Chapter 39: Purine and Pyrimidine Metabolism

Nucleotides serve as building blocks for DNA and RNA while functioning as energy carriers such as ATP and GTP, cofactors including NAD+ and FAD, and signaling molecules like cAMP and cGMP. Purine synthesis begins through a complex de novo pathway that assembles the purine ring from multiple precursors including glycine, ribose 5-phosphate, glutamine, aspartate, carbon dioxide, and N10-formyltetrahydrofolate, ultimately producing inosine monophosphate before diverging into adenosine and guanosine nucleotides. When dietary purines are available, salvage pathways provide an energy-efficient recycling mechanism through enzymes such as hypoxanthine-guanine phosphoribosyltransferase and adenine phosphoribosyltransferase; deficiencies in these enzymes cause severe clinical consequences including Lesch-Nyhan syndrome and adenosine deaminase deficiency-associated severe combined immunodeficiency. Purine degradation ultimately produces uric acid, whose overproduction triggers gout and is managed therapeutically with xanthine oxidase inhibitors. Pyrimidine synthesis follows a distinct pathway beginning with carbamoyl phosphate and aspartate, proceeding through orotate formation, and yielding uridine monophosphate under tight allosteric regulation at carbamoyl phosphate synthetase II. Inherited defects in pyrimidine metabolism produce hereditary orotic aciduria and secondary orotic aciduria associated with urea cycle disorders, treatable through nucleotide supplementation. Ribonucleotide reductase catalyzes the conversion of ribonucleotides to deoxyribonucleotides with sophisticated allosteric control ensuring balanced synthesis of DNA precursors. The chapter emphasizes clinical applications including management of hyperuricemia and acute gout attacks, exploitation of antifolate and antimetabolite drugs in cancer chemotherapy that inhibit nucleotide synthesis, and understanding genetic immunodeficiency states that arise from nucleotide metabolism abnormalities.