Dataset Information

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

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.

SUBMITTER: Lipowska J

PROVIDER: S-EPMC6686667 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Lipowska Joanna J Miks Charles Dylan CD Kwon Keehwan K Shuvalova Ludmilla L Zheng Heping H Lewiński Krzysztof K Cooper David R DR Shabalin Ivan G IG Minor Wladek W

International journal of biological macromolecules 20190615

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 nov ...[more]

PMID: 31207330

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Project description:Yersinia pestis, the causative agent of plague, has recently diverged from the less virulent enteropathogen Yersinia pseudotuberculosis. Its emergence has been characterized by massive genetic loss and inactivation and limited gene acquisition. The acquired genes include two plasmids, a filamentous phage, and a few chromosomal loci. The aim of this study was to characterize the chromosomal regions acquired by Y. pestis. Following in silico comparative analysis and PCR screening of 98 strains of Y. pseudotuberculosis and Y. pestis, we found that eight chromosomal loci (six regions [R1pe to R6pe] and two coding sequences [CDS1pe and CDS2pe]) specified Y. pestis. Signatures of integration by site specific or homologous recombination were identified for most of them. These acquisitions and the loss of ancestral DNA sequences were concentrated in a chromosomal region opposite to the origin of replication. The specific regions were acquired very early during Y. pestis evolution and were retained during its microevolution, suggesting that they might bring some selective advantages. Only one region (R3pe), predicted to carry a lambdoid prophage, is most likely no longer functional because of mutations. With the exception of R1pe and R2pe, which have the potential to encode a restriction/modification and a sugar transport system, respectively, no functions could be predicted for the other Y. pestis-specific loci. To determine the role of the eight chromosomal loci in the physiology and pathogenicity of the plague bacillus, each of them was individually deleted from the bacterial chromosome. None of the deletants exhibited defects during growth in vitro. Using the Xenopsylla cheopis flea model, all deletants retained the capacity to produce a stable and persistent infection and to block fleas. Similarly, none of the deletants caused any acute flea toxicity. In the mouse model of infection, all deletants were fully virulent upon subcutaneous or aerosol infections. Therefore, our results suggest that acquisition of new chromosomal materials has not been of major importance in the dramatic change of life cycle that has accompanied the emergence of Y. pestis.

Dataset Information

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

Publications

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

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