Purine and Pyrimidine Metabolism

Purine and pyrimidine nucleotides are essential for a vast number of biological processes such as RNA and DNA synthesis and as a component of high-energy nucleotides, e.g., adenosine triphosphate. Polygenic and Mendelian diseases are associated with altered purine and pyrimidine metabolism; thus, the genes associated with gout have only minor effects on serum urate levels, and the combination of such genetic factors as well as environmental factors causes the disease. Recent genome-wide association studies have identified such genes many of which code for transporters in renal tubules and related proteins. Mendelian diseases include enzyme abnormalities in the purine and pyrimidine pathways. Although most of the abnormalities were found by the candidate gene approach, more and more pathological mutations or variations are now discovered by whole-exome or whole-genome sequencing. To date, more than 30 defects associated with purine and pyrimidine metabolism have been described. Inherited disorders of purine and pyrimidine metabolism have a wide variety of clinical presentations including anemia, immunodeficiency, renal stones, convulsions, intellectual disability, autism, growth retardation, hearing disturbance, retinitis pigmentosa, cancer, and serious adverse reactions to medication. For immunodeficiency caused by adenosine deaminase deficiency, enzyme replacement therapy and somatic gene therapy targeted at hematopoietic stem cells have been successful.