MoaA and MoaC. I will also cover our recent progress in understanding the cause of human Moco deficiency disease from mechanistic enzymology point of view.