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Radical SAM enzymes: Nature's choice for radical reactions
Author(s) -
Broderick Joan B.,
Broderick William E.,
Hoffman Brian M.
Publication year - 2023
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.14519
Subject(s) - homolysis , chemistry , stereochemistry , enzyme , radical , enzyme catalysis , radical ion , regioselectivity , reactivity (psychology) , radical cyclization , bond cleavage , catalysis , biochemistry , organic chemistry , medicine , ion , alternative medicine , pathology
Enzymes that use a [4Fe‐4S] 1+ cluster plus S ‐adenosyl‐ l ‐methionine (SAM) to initiate radical reactions (radical SAM) form the largest enzyme superfamily, with over half a million members across the tree of life. This review summarizes recent work revealing the radical SAM reaction pathway, which ultimately liberates the 5′‐deoxyadenosyl (5′‐dAdo•) radical to perform extremely diverse, highly regio‐ and stereo‐specific, transformations. Most surprising was the discovery of an organometallic intermediate Ω exhibiting an Fe‐C5′‐adenosyl bond. Ω liberates 5′‐dAdo• through homolysis of the Fe–C5′ bond, in analogy to Co–C5′ bond homolysis in B 12 , previously viewed as biology's paradigmatic radical generator. The 5′‐dAdo• has been trapped and characterized in radical SAM enzymes via a recently discovered photoreactivity of the [4Fe‐4S] + /SAM complex, and has been confirmed as a catalytically active intermediate in enzyme catalysis. The regioselective SAM S–C bond cleavage to produce 5′‐dAdo• originates in the Jahn–Teller effect. The simplicity of SAM as a radical precursor, and the exquisite control of 5′‐dAdo• reactivity in radical SAM enzymes, may be why radical SAM enzymes pervade the tree of life, while B 12 enzymes are only a few.