| Pyrimidine-salvage pathways
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As with the purines, free pyrimidine bases, available from the diet or from the breakdown of nucleic acids, can be salvaged by a series of enzyme reactions. The first of these operates on uracil and is similar to the purine-salvage systems:
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The enzyme uracil phosphoribosyl transferase (UPRTase) is also required to activate some chemotherapeutic agents such as 5-fluorouracil (FU) or 5-fluorocytosine (FC). A second salvage reaction that is catalyzed by thymidine kinase is relatively specific for thymidine. It converts nucleosides into nucleotides by direct phosphorylation using ATP as the phosphate donor:
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| Orotic aciduria is a very rare genetic condition characterized by anemia resulting from defects in red cell maturation, accompanied by orotic aciduria. Orotic acid crystals form in urine on standing, but may also precipitate in vivo, causing obstruction of the urinary tract. The most severe form of orotic aciduria (Type 1) results from a deficiency of the enzyme UMP synthase. These patients are unable to convert orotic acid into UMP. The accumulated orotic acid is excreted in the urine. UMP synthase is a multifunctional protein containing both orotate phosphoribosyltransferase and OMP decarboxylase activity. The Type 1 form results from a complete loss of both activities. A second, rarer form of hereditary orotic aciduria (Type 2) is deficient in only OMP decarboxylase. This deficiency has been successfully treated with chronic uridine therapy. |
Other metabolic disorders such as ornithine transcarbamoylase deficiency or argininosuccinic acid synthetase deficiency that result in abnormally high ratios of uridine to adenosine nucleotides in liver can also produce elevated levels of orotic acid in urine. |
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| Figure 29.6 Synthesis of pyrimidine triphosphates. Synthesis of thymidine is inhibited by fluorodeoxyuridylate (FdUMP), methotrexate, aminopterin, and trimethoprim at the indicated sites. *Thioredoxin restores sulfhydryl residues on ribonucleotide reductase, regenerating the active enzyme (see p. 422). |
| In bacteria and some fungi, there is an additional salvage enzyme, cytosine deaminase, that converts cytosine into uracil, which is salvaged by UPRTase. Cytosine deaminase is not found in most higher eukaryotes, including humans. Therefore, cytosine is not salvaged in humans. Because of this, fluorocytosine is a potent antimicrobial compound. The microbial enzyme converts fluorocytosine into fluorouracil, which is toxic (see below).
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