Paradigm Shift for Radical S-Adenosyl- l -methionine Reactions: The Organometallic Intermediate ω 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, Jörn 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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 ω 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 ω 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 ω forms in a suite of RS enzymes chosen to span the totality of superfamily reaction types, implicating ω as essential in catalysis across the RS superfamily. Finally, EPR and electron nuclear double resonance spectroscopy establish that ω 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 B 12 ) 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 ω and coenzyme B 12 . However, coenzyme B 12 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 ω across the RS superfamily therefore dramatically enlarges the sphere of bio-organometallic chemistry in Nature.

Original languageEnglish (US)
Pages (from-to)8634-8638
Number of pages5
JournalJournal of the American Chemical Society
Volume140
Issue number28
DOIs
StatePublished - Jul 18 2018

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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