Denovosynthesisofpyrimidinenucleotides

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The pyrimidine ribonucleotides, those found in RNA, are uracil and cytosine, each containing the sugar ribose and a nitrogenous base. Pyrimidine nucleotides contain a single ring in the nitrogenous base. In contrast to the synthesis of purines, the pyrimidine ring is synthesized first and then joined to ribose. This pathway is conserved from bacteria to man, occurring in essentially the same manner for all species. The pathway begins with aspartate and carbamoyl phosphate as the first components to build the pyrimidine base. Carbamoyl phosphate is synthesized from bicarbonate ions and a nitrogen from glutamine. The condensation of aspartate and carbamoyl phosphate creates carbamoyl aspartate, which goes through ring closure and oxidation to create the precursor pyrimidine orotate. Orotate is joined to ribose phosphate and UMP is finally formed through decarboxylation. CTP is synthesized from UTP through amination using glutamine as the donor in mammals and ammonia in E.coli. This pathway is closely regulated to provide pyrimidines only when they are needed. The pathway is activated by ATP and inhibited by the end product, pyrimidines, providing an example of feedback inhibition. The deoxyribonucleotides found in DNA are synthesized through reduction of the ribose ring in ribonucleotides. Although the bacterial and human pathways are similar, the enzymes that catalyze the pathway reactions are quite distinct. In bacteria, the first three steps in the pathway are catalyzed by three separate polypeptides, but in humans a single polypeptide has all three enzymatic activities. Multifunctional enzyme complexes of this nature occur in other pathways as well, and increase the overall efficiency of a pathway by directing pathway intermediates directly from one step to the next rather than relying on diffusion between enzymes in the pathway.

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