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After studying this chapter, you should be able to:

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  • Compare and contrast the roles of dietary nucleic acids and of de novo biosynthesis in the production of purines and pyrimidines destined for polynucleotide biosynthesis.
  • Explain why antifolate drugs and analogs of the amino acid glutamine inhibit purine biosynthesis.
  • Outline the sequence of reactions that convert IMP, first to AMP and GMP, and subsequently to their corresponding nucleoside triphosphates.
  • Describe the formation from ribonucleotides of deoxyribonucleotides (dNTPs).
  • Indicate the regulatory role of PRPP in hepatic purine biosynthesis and the specific reaction of hepatic purine biosynthesis that is feedback inhibited by AMP and by GMP.
  • State the relevance of coordinated control of purine and pyrimidine nucleotide biosynthesis.
  • Identify reactions that are inhibited by anticancer drugs.
  • Write the structure of the end product of purine catabolism. Comment on its solubility and indicate its role in gout, Lesch–Nyhan syndrome, and von Gierke disease.
  • Identify reactions whose impairment leads to modified pathologic signs and symptoms.
  • Indicate why there are few clinically significant disorders of pyrimidine catabolism.

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Even when humans consume a diet rich in nucleoproteins, dietary purines and pyrimidines are not incorporated directly into tissue nucleic acids. Humans synthesize the nucleic acids, ATP, NAD+, coenzyme A, etc, from amphibolic intermediates. However, injected purine or pyrimidine analogs, including potential anticancer drugs, may be incorporated into DNA. The biosyntheses of purine and pyrimidine ribonucleotide triphosphates (NTPs) and dNTPs are precisely regulated events. Coordinated feedback mechanisms ensure their production in appropriate quantities and at times that match varying physiologic demand (eg, cell division). Human diseases that involve abnormalities in purine metabolism include gout, Lesch–Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. Diseases of pyrimidine biosynthesis are rarer, but include orotic acidurias. Unlike the low solubility of uric acid formed by catabolism of purines, the end-products of pyrimidine catabolism (carbon dioxide, ammonia, β-alanine, and γ-aminoisobutyrate) are highly water soluble. One genetic disorder of pyrimidine catabolism is β-hydroxybutyric aciduria, due to total or partial deficiency of the enzyme dihydropyrimidine dehydrogenase. This disorder of pyrimidine catabolism, also known as combined uraciluria-thyminuria, is also a disorder of β-amino acid biosynthesis, since the formation of β-alanine and of β-aminoisobutyrate is impaired. A nongenetic form can be triggered by administration of 5-fluorouracil to patients with low levels of dihydropyrimidine dehydrogenase.

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Normal human tissues can synthesize purines and pyrimidines from amphibolic intermediates in quantities and at times appropriate to meet variable physiologic demand. Ingested nucleic acids and nucleotides therefore are dietarily nonessential. Following their degradation in the intestinal tract, the resulting mononucleotides may be absorbed or converted to purine and pyrimidine bases. The purine bases are then oxidized to uric acid, which may be absorbed and excreted in the urine. While little or no dietary purine or pyrimidine is incorporated into tissue nucleic acids, injected compounds are incorporated. The incorporation of injected [3H]thymidine into newly synthesized DNA thus can be used to measure the rate of ...

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