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.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.05.149 | DOI Listing |
Sci Rep
January 2025
Department of Pharmacy, Affiliated Hospital of Southwest Jiao Tong University, The Third People's Hospital of Chengdu, Chengdu, 610014, China.
The pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear due to the complexity of its etiology. The emerging field of the epitranscriptome has shown significant promise in advancing the understanding of disease pathogenesis and developing new therapeutic approaches. Recent research has demonstrated that N4-acetylcytosine (ac4C), an RNA modification within the epitranscriptome, is implicated in progression of various diseases.
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January 2025
Chemistry Department, Faculty of Science, Tanta University, Tanta, 31527, Egypt.
In a quest to innovate biologically active molecules, the benzoylation of 4,6-dimethylpyrimidine-2-thiol hydrochloride (1) with benzoyl chloride derivatives was employed to produce a series of pyrimidine benzothioate derivatives (2-5). Subsequent sulfoxidation of these derivatives (2-5) using hydrogen peroxide and glacial acetic acid yielded a diverse array of pyrimidine sulfonyl methanone derivatives (6-9). In parallel, the sulfoxidation of pyrimidine sulfonothioates (10-12) yielded sulfonyl sulfonyl pyrimidines (13-15), originating from the condensation of compound 1 with sulfonyl chloride derivatives.
View Article and Find Full Text PDFFood Chem X
January 2025
College of Food Science, Southwest University, Chongqing 400715, China.
The cell-free supernatant of (LCFS) is considered a potential natural antimicrobial agent due to its outstanding antimicrobial activity. This study demonstrated that the cell-free supernatant of SHY96 (LCFS96) effectively inhibits the growth and biofilm formation of CMCC(B)54002 (_02) by reducing cell metabolic activity and damaging cell structure. Metabolomic analysis revealed that LCFS96 significantly altered 450 intracellular metabolites, affecting key metabolic pathways including linoleic acid metabolism, pyrimidine metabolism, purine metabolism, pantothenic acid and CoA biosynthesis, and the TCA cycle.
View Article and Find Full Text PDFRapid Commun Mass Spectrom
March 2025
Department of Pharmacy, The Affiliated Yixing Clinical School of Medical School of Yangzhou University, Yixing, China.
Objective: The aim of this study was to use metabolomics techniques to detect differential metabolites in the plasma of patients with aplastic anemia (AA). We explore important biomarkers and potential pathways in cyclosporine A (CsA) in the treatment of AA.
Methods: Plasma samples from five patients with AA before and after treatment and plasma samples from five healthy people were collected and analyzed by liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry.
Nat Commun
January 2025
Molecular and Cellular Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, 111 T. W. Alexander Drive, Research Triangle Park, NC, 27709, USA.
Coronaviruses evade detection by the host immune system with the help of the endoribonuclease Nsp15, which regulates levels of viral double stranded RNA by cleaving 3' of uridine (U). While prior structural data shows that to cleave double stranded RNA, Nsp15's target U must be flipped out of the helix, it is not yet understood whether Nsp15 initiates flipping or captures spontaneously flipped bases. We address this gap by designing fluorinated double stranded RNA substrates that allow us to directly relate a U's sequence context to both its tendency to spontaneously flip and its susceptibility to cleavage by Nsp15.
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