Pyrimidine metabolism by intracellular Chlamydia psittaci

Abstract

Pyrimidine metabolism was studied in the obligate intracellular bacterium Chlamydia psittaci AA Mp in the wild type and a variety of mutant host cell lines with well-defined mutations affecting pyrimidine metabolism.C. psittaci AA Mp cannot synthesize pyrimidines de novo, as assessed by its inability to incorporate aspartic acid into nucleic acid pyrimidines. In addition, the parasite cannot take UTP, CTP, or dCTP from the host cell, nor can it salvage exogenously supplied uridine, cytidine, or deoxycytidine. The (7,20). The species C. trachomatis and C pneumoniae are primarily human pathogens (6, 26).In contrast, C. psittaci has been isolated from humans and a very large number of avian and mammalian species, in which it produces a variety of diseases (26,28). Despite the clinical and economic importance of chlamydiae, many aspects of their basic biology have not been studied and the metabolic relationships that exist between the parasites and their hosts remain largely unknown (20). This is, in part, due to the fact that axenic growth of chlamydiae has not been realized. In addition, host-free chlamydiae display limited metabolic activity (12,20).Our laboratory is particularly interested in nucleotide metabolism in chlamydiae. To study nucleotide metabolism in C. trachomatis, we have employed an in situ approach with well-defined mutant host cell lines and several different radiolabelled nucleic acid precursors (4,5,18,24,29,30). The results generated indicate that C. trachomatis (i) cannot de novo synthesize purines or pyrimidines, (ii) lacks the ability to salvage preformed purine or pyrimidine nucleobases and (deoxy)nucleosides, (iii) can obtain all four ribonucleotides directly from the host cell, (iv) encodes a ribonucleotide reductase and thymidylate synthase for synthesizing deoxyribonucleotides from host-derived ribonucle-* Corresponding author. t Present address:

Inhibition of Chlamydiae by Primary Alcohols Correlates with the Strain-Specific Complement of Plasticity Zone Phospholipase D Genes

“…Chlamydial pzPLD have homology to nucleases, such as Nuc (26); moreover, C. trachomatis is auxotrophic for three of four ribonucleosides and acquires all four from host cells (22). Three additional lines of correlative evidence support this speculation.…”

Crystal Structure of Escherichia coli Cytidine Triphosphate Synthetase, a Nucleotide-Regulated Glutamine Amidotransferase/ATP-Dependent Amidoligase Fusion Protein and Homologue of Anticancer and Antiparasitic Drug Targets,

“…The most prominent feature is a large trench, 35 The glutaminase active site is indicated by the characteristic GATase Cys-His-Glu catalytic triad (82) (Figures 3b and 6a). Nearby, a cleft with dimensions 15 × 10 × 12 Å is juxtaposed between the GATase and ALase domains near the A-A′ dimer interface.…”

“…The requirement for de novo CTP makes CTPS activity key to the viability of a number of cancers (29)(30)(31), viruses (32)(33)(34), pathogenic bacteria (35,36), and protozoan parasites (37)(38)(39). As a result, CTPSs are both the targets for therapeutics and responsible for resistance to them by selected mutations.…”

Permeability of Coxiella burnetii to ribonucleosides

“…C. psittaci also possesses an ATP\ADP exchange transporter similar in function to that seen in R. prowazekii (Hatch et al, 1982). Chlamydia trachomatis must transport purine nucleotides and uracil from its host cell to compensate for a lack of ability to form deoxyribonucleoside triphosphates (dNTPs) de novo (McClarty & Tipples, 1991 ;McClarty & Qin, 1993), and is believed to have separate nucleotide transport pathways for energy supply and RNA synthesis (Tjaden et al, 1999).…”