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

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

doi:10.1016/j.ijbiomac.2019.05.149

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

Journal Article · 14 June 2019 · International Journal of Biological Macromolecules

DOI: https://doi.org/10.1016/j.ijbiomac.2019.05.149 · OSTI ID:1547410

Lipowska, Joanna ^[1]; Miks, Charles Dylan ^[2]; Kwon, Keehwan ^[3]; Shuvalova, Ludmilla ^[4]; Zheng, Heping ^[2]; Lewiński, Krzysztof ^[5]; Cooper, David R. ^[2]; Shabalin, Ivan G. ^[2]; Minor, Wladek ^[2]

Univ. of Virginia, Charlottesville, VA (United States); Jagiellonian Univ., Krakow (Poland)
Univ. of Virginia, Charlottesville, VA (United States)
J. Craig Venter Inst., Rockville, MD (United States)
Center for Structural Genomics of Infectious Diseases (CSGID), Chicago, IL (United States)
Jagiellonian Univ., Krakow (Poland)

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. Furthermore, we also generated a homology model for DHO from Plasmodium falciparum.

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Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: Michigan Economic Development Corporation; National Institute of General Medical Sciences; US Dept. of Health and Human Services (HHS); USDOE

OSTI ID:: 1547410

Journal Information:: International Journal of Biological Macromolecules, Journal Name: International Journal of Biological Macromolecules Journal Issue: C Vol. 136; ISSN 0141-8130

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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

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