Radical-SAM Enzymes Nature’s Choice to Initiate Radical Reactions

Radical reactions are central to enzymatic catalysis, and overwhelmingly are carried out by Nature’s largest enzyme superfamily, the radical S-adenosyl-L-methionine (SAM) enzymes (RS enzymes), with over 700,00 members that span all kingdoms of life and exhibit remarkable catalytic diversity. These enzymes initiate a reaction through H-atom abstraction from substrate by the 5'-deoxyadenosyl (5'-dAdo•) radical, which is created by regioselective reductive cleavage of the S-C5? bond of SAM, induced by electron transfer from a [4Fe-4S]1+ cluster that chelates the SAM amino-acid moiety. In collaboration with Prof. Joan Broderick, we have shown that the catalytic process surprisingly involves the obligatory formation of a bio-organometallic intermediate, denoted, omega. This talk walks through the new paradigm for RS function revealed by EPR/ENDOR characterization of omega and other intermediates. In particular we have captured and characterized the long-sought, but elusive 5'-dAdo•, and find it to be intimately chaperoned by the enzyme active site. In taking this walk we answer the equally long-sought, foundational question: Why is the title true?

Speaker: Brian Hoffman, Northwestern University