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

Journal Article · · International Journal of Biological Macromolecules
 [1];  [2];  [3];  [4];  [2];  [5];  [2];  [2];  [2]
  1. Univ. of Virginia, Charlottesville, VA (United States); Jagiellonian Univ., Krakow (Poland)
  2. Univ. of Virginia, Charlottesville, VA (United States)
  3. J. Craig Venter Inst., Rockville, MD (United States)
  4. Center for Structural Genomics of Infectious Diseases (CSGID), Chicago, IL (United States)
  5. 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE; US Dept. of Health and Human Services (HHS); National Institute of General Medical Sciences; Michigan Economic Development Corporation
Grant/Contract Number:
HHSN272201200026C; HHSN272201700060C; GM117325; GM117080; 085P1000817
OSTI ID:
1547410
Journal Information:
International Journal of Biological Macromolecules, Vol. 136, Issue C; ISSN 0141-8130
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 16 works
Citation information provided by
Web of Science

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