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Synthesis

For radical enzyme catalysis, an organometallic intermediate is pinpointed

An iron-sulfur cluster may bind 5′-deoxyadenosyl in enzymes that use S-adenosylmethionine

by Jyllian Kemsley
May 16, 2016 | APPEARED IN VOLUME 94, ISSUE 20

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Credit: Science
The proposed dAdo-[4Fe-4S] intermediate (right) and methionine (left) are modeled in the pyruvate formate-lyase activating enzyme active site.
Credit: Science
The proposed dAdo-[4Fe-4S] intermediate (right) and methionine (left) are modeled in the pyruvate formate-lyase activating enzyme active site.

Synthesizing heme and some vitamin and antibiotic compounds requires enzymes that mediate radical chemistry. But enzymes must carefully control radical compounds, lest they escape and wreak havoc within a cell. A study suggests a new role for an iron-sulfur cluster in one superfamily of 100,000 enzymes that use S-adenosylmethionine (SAM) to catalyze radical reactions. Researchers knew from earlier studies that the cluster cleaves SAM to produce 5′-deoxyadenosyl radical (5′-dAdo). Now, they have discovered that the cluster also binds 5′-dAdo through an Fe–C bond (Science 2016, DOI: 10.1126/science.aaf5327). A team led by Joan B. Broderick of Montana State University and Brian M. Hoffman of Northwestern University trapped a reaction intermediate of pyruvate formate-lyase activating enzyme, which uses SAM to generate a glycyl radical on the target lyase. They used electron nuclear double resonance spectroscopy to study the intermediate and found that it is an organometallic species, with a covalent link between the 5′-C of 5′-dAdo and an iron atom of the cluster. Although it is unclear whether other radical SAM enzymes follow the same mechanism, this scheme echoes that of enzymes that use vitamin B-12 (adenosylcobalamin) to conduct radical chemistry.

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