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Communication Dans Un Congrès Année : 2015

Radically new methylation reactions in antibiotic biosynthesis: Insights into the mechanism of B12-dependent radical SAM enzymes

Résumé

Natural products are the major source of clinically approved antibiotics and anti-cancer agents. Recently, a novel family of methyltransferases has emerged as an important player in the biosynthesis of a myriad of natural products. These enzymes, which constitute one of the largest groups within the radical SAM (rSAM) superfamily of enzymes, catalyze unusual methyl transfer reactions under the dependence of both S-adenosyl-L-methionine and vitamin B12 and are thus called: B12/rSAM enzymes. Despite their broad distribution in natural product biosynthetic pathways, almost nothing is known on the catalytic mechanism of these B12/rSAM enzymes. We have investigated the mechanism of TsrM, a B12/rSAM enzyme catalyzing a key step in the biosynthesis of the antibiotic and an anti-cancer agent thiostrepton A [1]. We have demonstrated that this enzyme is able to transfer a methyl group to the electrophilic C2 of tryptophan via an unconventional mechanism. Further investigations allowed us to demonstrate that TsrM, in opposite to most rSAM enzymes, does not use the 5'-deoxyadenosyl radical as a central reaction intermediate. Our data are consistent with an unprecedented radical-based mechanism for enzymatic methyl transfer. Finally, our study further expands the chemical versatility of rSAM enzymes and enlightens novel strategies in natural product biosynthetic pathways. [1]- Pierre S, Guillot A, Benjdia A, Sandström C, Langella P, Berteau O*. 2012; Nat Chem Biol. ;8(12):957-9.
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Dates et versions

hal-01536523 , version 1 (11-06-2017)

Identifiants

  • HAL Id : hal-01536523 , version 1
  • PRODINRA : 339966
  • WOS : 000361470504238

Citer

Olivier Berteau, Stéphane Pierre, Alhosna Benjdia, Carmen Gherasim, Ruma Banerjee. Radically new methylation reactions in antibiotic biosynthesis: Insights into the mechanism of B12-dependent radical SAM enzymes. Experimental Biology Meeting, Mar 2015, Boston, United States. ⟨hal-01536523⟩
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