Structures of Medicago truncatula L-Histidinol Dehydrogenase Show Rearrangements Required for NAD+ Binding and the Cofactor Positioned to Accept a Hydride

Abstract Plants, lower eukaryotes, bacteria, and archaebacteria synthesise L-histidine (His) in a similar, multistep pathway that is absent in mammals. This makes the His biosynthetic route a promising target for herbicides, antifungal agents, and antibiotics. The last enzyme of the pathway, bifunct...

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Autores principales:	Milosz Ruszkowski, Zbigniew Dauter
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ff9b75a0a4d44e0a9b804979d0e0d119
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spelling	oai:doaj.org-article:ff9b75a0a4d44e0a9b804979d0e0d1192021-12-02T15:05:55ZStructures of Medicago truncatula L-Histidinol Dehydrogenase Show Rearrangements Required for NAD+ Binding and the Cofactor Positioned to Accept a Hydride10.1038/s41598-017-10859-02045-2322https://doaj.org/article/ff9b75a0a4d44e0a9b804979d0e0d1192017-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-10859-0https://doaj.org/toc/2045-2322Abstract Plants, lower eukaryotes, bacteria, and archaebacteria synthesise L-histidine (His) in a similar, multistep pathway that is absent in mammals. This makes the His biosynthetic route a promising target for herbicides, antifungal agents, and antibiotics. The last enzyme of the pathway, bifunctional L-histidinol dehydrogenase (HDH, EC 1.1.1.23), catalyses two oxidation reactions: from L-histidinol (HOL) to L-histidinaldehyde and from L-histidinaldehyde to His. Over the course of the reaction, HDH utilises two molecules of NAD+ as the hydride acceptor. The object of this study was the HDH enzyme from the model legume plant, Medicago truncatula (MtHDH). Three crystal structures complexed with imidazole, HOL, and His with NAD+ provided in-depth insights into the enzyme architecture, its active site, and the cofactor binding mode. The overall structure of MtHDH is similar to the two bacterial orthologues whose three-dimensional structures have been determined. The three snapshots, with the MtHDH enzyme captured in different states, visualise structural rearrangements that allow for NAD+ binding for the first time. Furthermore, the MtHDH complex with His and NAD+ displays the cofactor molecule situated in a way that would allow for a hydride transfer.Milosz RuszkowskiZbigniew DauterNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Milosz Ruszkowski Zbigniew Dauter Structures of Medicago truncatula L-Histidinol Dehydrogenase Show Rearrangements Required for NAD+ Binding and the Cofactor Positioned to Accept a Hydride
description	Abstract Plants, lower eukaryotes, bacteria, and archaebacteria synthesise L-histidine (His) in a similar, multistep pathway that is absent in mammals. This makes the His biosynthetic route a promising target for herbicides, antifungal agents, and antibiotics. The last enzyme of the pathway, bifunctional L-histidinol dehydrogenase (HDH, EC 1.1.1.23), catalyses two oxidation reactions: from L-histidinol (HOL) to L-histidinaldehyde and from L-histidinaldehyde to His. Over the course of the reaction, HDH utilises two molecules of NAD+ as the hydride acceptor. The object of this study was the HDH enzyme from the model legume plant, Medicago truncatula (MtHDH). Three crystal structures complexed with imidazole, HOL, and His with NAD+ provided in-depth insights into the enzyme architecture, its active site, and the cofactor binding mode. The overall structure of MtHDH is similar to the two bacterial orthologues whose three-dimensional structures have been determined. The three snapshots, with the MtHDH enzyme captured in different states, visualise structural rearrangements that allow for NAD+ binding for the first time. Furthermore, the MtHDH complex with His and NAD+ displays the cofactor molecule situated in a way that would allow for a hydride transfer.
format	article
author	Milosz Ruszkowski Zbigniew Dauter
author_facet	Milosz Ruszkowski Zbigniew Dauter
author_sort	Milosz Ruszkowski
title	Structures of Medicago truncatula L-Histidinol Dehydrogenase Show Rearrangements Required for NAD+ Binding and the Cofactor Positioned to Accept a Hydride
title_short	Structures of Medicago truncatula L-Histidinol Dehydrogenase Show Rearrangements Required for NAD+ Binding and the Cofactor Positioned to Accept a Hydride
title_full	Structures of Medicago truncatula L-Histidinol Dehydrogenase Show Rearrangements Required for NAD+ Binding and the Cofactor Positioned to Accept a Hydride
title_fullStr	Structures of Medicago truncatula L-Histidinol Dehydrogenase Show Rearrangements Required for NAD+ Binding and the Cofactor Positioned to Accept a Hydride
title_full_unstemmed	Structures of Medicago truncatula L-Histidinol Dehydrogenase Show Rearrangements Required for NAD+ Binding and the Cofactor Positioned to Accept a Hydride
title_sort	structures of medicago truncatula l-histidinol dehydrogenase show rearrangements required for nad+ binding and the cofactor positioned to accept a hydride
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ff9b75a0a4d44e0a9b804979d0e0d119
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Structures of Medicago truncatula L-Histidinol Dehydrogenase Show Rearrangements Required for NAD+ Binding and the Cofactor Positioned to Accept a Hydride

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