Pyrimidine biosynthesis in pathogens – Structures and analysis of dihydroorotases from Yersinia pestis and Vibrio cholerae

Joanna Lipowska, Charles Dylan Miks, Keehwan Kwon, Ludmilla A Shuvalova, Heping Zheng, Krzysztof Lewiński, David R. Cooper, Ivan G. Shabalin*, Wladek Minor

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

The de novo pyrimidine biosynthesis pathway is essential for the proliferation of many pathogens. One of the pathway enzymes, dihydroorotase (DHO), catalyzes the reversible interconversion of N-carbamoyl-L-aspartate to 4,5-dihydroorotate. The substantial difference between bacterial and mammalian DHOs makes it a promising drug target for disrupting bacterial growth and thus an important candidate to evaluate as a response to antimicrobial resistance on a molecular level. Here, we present two novel three-dimensional structures of DHOs from Yersinia pestis (YpDHO), the plague-causing pathogen, and Vibrio cholerae (VcDHO), the causative agent of cholera. The evaluations of these two structures led to an analysis of all available DHO structures and their classification into known DHO types. Comparison of all the DHO active sites containing ligands that are listed in DrugBank was facilitated by a new interactive, structure-comparison and presentation platform. In addition, we examined the genetic context of characterized DHOs, which revealed characteristic patterns for different types of DHOs. We also generated a homology model for DHO from Plasmodium falciparum.

Original languageEnglish (US)
Pages (from-to)1176-1187
Number of pages12
JournalInternational Journal of Biological Macromolecules
Volume136
DOIs
StatePublished - Sep 1 2019

Keywords

  • Crystal structure
  • Dihydroorotase
  • Drug target
  • Plasmodium falciparum
  • Vibrio cholera
  • Yersinia pestis

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Economics and Econometrics
  • Energy(all)

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