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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylase

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Lunev, Sergey [1] ; Bosch, Soraya S. [2] ; Batista, Fernando A. [1] ; Wang, Chao [1] ; Li, Jingyao [1] ; Linzke, Marleen [2] ; Kruithof, Paul [1] ; Chamoun, George [1] ; Domling, Alexander S. S. [1] ; Wrenger, Carsten [2] ; Groves, Matthew R. [1]
Total Authors: 11
[1] Univ Groningen, Fac Sci & Engn, Antonius Deusinglaan 1, NL-9713 AV Groningen - Netherlands
[2] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Unit Drug Discovery, Ave Prof Lineu Prestes 1374, BR-05508000 Sao Paulo, SP - Brazil
Total Affiliations: 2
Document type: Journal article
Source: Biochemical and Biophysical Research Communications; v. 497, n. 3, p. 835-842, MAR 11 2018.
Web of Science Citations: 0

Aspartate transcarbamoylase catalyzes the second step of de-novo pyrimidine biosynthesis. As malarial parasites lack pyrimidine salvage machinery and rely on de-novo production for growth and proliferation, this pathway is a target for drug discovery. Previously, an apo crystal structure of aspartate transcarbamoylase from Plasmodium falciparum (PfATC) in its T-state has been reported. Here we present crystal structures of PfATC in the liganded R-state as well as in complex with the novel inhibitor, 2,3-napthalenediol, identified by high-throughput screening. Our data shows that 2,3-napthalediol binds in close proximity to the active site, implying an allosteric mechanism of inhibition. Furthermore, we report biophysical characterization of 2,3-napthalenediol. These data provide a promising starting point for structure based drug design targeting PfATC and malarial de-novo pyrimidine biosynthesis. (C) 2018 Elsevier Inc. All rights reserved. (AU)

FAPESP's process: 15/26722-8 - Drug discovery against human infectious diseases
Grantee:Carsten Wrenger
Support type: Research Projects - Thematic Grants
FAPESP's process: 13/17577-9 - Analysis of the ATCase catalysis within the amino acid metabolism of the human malaria parasite Plasmodium falciparum
Grantee:Soraya Soledad Bosch
Support type: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 14/23330-9 - Morphologic Analysis of the Apicoplast Formation in Plasmodium falciparum
Grantee:Marleen Linzke
Support type: Scholarships in Brazil - Doctorate