Resolving the Multidecade-Long Mystery in MoaA Radical SAM Enzyme Reveals New Opportunities to Tackle Human Health Problems

Abstract

MoaA is one of the most conserved radical S -adenosyl- l -methionine (SAM) enzymes, and is found in most organisms in all three kingdoms of life. MoaA contributes to the biosynthesis of molybdenum cofactor (Moco), a redox enzyme cofactor used in various enzymes such as purine and sulfur catabolism in humans and anaerobic respiration in bacteria. Unlike many other cofactors, in most organisms, Moco cannot be taken up as a nutrient and requires de novo biosynthesis. Consequently, Moco biosynthesis has been linked to several human health problems, such as human Moco deficiency disease and bacterial infections. Despite the medical and biological significance, the biosynthetic mechanism of Moco’s characteristic pyranopterin structure remained elusive for more than two decades. This transformation requires the actions of the MoaA radical SAM enzyme and another protein, MoaC. Recently, MoaA and MoaC functions were elucidated as a radical SAM GTP 3′,8-cyclase and cyclic pyranopterin monophosphate (cPMP) synthase, respectively. This finding resolved the key mystery in the field and revealed new opportunities in studying the enzymology and chemical biology of MoaA and MoaC to elucidate novel mechanisms in enzyme catalysis or to address unsolved questions in Moco-related human health problems. Here, we summarize the recent progress in the functional and mechanistic studies of MoaA and MoaC and discuss the field’s future directions.

Twenty Years of Radical SAM! The Genesis of the Superfamily

“…54 The Perspective by Yokoyama, Li, and Pang describes heroic studies by the Yokoyama lab, and others, to dissect a complex transformation by MoaA, an RS enzyme, and a partner protein, MoaC, during the biosynthesis of molybdopterin. 55 Molybdopterin is an essential redox cofactor used in molybdenumcontaining enzymes. The inability to synthesize the cofactor in humans results in several potentially fatal diseases.…”