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Science. 2016 Mar 18;351(6279):1320-3. doi: 10.1126/science.aad8995.

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

Author information

1
Université Grenoble-Alpes, Institut Nanosciences et Cryogénie (INAC)-Service de Chimie Inorganique et Biologique (SCIB)/Laboratoire de Résonance Magnétique (LRM), F-38000 Grenoble, France. Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), INAC-SCIB/LRM, F-38000 Grenoble, France.
2
Metalloproteins Unit, Institut de Biologie Structurale, CEA, CNRS, Université Grenoble-Alpes, 71, Avenue des Martyrs, 38044 Grenoble Cedex 9, France.
3
Laboratoire National des Champs Magnétiques Intenses, UPR CNRS 3228, F-38048 Grenoble, France.
4
Université Grenoble-Alpes, Institut Nanosciences et Cryogénie (INAC)-Service de Chimie Inorganique et Biologique (SCIB)/Laboratoire de Résonance Magnétique (LRM), F-38000 Grenoble, France. Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), INAC-SCIB/LRM, F-38000 Grenoble, France. yvain.nicolet@ibs.fr serge.gambarelli@cea.fr.
5
Metalloproteins Unit, Institut de Biologie Structurale, CEA, CNRS, Université Grenoble-Alpes, 71, Avenue des Martyrs, 38044 Grenoble Cedex 9, France. yvain.nicolet@ibs.fr serge.gambarelli@cea.fr.

Abstract

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.

PMID:
26989252
DOI:
10.1126/science.aad8995
[Indexed for MEDLINE]
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