Comparative Aspects of Nucleotide and Amino-acid Metabolism in Toxoplasma gondii and other Apicomplexa

Chaudhary, Kshitiz; Fox, Barbara A.; Bzik, David J.

doi:10.1016/b978-012369542-0/50020-9

Cited by 2 publications

(3 citation statements)

References 231 publications

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“…The major negative impact on the ability to complement by mutating residues that selectively affect up-regulation by ornithine in E. coli CPS, regardless of whether the allosteric effects of UMP or IMP are maintained, may indicate allosteric regulation by ornithine or a related effector in Toxoplasma gondii and could indicate points at which to intervene biochemically. It is notable that T. gondii is metabolically distinct from animals and many eukaryotes in being naturally auxotrophic for both ornithine and purines (Chaudhary, 2007; Fox, 2007). These natural auxotrophic requirements for parasite growth may be linked to novel strategies for allosteric regulation of CPSII, control of pyrimidine biosynthesis and balancing of purine and pyrimidine pools in protozoan parasites (Asai et al, 1983; Nara et al, 1998; Fox and Bzik, 2003).…”

Section: Resultsmentioning

confidence: 99%

“…Consequently, development of new drug treatments exhibiting good efficacy, low toxicity, selectivity to parasite but not host, and delayed development of widespread drug resistance is a high piority. Apicomplexan parasites such as Plasmodium falciparum and Toxoplasma gondii rely on a de novo pyrimidine synthesis pathway that is an excellent target for chemotherapy to inhibit both RNA and DNA synthesis (Fox and Bzik, 2002; Chaudhary, 2007; Fox, 2007; Painter et al, 2007). Genetic disruption of carbamoyl phosphate synthetase II (CPSII) in T. gondii induces a severe uracil auxotrophy as demonstrated by the complete absence of parasite replication in vitro and extreme attenuation of virulence in murine infection, even in severely immune deficient IFN −/− mice (Fox and Bzik, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Genetic identification of essential indels and domains in carbamoyl phosphate synthetase II of Toxoplasma gondii

Fox

Ristuccia

Bzik

2009

International Journal for Parasitology

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New treatments need to be developed for the significant human diseases of toxoplasmosis and malaria to circumvent problems with current treatments and drug resistance. Apicomplexan parasites causing these lethal diseases are deficient in pyrimidine salvage suggesting that selective inhibition of de novo pyrimidine biosynthesis can lead to a severe loss of UMP and dTMP pools thereby inhibiting parasite RNA and DNA synthesis. Disruption of Toxoplasma gondii carbamoyl phosphate synthetase II (CPSII) induces a severe uracil auxotrophy with no detectable parasite replication in vitro and complete attenuation of virulence in mice. Here we show that a CPSII cDNA minigene efficiently complements the uracil auxotrophy of CPSII deficient mutants restoring parasite growth and virulence. Our complementation assays reveal that engineered mutations within or proximal to the catalytic triad of the N-terminal glutamine amidotransferase (GATase) domain inactivate the complementation activity of T. gondii CPSII and demonstrate a critical dependence on the apicomplexan CPSII GATase domain in vivo. Surprisingly, indels present within the T. gondii CPSII GATase domain as well as the C-terminal allosteric regulatory domain are found to be essential. In addition several mutations directed at residues implicated in allosteric regulation in Escherichia coli CPS either abolish or markedly suppress complementation and further define the functional importance of the allosteric regulatory region. Collectively, these findings identify novel features of T. gondii CPSII as potential parasite-selective targets for drug development.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genetic identification of essential indels and domains in carbamoyl phosphate synthetase II of Toxoplasma gondii

Fox

Ristuccia

Bzik

2009

International Journal for Parasitology

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“…However, it is also known that anabolism of polyamines is linked to the synthesis of a molecule, known as 5′‐methylthioadenosine (MTA). In majority of the organisms, this MTA is associated with adenine and methionine biosynthesis (Chaudhary, Barbara, & David, 2014).…”

Section: Introductionmentioning

confidence: 99%

Regulation of the hypothalamic GnRH–GnIH system by putrescine in adult female rats and GT1‐7 neuronal cell line

et al. 2020

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The gonadotropin‐releasing hormone—gonadotropin inhibitor (GnRH–GnIH) system in the hypothalamus of mammals is the key factor that controls the entire reproductive system. The aim of this study was to immunolocalize GnIH (RFRP‐3) in the hypothalamus during the estrous cycle and to study the effect of putrescine on the expression of GnRH‐I and GnIH through both in vivo and in vitro (GT1‐7 cells) approach and the circulatory levels of GnRH‐I, GnIH, and gonadotropins were also investigated. The study also aims in analyzing all the immunofluorescence images by measuring the relative pixel count of an image. This study showed the effect of putrescine on the morphology of ovary, uterus, and the expression of the steroidogenic acute regulatory protein in the ovary. This study showed GnIH expression was intense during the diestrus and moderate during proestrus and estrus, whereas mild staining during the metestrus. The study further showed that putrescine supplementation to adult female rats increased both GnRH‐I expression in the hypothalamus as well as the GnRH‐I levels in circulation. The study, for the first time, also showed that putrescine supplementation decreased the expression and release of GnIH. These effects of upregulating GnRH‐I expression and downregulating GnIH expression were confirmed by in vitro experiments using GT1‐7 cells. Putrescine supplementation also increased the gonadotropin levels in the serum. To summarize, putrescine can regulate the hypothalamic–pituitary–gonadal axis by increasing the GnRH‐I, luteinizing hormone, and follicle‐stimulating hormone levels and suppressing GnIH levels. This is the first report showing the simultaneous effects of putrescine on the regulation of both GnRH‐I and GnIH in the hypothalamus.

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Comparative Aspects of Nucleotide and Amino-acid Metabolism in Toxoplasma gondii and other Apicomplexa

Cited by 2 publications

References 231 publications

Genetic identification of essential indels and domains in carbamoyl phosphate synthetase II of Toxoplasma gondii

Genetic identification of essential indels and domains in carbamoyl phosphate synthetase II of Toxoplasma gondii

Regulation of the hypothalamic GnRH–GnIH system by putrescine in adult female rats and GT1‐7 neuronal cell line

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