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J Am Chem Soc. 2018 Dec 5;140(48):16661-16668. doi: 10.1021/jacs.8b09142. Epub 2018 Nov 16.

Radical S-Adenosyl-l-methionine Tryptophan Lyase (NosL): How the Protein Controls the Carboxyl Radical •CO2- Migration.

Author information

1
Univ. Grenoble Alpes, CEA, CNRS, IBS , Metalloproteins Unit , F-38000 Grenoble , France.
2
Univ. Grenoble Alpes, CNRS, CEA , INAC-SyMMES , 38000 Grenoble , France.

Abstract

The radical S-adenosyl-l-methionine tryptophan lyase uses radical-based chemistry to convert l-tryptophan into 3-methyl-2-indolic acid, a fragment in the biosynthesis of the thiopeptide antibiotic nosiheptide. This complex reaction involves several successive steps corresponding to (i) the activation by a specific hydrogen-atom abstraction, (ii) an unprecedented •CO2- radical migration, (iii) a cyanide fragment release, and (iv) the termination of the radical-based reaction. In vitro study of this reaction is made more difficult because the enzyme produces a significant amount of a shunt product instead of the natural product. Here, using a combination of X-ray crystallography, electron paramagnetic resonance spectroscopy, and quantum and hybrid quantum mechanical/molecular mechanical calculations, we have deciphered the fine mechanism of the key •CO2- radical migration, highlighting how the preorganized active site of the protein tightly controls this reaction.

PMID:
30418774
DOI:
10.1021/jacs.8b09142
[Indexed for MEDLINE]

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