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

doi:10.1016/j.ijbiomac.2019.05.149

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

Pharmacology

Research output: Contribution to journal › Article › peer-review

22 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 language	English (US)
Pages (from-to)	1176-1187
Number of pages	12
Journal	International Journal of Biological Macromolecules
Volume	136
DOIs	https://doi.org/10.1016/j.ijbiomac.2019.05.149
State	Published - Sep 1 2019

Funding

This work was supported by federal funds from the National Institute of Allergy and Infectious Diseases , National Institutes of Health , Department of Health and Human Services under contracts HHSN272201200026C and HHSN272201700060C and National Institute of General Medical Sciences under grant numbers GM117325 and GM117080 . We also thank beamline scientists, especially Randy Alkire and Norma Duke from SBC-CAT, and Spencer Anderson and Zdzislaw Wawrzak from LS-CAT for assistance in data collection. Results shown in this article are derived from work performed at Argonne National Laboratory, Structural Biology Center (SBC) and Life Sciences Collaborative Access Team (LS-CAT) at the Advanced Photon Source (APS). APS is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817).

Keywords

Crystal structure
Dihydroorotase
Drug target
Plasmodium falciparum
Vibrio cholera
Yersinia pestis

ASJC Scopus subject areas

Structural Biology
Biochemistry
Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ijbiomac.2019.05.149

Cite this

Lipowska, J., Miks, C. D., Kwon, K., Shuvalova, L. A., Zheng, H., Lewiński, K., Cooper, D. R., Shabalin, I. G., & Minor, W. (2019). Pyrimidine biosynthesis in pathogens – Structures and analysis of dihydroorotases from Yersinia pestis and Vibrio cholerae. International Journal of Biological Macromolecules, 136, 1176-1187. https://doi.org/10.1016/j.ijbiomac.2019.05.149

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

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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