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

Autor(es):Mostrar menos -

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]

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: Biochemical and Biophysical Research Communications; v. 497, n. 3, p. 835-842, MAR 11 2018.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 15/26722-8 - Drug discovery contra doenças infecciosas humanos
• Beneficiário: Carsten Wrenger
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/17577-9 - Análise da catálise da ATCase no metabolismo de Plasmodium falciparum
• Beneficiário: Soraya Soledad Bosch
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 14/23330-9 - Análise morfológica da formação de apicoplasto em Plasmodium falciparum
• Beneficiário: Marleen Linzke
• Modalidade de apoio: Bolsas no Brasil - Doutorado