Mycobacterium tuberculosis glucosyl-3-phosphoglycerate synthase: structure of a key enzyme in methylglucose lipopolysaccharide biosynthesis.

Tuberculosis constitutes today a serious threat to human health worldwide, aggravated by the increasing number of identified multi-resistant strains of Mycobacterium tuberculosis, its causative agent, as well as by the lack of development of novel mycobactericidal compounds for the last few decades....

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Pedro José Barbosa Pereira, Nuno Empadinhas, Luciana Albuquerque, Bebiana Sá-Moura, Milton S da Costa, Sandra Macedo-Ribeiro
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c6d31d971aee41ac9398c1206feb108e
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:c6d31d971aee41ac9398c1206feb108e
record_format	dspace
spelling	oai:doaj.org-article:c6d31d971aee41ac9398c1206feb108e2021-11-25T06:18:29ZMycobacterium tuberculosis glucosyl-3-phosphoglycerate synthase: structure of a key enzyme in methylglucose lipopolysaccharide biosynthesis.1932-620310.1371/journal.pone.0003748https://doaj.org/article/c6d31d971aee41ac9398c1206feb108e2008-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19015727/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Tuberculosis constitutes today a serious threat to human health worldwide, aggravated by the increasing number of identified multi-resistant strains of Mycobacterium tuberculosis, its causative agent, as well as by the lack of development of novel mycobactericidal compounds for the last few decades. The increased resilience of this pathogen is due, to a great extent, to its complex, polysaccharide-rich, and unusually impermeable cell wall. The synthesis of this essential structure is still poorly understood despite the fact that enzymes involved in glycosidic bond synthesis represent more than 1% of all M. tuberculosis ORFs identified to date. One of them is GpgS, a retaining glycosyltransferase (GT) with low sequence homology to any other GTs of known structure, which has been identified in two species of mycobacteria and shown to be essential for the survival of M. tuberculosis. To further understand the biochemical properties of M. tuberculosis GpgS, we determined the three-dimensional structure of the apo enzyme, as well as of its ternary complex with UDP and 3-phosphoglycerate, by X-ray crystallography, to a resolution of 2.5 and 2.7 A, respectively. GpgS, the first enzyme from the newly established GT-81 family to be structurally characterized, displays a dimeric architecture with an overall fold similar to that of other GT-A-type glycosyltransferases. These three-dimensional structures provide a molecular explanation for the enzyme's preference for UDP-containing donor substrates, as well as for its glucose versus mannose discrimination, and uncover the structural determinants for acceptor substrate selectivity. Glycosyltransferases constitute a growing family of enzymes for which structural and mechanistic data urges. The three-dimensional structures of M. tuberculosis GpgS now determined provide such data for a novel enzyme family, clearly establishing the molecular determinants for substrate recognition and catalysis, while providing an experimental scaffold for the structure-based rational design of specific inhibitors, which lay the foundation for the development of novel anti-tuberculosis therapies.Pedro José Barbosa PereiraNuno EmpadinhasLuciana AlbuquerqueBebiana Sá-MouraMilton S da CostaSandra Macedo-RibeiroPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 11, p e3748 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pedro José Barbosa Pereira Nuno Empadinhas Luciana Albuquerque Bebiana Sá-Moura Milton S da Costa Sandra Macedo-Ribeiro Mycobacterium tuberculosis glucosyl-3-phosphoglycerate synthase: structure of a key enzyme in methylglucose lipopolysaccharide biosynthesis.
description	Tuberculosis constitutes today a serious threat to human health worldwide, aggravated by the increasing number of identified multi-resistant strains of Mycobacterium tuberculosis, its causative agent, as well as by the lack of development of novel mycobactericidal compounds for the last few decades. The increased resilience of this pathogen is due, to a great extent, to its complex, polysaccharide-rich, and unusually impermeable cell wall. The synthesis of this essential structure is still poorly understood despite the fact that enzymes involved in glycosidic bond synthesis represent more than 1% of all M. tuberculosis ORFs identified to date. One of them is GpgS, a retaining glycosyltransferase (GT) with low sequence homology to any other GTs of known structure, which has been identified in two species of mycobacteria and shown to be essential for the survival of M. tuberculosis. To further understand the biochemical properties of M. tuberculosis GpgS, we determined the three-dimensional structure of the apo enzyme, as well as of its ternary complex with UDP and 3-phosphoglycerate, by X-ray crystallography, to a resolution of 2.5 and 2.7 A, respectively. GpgS, the first enzyme from the newly established GT-81 family to be structurally characterized, displays a dimeric architecture with an overall fold similar to that of other GT-A-type glycosyltransferases. These three-dimensional structures provide a molecular explanation for the enzyme's preference for UDP-containing donor substrates, as well as for its glucose versus mannose discrimination, and uncover the structural determinants for acceptor substrate selectivity. Glycosyltransferases constitute a growing family of enzymes for which structural and mechanistic data urges. The three-dimensional structures of M. tuberculosis GpgS now determined provide such data for a novel enzyme family, clearly establishing the molecular determinants for substrate recognition and catalysis, while providing an experimental scaffold for the structure-based rational design of specific inhibitors, which lay the foundation for the development of novel anti-tuberculosis therapies.
format	article
author	Pedro José Barbosa Pereira Nuno Empadinhas Luciana Albuquerque Bebiana Sá-Moura Milton S da Costa Sandra Macedo-Ribeiro
author_facet	Pedro José Barbosa Pereira Nuno Empadinhas Luciana Albuquerque Bebiana Sá-Moura Milton S da Costa Sandra Macedo-Ribeiro
author_sort	Pedro José Barbosa Pereira
title	Mycobacterium tuberculosis glucosyl-3-phosphoglycerate synthase: structure of a key enzyme in methylglucose lipopolysaccharide biosynthesis.
title_short	Mycobacterium tuberculosis glucosyl-3-phosphoglycerate synthase: structure of a key enzyme in methylglucose lipopolysaccharide biosynthesis.
title_full	Mycobacterium tuberculosis glucosyl-3-phosphoglycerate synthase: structure of a key enzyme in methylglucose lipopolysaccharide biosynthesis.
title_fullStr	Mycobacterium tuberculosis glucosyl-3-phosphoglycerate synthase: structure of a key enzyme in methylglucose lipopolysaccharide biosynthesis.
title_full_unstemmed	Mycobacterium tuberculosis glucosyl-3-phosphoglycerate synthase: structure of a key enzyme in methylglucose lipopolysaccharide biosynthesis.
title_sort	mycobacterium tuberculosis glucosyl-3-phosphoglycerate synthase: structure of a key enzyme in methylglucose lipopolysaccharide biosynthesis.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/c6d31d971aee41ac9398c1206feb108e
work_keys_str_mv	AT pedrojosebarbosapereira mycobacteriumtuberculosisglucosyl3phosphoglyceratesynthasestructureofakeyenzymeinmethylglucoselipopolysaccharidebiosynthesis AT nunoempadinhas mycobacteriumtuberculosisglucosyl3phosphoglyceratesynthasestructureofakeyenzymeinmethylglucoselipopolysaccharidebiosynthesis AT lucianaalbuquerque mycobacteriumtuberculosisglucosyl3phosphoglyceratesynthasestructureofakeyenzymeinmethylglucoselipopolysaccharidebiosynthesis AT bebianasamoura mycobacteriumtuberculosisglucosyl3phosphoglyceratesynthasestructureofakeyenzymeinmethylglucoselipopolysaccharidebiosynthesis AT miltonsdacosta mycobacteriumtuberculosisglucosyl3phosphoglyceratesynthasestructureofakeyenzymeinmethylglucoselipopolysaccharidebiosynthesis AT sandramacedoribeiro mycobacteriumtuberculosisglucosyl3phosphoglyceratesynthasestructureofakeyenzymeinmethylglucoselipopolysaccharidebiosynthesis
_version_	1718413952170328064

Mycobacterium tuberculosis glucosyl-3-phosphoglycerate synthase: structure of a key enzyme in methylglucose lipopolysaccharide biosynthesis.

Ejemplares similares