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J Am Chem Soc ; 140(28): 8634-8638, 2018 07 18.
Article in English | MEDLINE | ID: mdl-29954180

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 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 Ω 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 Ω across the RS superfamily therefore dramatically enlarges the sphere of bio-organometallic chemistry in Nature.


Subject(s)
Bacteria/enzymology , Cobamides/metabolism , Deoxyadenosines/metabolism , Enzymes/metabolism , S-Adenosylmethionine/metabolism , Acetyltransferases , Bacteria/chemistry , Bacteria/metabolism , Biocatalysis , Cobamides/chemistry , Deoxyadenosines/chemistry , Electron Spin Resonance Spectroscopy , Enzymes/chemistry , Escherichia coli/chemistry , Escherichia coli/enzymology , Escherichia coli/metabolism , Models, Molecular , Protein Conformation , S-Adenosylmethionine/chemistry
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