Paradigm Shift for Radical S-Adenosyl-l-methionine Reactions: The Organometallic Intermediate ? Is Central to Catalysis


Amanda S. Byer, Hao Yang, Elizabeth C. McDaniel, Venkatesan Kathiresan, Stella Impano, Adrien Pagnier, Hope Watts, Carly Denler, Anna L. Vagstad, Jorn Piel, Kaitlin S. Duschene, Eric M. Shepard, Thomas P. Shields, Lincoln G. Scott, Edward A. Lilla, Kenichi Yokoyama, William E. Broderick, Brian M. Hoffman, Joan B. Broderick


Journal of the American Chemical Society


Radical S-adenosyl-l-methionine (SAM) enzymes comprise a vast superfamily catalyzing diverse reactions essential to all life through homolytic SAM cleavage to liberate the highly reactive 5'-deoxyadenosyl radical (5'-dAdo·). Our recent observation of a catalytically competent organometallic intermediate ? that forms during reaction of the radical SAM (RS) enzyme pyruvate formate-lyase activating-enzyme (PFL-AE) was therefore quite surprising, and led to the question of its broad relevance in the superfamily. We now show that ? in PFL-AE forms as an intermediate under a variety of mixing order conditions, suggesting it is central to catalysis in this enzyme. We further demonstrate that ? forms in a suite of RS enzymes chosen to span the totality of superfamily reaction types, implicating ? as essential in catalysis across the RS superfamily. Finally, EPR and electron nuclear double resonance spectroscopy establish that ? involves an Fe-C5' bond between 5'-dAdo· and the [4Fe-4S] cluster. An analogous organometallic bond is found in the well-known adenosylcobalamin (coenzyme B12) cofactor used to initiate radical reactions via a 5'-dAdo· intermediate. Liberation of a reactive 5'-dAdo· intermediate via homolytic metal-carbon bond cleavage thus appears to be similar for ? and coenzyme B12. However, coenzyme B12 is involved in enzymes catalyzing only a small number (?12) of distinct reactions, whereas the RS superfamily has more than 100?000 distinct sequences and over 80 reaction types characterized to date. The appearance of ? across the RS superfamily therefore dramatically enlarges the sphere of bio-organometallic chemistry in Nature.



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