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analysis of pyrimidine biosynthesis enzymes ..

Pyrimidine biosynthesis - WikiVisually

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Pyrimidine biosynthesis occurs both in the body and ..

The human liver can synthesize all the necessary levels of cholesterol and will reduce its own synthesis if cholesterol is taken in during a meal (only from animal sources).

Pyrimidine Nucleotides Metabolism: Biosynthesis and Catabolism

Whereas pyrimidine biosynthesis pathways are highly conserved between worms and humans, no human thymidine phosphorylase homolog has been identified in C.

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On Dec 31, 2004 Monika Löffler (and others) published: Pyrimidine Biosynthesis

Although the intergenic regions of the pyrimidine biosynthesis locus of L. donovani were not sequenced in this study, all five genes were syntenic, as expected from the mapped pyrimidine loci of Leishmania species () and T. cruzi (), because they were physically co-localized to a single cosmid DNA. T. brucei, however, exhibits a loss of synteny at the DHO locus (). To our knowledge, the pyrimidine biosynthetic pathway genes represent the only example of microsyntenic clustering of an entire biosynthetic pathway in trypanosomatids. Conversely, UPRT as well as the pyrimidine nucleoside interconversion enzymes are non-syntenic with the biosynthetic cluster and with each other. Furthermore, our limited analysis revealed that CPS and DHODH were located at the 5′- and 3′-ends, respectively, of the pyrimidine biosynthesis locus, similar to other Leishmania species and T. cruzi, whose genomes have been sequenced, suggesting shared synteny of the entire locus. Bioinformatic analysis also revealed the presence of a gene encoding a hypothetical protein and several histone genes within the pyrimidine clusters of L. major, L. mexicana, and L. infantum (). Whether other essential genes have integrated into the pyrimidine gene cluster in L. donovani is currently being investigated via attempts to delete the entire complement of pyrimidine biosynthesis enzymes by targeted gene replacement.

The L. donovani CPS was isolated from a cosmid library as part of a strategy to isolate the entire complement of pyrimidine biosynthesis genes. Given that the genes encoding the biosynthetic pathway are known to be colocalized on the genomes of T. cruzi, T. brucei, L. major, L. mexicana, and L. infantum trypanosomatids (–), sequences within the 5′- and 3′-ORFs of the L. major cluster, CPS and DHODH, respectively, were amplified by PCR from L. major genomic DNA, and each was used to probe replica filters containing DNAs from an L. donovani cosmid library. Several cosmids that accommodated the entire ensemble of pyrimidine biosynthesis genes were obtained, and the ORFs of CPS, ACT, DHO, DHODH, and UMPS were sequenced. The L. donovani CPS is a polypeptide of 1,842 amino acids and, like the other trypanosomatid CPSs, is a bifunctional polypeptide that encodes an NH2-terminal glutamine amidotransferase domain that removes the amido nitrogen from glutamine to enable carbamoylphosphate synthesis from CO2. Unlike the mammalian enzyme (, ), the trypanosomatid CPS proteins, including the L. donovani CPS, are not part of a trifunctional polypeptide encoding ACT and DHO. A multisequence alignment of the L. donovani, T. cruzi, human, and Saccharomyces cerevisiae CPS proteins is shown in . The properties of the other L. donovani pyrimidine biosynthetic enzymes have been described () or will be described elsewhere.

pyrimidine biosynthesis at the level of PRPP formation.


Hoogenraad NJ and Lee DC (1974) Effect of uridine on de novo pyrimidine biosynthesis in rat hepatoma cells in culture. Journal of Biological Chemistry 249: 2763–2768.

Knockdown of other pyrimidine biosynthesis enzyme homologs, such as uridine monophosphate kinase and uridine monophosphate synthetase, also resulted in 5‐FU resistance.

Diseases of pyrimidine biosynthesis …
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    Biosynthesis of Pyrimidine 2

  • and biochemistry of purine and pyrimidine biosynthesis ..

    in pyrimidine biosynthesis.

  • Pyrimidine Biosynthesis Flashcards | Quizlet

    Regulation of Pyrimidine Nucleotide Biosynthesis; Humans Catabolize ..

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Salvage and Biosynthetic Pathways; Pyrimidine ..

The purine pathway in protozoan parasites has garnered extensive attention because, unlike their vertebrate hosts, all protozoan parasites that have been studied to date lack the capacity to synthesize the purine ring de novo (). Thus, all of these human pathogens must obligatorily scavenge purines from their hosts in order to survive and proliferate. In contrast, most, but not all, protozoan parasites can synthesize pyrimidine nucleotides (). Leishmania are pyrimidine prototrophs but also express a variety of salvage and interconversion enzymes that enable them to acquire preformed pyrimidine nucleobases or nucleosides from either the culture medium or the host environment. Studies on the pyrimidine pathway in Leishmania, however, have been very limited. All six enzymes of the pyrimidine biosynthetic pathway have been detected in Leishmania mexicana (), and the carbamoyl phosphate synthetase (CPS) gene sequence from L. mexicana has been reported (). In addition, Leishmania express uracil and uridine transport activities (, , ) as well as uracil phosphoribosyltransferase (UPRT) (), uridine hydrolase (), cytidine deaminase (, ), and thymidylate synthase (, ) activities. The uridine transporter of L. donovani (, ), the uridine hydrolase from both L. donovani () and Leishmania major (), and the bifunctional dihydrofolate reductase-thymidylate synthase proteins from several Leishmania species (, , ) have been identified at the molecular level and characterized. Biochemical and genetic investigations on the pyrimidine biosynthetic enzymes as well as the enzymes that salvage preformed pyrimidines from the host are virtually nonexistent at the molecular level for this genus. A schematic representation of the pyrimidine transport, biosynthesis, salvage, and interconversion pathways is depicted in .

Pyrimidine biosynthesis - Revolvy

Aoki and co-workers () first noted that the genes encoding all six pyrimidine biosynthetic enzymes of Trypanosoma cruzi, another protozoan parasite and member of the Trypanosomatidae family, are syntenic in the genome of the parasite. Bioinformatic analysis of the annotated genomes of four Leishmania species as well as the genome of Trypanosoma brucei reveal a similar clustering of pyrimidine biosynthesis genes in all of these human pathogens (–). Limited in vitro studies on the pyrimidine biosynthetic pathway enzymes in cultured trypanosomatids have been performed. These include one report that implies that disruption of the dihydroorotate dehydrogenase (DHODH) genes that encode the fourth enzyme in the biosynthetic pathway in T. cruzi is a lethal event () and a similar analysis in T. brucei in which RNAi knockdown of DHODH restrained parasite growth in pyrimidine-deficient growth medium (). In addition, a recent article showed a modest (~3-fold) growth inhibition of intracellular amastigotes upon genetic ablation of the CPS gene in T. cruzi (). However, in vivo evaluation of the relative contributions of trypanosomatid pyrimidine salvage and de novo synthesis pathways to parasite survival are lacking.

Genetic Dissection of Pyrimidine Biosynthesis and …

The human genome has been found to contain only 5% coding sequences (genes that make proteins), while half of all non-coding portions are made of transposable elements reminiscent of viral DNA.

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