Structural investigations on orotate phosphoribosyltransferase from Mycobacterium tuberculosis, a key enzyme of the de novo pyrimidine biosynthesis

Abstract The Mycobacterium tuberculosis orotate phosphoribosyltransferase (MtOPRT) catalyses the conversion of α-D-5-phosphoribosyl-1-pyrophosphate (PRPP) and orotate (OA) in pyrophosphate and orotidine 5′-monophosphate (OMP), in presence of Mg2+. This enzyme is the only responsible for the synthesi...

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Autores principales:	Stefano Donini, Davide M. Ferraris, Riccardo Miggiano, Alberto Massarotti, Menico Rizzi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0ec3c764078249c39a6a0b3f9b936c3b
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spelling	oai:doaj.org-article:0ec3c764078249c39a6a0b3f9b936c3b2021-12-02T12:32:06ZStructural investigations on orotate phosphoribosyltransferase from Mycobacterium tuberculosis, a key enzyme of the de novo pyrimidine biosynthesis10.1038/s41598-017-01057-z2045-2322https://doaj.org/article/0ec3c764078249c39a6a0b3f9b936c3b2017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01057-zhttps://doaj.org/toc/2045-2322Abstract The Mycobacterium tuberculosis orotate phosphoribosyltransferase (MtOPRT) catalyses the conversion of α-D-5-phosphoribosyl-1-pyrophosphate (PRPP) and orotate (OA) in pyrophosphate and orotidine 5′-monophosphate (OMP), in presence of Mg2+. This enzyme is the only responsible for the synthesis of orotidine 5′-monophosphate, a key precursor in the de novo pyrimidine biosynthesis pathway, making MtOPRT an attractive drug target for the development of antitubercular agents. We report the crystal structures of MtOPRT in complex with PRPP (2.25 Å resolution), inorganic phosphate (1.90 Å resolution) and the exogenous compound Fe(III) dicitrate (2.40 Å resolution). The overall structure of the mycobacterial enzyme is highly similar to those described for other OPRTases, with the “flexible loop” assuming a well define conformation and making specific contacts with the Fe(III)-dicitrate complex. The structures here reported add to the knowledge of a potential drug target for tuberculosis, and will provide a useful tool for the structure-based drug design of potent enzyme inhibitors.Stefano DoniniDavide M. FerrarisRiccardo MiggianoAlberto MassarottiMenico RizziNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Stefano Donini Davide M. Ferraris Riccardo Miggiano Alberto Massarotti Menico Rizzi Structural investigations on orotate phosphoribosyltransferase from Mycobacterium tuberculosis, a key enzyme of the de novo pyrimidine biosynthesis
description	Abstract The Mycobacterium tuberculosis orotate phosphoribosyltransferase (MtOPRT) catalyses the conversion of α-D-5-phosphoribosyl-1-pyrophosphate (PRPP) and orotate (OA) in pyrophosphate and orotidine 5′-monophosphate (OMP), in presence of Mg2+. This enzyme is the only responsible for the synthesis of orotidine 5′-monophosphate, a key precursor in the de novo pyrimidine biosynthesis pathway, making MtOPRT an attractive drug target for the development of antitubercular agents. We report the crystal structures of MtOPRT in complex with PRPP (2.25 Å resolution), inorganic phosphate (1.90 Å resolution) and the exogenous compound Fe(III) dicitrate (2.40 Å resolution). The overall structure of the mycobacterial enzyme is highly similar to those described for other OPRTases, with the “flexible loop” assuming a well define conformation and making specific contacts with the Fe(III)-dicitrate complex. The structures here reported add to the knowledge of a potential drug target for tuberculosis, and will provide a useful tool for the structure-based drug design of potent enzyme inhibitors.
format	article
author	Stefano Donini Davide M. Ferraris Riccardo Miggiano Alberto Massarotti Menico Rizzi
author_facet	Stefano Donini Davide M. Ferraris Riccardo Miggiano Alberto Massarotti Menico Rizzi
author_sort	Stefano Donini
title	Structural investigations on orotate phosphoribosyltransferase from Mycobacterium tuberculosis, a key enzyme of the de novo pyrimidine biosynthesis
title_short	Structural investigations on orotate phosphoribosyltransferase from Mycobacterium tuberculosis, a key enzyme of the de novo pyrimidine biosynthesis
title_full	Structural investigations on orotate phosphoribosyltransferase from Mycobacterium tuberculosis, a key enzyme of the de novo pyrimidine biosynthesis
title_fullStr	Structural investigations on orotate phosphoribosyltransferase from Mycobacterium tuberculosis, a key enzyme of the de novo pyrimidine biosynthesis
title_full_unstemmed	Structural investigations on orotate phosphoribosyltransferase from Mycobacterium tuberculosis, a key enzyme of the de novo pyrimidine biosynthesis
title_sort	structural investigations on orotate phosphoribosyltransferase from mycobacterium tuberculosis, a key enzyme of the de novo pyrimidine biosynthesis
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/0ec3c764078249c39a6a0b3f9b936c3b
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Structural investigations on orotate phosphoribosyltransferase from Mycobacterium tuberculosis, a key enzyme of the de novo pyrimidine biosynthesis

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