Purine and Pyrimidine Metabolism

• Purine and pyrimidine nucleotides can both be synthesized from scratch (de novo) or salvaged from existing bases.
• De novo purine synthesis is complex, requiring 11 steps and 6 molecules of adenosine triphosphate for every purine synthesized. Purines are initially synthesized in the ribonucleotide form.
• The precursors for de novo purine synthesis are glycine, ribose 5-phosphate, glutamine, aspartate, carbon dioxide, and N¹⁰-formyltetrahydrofolate.
• The initial purine ribonucleotide synthesized is inosine monophosphate. Adenosine monophosphate and guanosine monophosphate are each derived from inosine monophosphate.
• Since de novo purine synthesis requires a large amount of energy, purine nucleotide salvage pathways exist such that free purine bases can be converted to nucleotides.
• Mutations in purine salvage enzymes are associated with severe diseases, such as Lesch-Nyhan syndrome and severe combined immunodeficiency disease.
• Pyrimidine bases are initially synthesized as the free base and then converted to nucleotides.
• Aspartate and cytoplasmic carbamoyl phosphate are the precursors for pyrimidine ring synthesis.
• The initial pyrimidine nucleotide synthesized is orotate monophosphate, which is converted to uridine monophosphate. The other pyrimidine nucleotides will be derived from a uracil-containing intermediate.
• Deoxyribonucleotides are derived by reduction of ribonucleotides, as catalyzed by ribonucleotide reductase. The regulation of ribonucleotide reductase is complex.
• Degradation of purine containing nucleotides results in uric acid production, which is eliminated in the urine. Elevated uric acid levels in the blood lead to gout.