TY - JOUR
T1 - Pyrimidine biosynthesis in pathogens – Structures and analysis of dihydroorotases from Yersinia pestis and Vibrio cholerae
AU - Lipowska, Joanna
AU - Miks, Charles Dylan
AU - Kwon, Keehwan
AU - Shuvalova, Ludmilla A
AU - Zheng, Heping
AU - Lewiński, Krzysztof
AU - Cooper, David R.
AU - Shabalin, Ivan G.
AU - Minor, Wladek
N1 - Funding Information:
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).
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
KW - Crystal structure
KW - Dihydroorotase
KW - Drug target
KW - Plasmodium falciparum
KW - Vibrio cholera
KW - Yersinia pestis
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U2 - 10.1016/j.ijbiomac.2019.05.149
DO - 10.1016/j.ijbiomac.2019.05.149
M3 - Article
C2 - 31207330
AN - SCOPUS:85068086785
SN - 0141-8130
VL - 136
SP - 1176
EP - 1187
JO - International Journal of Biological Macromolecules
JF - International Journal of Biological Macromolecules
ER -