Cyclization Reaction Catalyzed by Cyclodipeptide Synthases Relies on a Conserved Tyrosine Residue

Abstract Cyclodipeptide synthases (CDPSs) form various cyclodipeptides from two aminoacyl tRNAs via a stepwise mechanism with the formation of a dipeptidyl enzyme intermediate. As a final step of the catalytic reaction, the dipeptidyl group undergoes intramolecular cyclization to generate the target...

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Autores principales:	Emmanuelle Schmitt, Gabrielle Bourgeois, Muriel Gondry, Alexey Aleksandrov
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/67204e16422a4345b9f2793575e3a217
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spelling	oai:doaj.org-article:67204e16422a4345b9f2793575e3a2172021-12-02T12:33:00ZCyclization Reaction Catalyzed by Cyclodipeptide Synthases Relies on a Conserved Tyrosine Residue10.1038/s41598-018-25479-52045-2322https://doaj.org/article/67204e16422a4345b9f2793575e3a2172018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25479-5https://doaj.org/toc/2045-2322Abstract Cyclodipeptide synthases (CDPSs) form various cyclodipeptides from two aminoacyl tRNAs via a stepwise mechanism with the formation of a dipeptidyl enzyme intermediate. As a final step of the catalytic reaction, the dipeptidyl group undergoes intramolecular cyclization to generate the target cyclodipeptide product. In this work, we investigated the cyclization reaction in the cyclodipeptide synthase AlbC using QM/MM methods and free energy simulations. The results indicate that the catalytic Y202 residue is in its neutral protonated form, and thus, is not likely to serve as a general base during the reaction. We further demonstrate that the reaction relies on the conserved residue Y202 serving as a proton relay, and the direct proton transfer from the amino group to S37 of AlbC is unlikely. Calculations reveal that the hydroxyl group of tyrosine is more suitable for the proton transfer than hydroxyl groups of other amino acids, such as serine and threonine. Results also show that the residues E182, N40, Y178 and H203 maintain the correct conformation of the dipeptide needed for the cyclization reaction. The mechanism discovered in this work relies on the amino groups conserved among the entire CDPS family and, thus is expected to be universal among CDPSs.Emmanuelle SchmittGabrielle BourgeoisMuriel GondryAlexey AleksandrovNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Emmanuelle Schmitt Gabrielle Bourgeois Muriel Gondry Alexey Aleksandrov Cyclization Reaction Catalyzed by Cyclodipeptide Synthases Relies on a Conserved Tyrosine Residue
description	Abstract Cyclodipeptide synthases (CDPSs) form various cyclodipeptides from two aminoacyl tRNAs via a stepwise mechanism with the formation of a dipeptidyl enzyme intermediate. As a final step of the catalytic reaction, the dipeptidyl group undergoes intramolecular cyclization to generate the target cyclodipeptide product. In this work, we investigated the cyclization reaction in the cyclodipeptide synthase AlbC using QM/MM methods and free energy simulations. The results indicate that the catalytic Y202 residue is in its neutral protonated form, and thus, is not likely to serve as a general base during the reaction. We further demonstrate that the reaction relies on the conserved residue Y202 serving as a proton relay, and the direct proton transfer from the amino group to S37 of AlbC is unlikely. Calculations reveal that the hydroxyl group of tyrosine is more suitable for the proton transfer than hydroxyl groups of other amino acids, such as serine and threonine. Results also show that the residues E182, N40, Y178 and H203 maintain the correct conformation of the dipeptide needed for the cyclization reaction. The mechanism discovered in this work relies on the amino groups conserved among the entire CDPS family and, thus is expected to be universal among CDPSs.
format	article
author	Emmanuelle Schmitt Gabrielle Bourgeois Muriel Gondry Alexey Aleksandrov
author_facet	Emmanuelle Schmitt Gabrielle Bourgeois Muriel Gondry Alexey Aleksandrov
author_sort	Emmanuelle Schmitt
title	Cyclization Reaction Catalyzed by Cyclodipeptide Synthases Relies on a Conserved Tyrosine Residue
title_short	Cyclization Reaction Catalyzed by Cyclodipeptide Synthases Relies on a Conserved Tyrosine Residue
title_full	Cyclization Reaction Catalyzed by Cyclodipeptide Synthases Relies on a Conserved Tyrosine Residue
title_fullStr	Cyclization Reaction Catalyzed by Cyclodipeptide Synthases Relies on a Conserved Tyrosine Residue
title_full_unstemmed	Cyclization Reaction Catalyzed by Cyclodipeptide Synthases Relies on a Conserved Tyrosine Residue
title_sort	cyclization reaction catalyzed by cyclodipeptide synthases relies on a conserved tyrosine residue
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/67204e16422a4345b9f2793575e3a217
work_keys_str_mv	AT emmanuelleschmitt cyclizationreactioncatalyzedbycyclodipeptidesynthasesreliesonaconservedtyrosineresidue AT gabriellebourgeois cyclizationreactioncatalyzedbycyclodipeptidesynthasesreliesonaconservedtyrosineresidue AT murielgondry cyclizationreactioncatalyzedbycyclodipeptidesynthasesreliesonaconservedtyrosineresidue AT alexeyaleksandrov cyclizationreactioncatalyzedbycyclodipeptidesynthasesreliesonaconservedtyrosineresidue
_version_	1718393862158811136

Cyclization Reaction Catalyzed by Cyclodipeptide Synthases Relies on a Conserved Tyrosine Residue

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