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Radical SAM Enzymes

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Radicals play an important role in many chemical processes including combustion, atmospheric chemistry, polymerization, etc. They are also commonly encountered in numerous biological reactions. Many metalloenzymes, such as cytochrome P450 enzymes, non-heme iron enzymes and the adenosylcobalamin (B12) enzymes, ...

Radicals play an important role in many chemical processes including combustion, atmospheric chemistry, polymerization, etc. They are also commonly encountered in numerous biological reactions. Many metalloenzymes, such as cytochrome P450 enzymes, non-heme iron enzymes and the adenosylcobalamin (B12) enzymes, catalyze reactions using organic radical intermediates. These radical species are tightly controlled in the enzyme pocket to ensure that no radical intermediates would diffuse out causing deleterious side reactions. An important recent addition to the already intriguing radical enzymology is the discovery of the so-called radical S-adenosylmethionine (SAM) superfamily. The superfamily was composed of ~ 600 members in 2001 when it was first defined; the latest bioinformatics studies using the characteristic tri-cysteine CxxxCxxC motif however identified > 50,000 enzymes in more than > 3,000 organisms, firmly establishing its superfamily status. Further, more and more enzymes containing other three-cysteine motifs have been found to also facilitate the same radical chemistry. Therefore, the actual size of the superfamily may be even bigger.

All members in the radical SAM superfamily share the following common scheme to generate the catalytic radical species. The signature motif provides three cysteinates as external ligands to a [4Fe-4S] cluster and the S-adenosylmethionine (SAM) is bound to the fourth iron via its carboxylate and amino moieties in a bidentate fashion. At the [4Fe-4S] + oxidation state, the cluster donates one electron to SAM to reduce the sulfonium moiety by cleaving the C-S bond and generating a methionine and a 5′-deoxyadenosyl radical (5′-dA•). The 5′-dA• then abstracts an H atom from normally un-activated C-H bonds in substrates, to initiate a wide range of substrate modification reactions, including sulfuration, methylation, methylthiolation, hydroxylation, C-C bond formation or fragmentation, dehydrogenation, decarboxylation, metallocofactor maturation, and structural rearrangements in numerous biological processes such as DNA synthesis and repair, the biosynthesis of cofactors, posttranslational modification, and antiviral response.

Although still at the very early stage, mechanistic studies on enzymes in this superfamily have already radically altered our view in biocatalysis and opened a new chapter in radical enzymology. Undoubtedly, the continuing research will provide more exciting mechanistic insights into biological reactions and expand our knowledge on strategies radical enzymes utilize to achieve efficient catalysis with a wide range of substrates.


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