Broken-Symmetry Density Functional Theory Analysis of the Intermediate in Radical S-Adenosyl-L-methionine Enzymes: Evidence for a Near-Attack Conformer over an Organometallic Species
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY(2022)
Abstract
Radical S-adenosyl-L-methionine (SAM) enzymes are found in all domains of life and catalyze a wide range of biochemical reactions. Recently, an organometallic intermediate, Omega, has been experimentally implicated in the 5'-deoxyadenosyl radical generation mechanism of the radical SAM superfamily. In this work, we employ broken-symmetry density functional theory to evaluate several structural models of Omega. The results show that the calculated hyperfine coupling constants (HFCCs) for the proposed organometallic structure of Omega are inconsistent with the experiment. In contrast, a near-attack conformer of SAM bound to the catalytic [4Fe-4S] cluster, in which the distance between the unique iron and SAM sulfur is similar to 3 angstrom, yields HFCCs that are all within 1 MHz of the experimental values. These results clarify the structure of the ubiquitous Omega intermediate and suggest a paradigm shift reversal regarding the mechanism of SAM cleavage by members of the radical SAM superfamily.
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Key words
enzymes,broken-symmetry broken-symmetry,radical,near-attack
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