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Fine-tuning of a radical-based reaction by radical S-adenosyl-L-methionine tryptophan lyase

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Sicoli, G. | Mouesca, J.-M. | Zeppieri, Laura | Amara, Patricia | Martin, Lydie | Barra, A.-L. | Fontecilla-Camps, Juan-Carlos | Gambarelli, S. | Nicolet, Yvain

Edité par CCSD ; American Association for the Advancement of Science (AAAS) -

International audience. The radical S-adenosyl-L-methionine tryptophan lyase NosL converts L-tryptophan into 3-methylindolic acid, which is a precursor in the synthesis of the thiopeptide antibiotic nosiheptide. Using electron paramagnetic resonance spectroscopy and multiple L-tryptophan isotopologues, we trapped and characterized radical intermediates that indicate a carboxyl fragment migration mechanism for NosL. This is in contrast to a proposed fragmentation-recombination mechanism that implied Cα-Cβ bond cleavage of L-tryptophan. Although NosL resembles related tyrosine lyases, subtle substrate motions in its active site are responsible for a fine-tuned radical chemistry, which selects the Cα-C bond for disruption. This mechanism highlights evolutionary adaptation to structural constraints in proteins as a route to alternative enzyme function.

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