Questions and Answers
What is the function of the second gene in pyrimidine biosynthesis?
What is the effect of Azathymidine on viral reverse transcriptase?
What is the source of ribose 1-phosphate in pyrimidine biosynthesis?
What is the function of Pyr 13 in pyrimidine biosynthesis?
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What is the result of PRPP deficiency on purine and pyrimidine nucleotide synthesis?
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What is the effect of adenosine on cultured mammalian cells?
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What is the product of the reaction catalyzed by dihydro-orotate dehydrogenase?
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What is the function of uridylate kinase in pyrimidine biosynthesis?
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How does PRPP affect purine nucleotide biosynthesis?
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What is the result of pyrimidine starvation on nucleotide synthesis?
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What is the role of multifunctional polypeptides in pyrimidine biosynthesis?
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What is the amino acid 'nucleus' used in pyrimidine biosynthesis?
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How does ATP affect pyrimidine nucleotide biosynthesis?
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What is required for the biosynthesis of purine and pyrimidine nucleotides?
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What is the effect of increased PRPP levels on purine and pyrimidine nucleotide biosynthesis?
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What is the role of PRPP in pyrimidine nucleotide biosynthesis?
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What is the effect of increased levels of purine nucleotides on PRPP synthesis?
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What is the main organ responsible for pyrimidine catabolism?
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What is the characteristic of hereditary orotic aciduria?
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What is the effect of adenosine on the conversion of orotic acid to orotidine-5'-monophosphate?
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What is the treatment for hereditary orotic aciduria?
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What is the term for the inhibition of formation of pyrimidine nucleotides in the presence of excess purine nucleosides and nucleotides?
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What is the characteristic of pyrimidine auxotrophs?
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What is the effect of adenosine deaminase on the toxic effect of adenosine?
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Study Notes
Nucleotide Synthesis Inhibitors
- Azathymidine (AZT) inhibits viral reverse transcriptase and is used to treat AIDS.
- AZT works by converting to its corresponding 5'-triphosphate, which then inhibits viral reverse transcriptase.
Coordination of Purine and Pyrimidine Nucleotide Biosynthesis
- A balanced synthesis of pyrimidine and purine nucleotides is essential for the biosynthesis of nucleic acids in growing cells.
- PRPP (5-phosphoribosyl-1-pyrophosphate) affects purine and pyrimidine nucleotide biosynthesis.
- PRPP formation is activated by inorganic phosphate and inhibited by several end products of pathways that use PRPP.
- PRPP activates enzymes in both purine and pyrimidine synthesis pathways.
- Changes in PRPP levels bring about concordant changes in both pathways.
Mechanisms of Coordination
- ATP activates CPS II (carbamoyl phosphate synthetase II).
- A deficiency of PRPP synthetase leads to orotic aciduria and hypouricemia, consistent with decreased synthesis of purine and pyrimidine nucleotides.
Pyrimidine Nucleotide Biosynthesis
- One gene codes for a multifunctional polypeptide (Pyr 13) with carbamoyl phosphate synthetase II, aspartate transcarbamoylase, and dihydroorotase activity.
- The second gene codes for dihydro-orotate dehydrogenase.
- The third gene codes for UMP synthase (Pyr 5,6) with orotate phosphoribosyltransferase and orotidylate decarboxylase activity.
- Multifunctional polypeptides are efficient, as intermediates do not accumulate or become consumed in side reactions.
Conversion of Dihydroorotate to Orotate
- Dihydroorotate is converted to orotate by dihydroorotate dehydrogenase, a metalloflavoprotein containing nonheme iron atoms and flavin adenine nucleotides.
Requirements for Nucleotide Synthesis
- Purine and pyrimidine nucleotide biosynthesis requires carbon dioxide and the amide nitrogen of glutamine.
- Both use an amino acid "nucleus" (glycine in purine biosynthesis and aspartate in pyrimidine biosynthesis).
- Both use PRPP as the source of ribose 1-phosphate.
UMP Formation and Conversion
- UMP is converted to UTP by uridylate kinase and nucleoside diphosphate kinase.
- Adenosine inhibits the conversion of orotic acid to orotidine-5'-monophosphate, leading to pyrimidine starvation.
Catabolism of Pyrimidine Nucleotides
- Pyrimidine catabolism occurs mainly in the liver and yields highly soluble end products.
Abnormalities of Pyrimidine Metabolism
- Hereditary orotic aciduria is a rare autosomal recessive trait characterized by a deficiency of orotate phosphoribosyltransferase and orotidine-5'-monophosphate decarboxylase activities.
- Symptoms include failure of normal growth, hypochromic erythrocytes, megaloblastic bone marrow, and leukopenia.
- Treatment with uridine results in marked improvement in hematological abnormalities and growth and development.
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Description
Understand the role of nucleotide synthesis inhibitors, such as AZT, and the coordination of purine and pyrimidine nucleotide biosynthesis in growing cells. Learn how PRPP affects purine and pyrimidine biosynthesis.
