Disorders of Purine and Pyrimidine Metabolism

Purine nucleotides are essential cellular constituents that are involved in energy transfer, metabolic regulation, and synthesis of DNA and RNA. Purine metabolism can be divided into three pathways (. Fig. 32.1). 1. De novo purine synthesis (DNPS) comprises a series of 10 enzymatic reactions that are critical to purine formation. This pathway starts with the formation of phosphoribosyl pyrophosphate (PRPP) and leads to the synthesis of inosine monophosphate (IMP). Purine nucleotide synthesis is completed by the interconversion of IMP to adenosine and guanosine nucleotides. Adenosine monophosphate (AMP) synthesis from IMP requires adenylosuccinate synthase (ADSS) and adenylosuccinate lyase (ADSL), while the synthesis of guanosine monophosphate (GMP) occurs via IMP dehydrogenase (IMPDH) and GMP synthetase. Mononucleotides can further be phosphorylated into di- and trinucleotides and reduced into deoxyribonucleotides. Nucleoside triphosphates (NTPs) and their deoxy counterparts (dNTPs) are incorporated into RNA and DNA, involved in cell signaling or used as energy transfer in cells. 2. The catabolic pathway starts from GMP, IMP, and AMP. Its final product is uric acid, a poorly soluble metabolite excreted in urine, that tends to crystallize once its plasma concentration exceeds 6.5–7.0 mg/ dL (0.38–0.47 mmol/L). 3. The salvage pathway allows the recovery of purine bases and nucleosides. Guanine, hypoxanthine, and adenine, which are provided by food intake or catabolic pathways, are reconverted into GMP, IMP, and AMP, respectively. Salvage of the nucleosides adenosine and guanosine, and their deoxy counterparts, is catalyzed by several specific kinases. The salvage pathway additionally converts several pharmacological anticancer agents and antiviral nucleoside analogs into their active forms. Similar to that of purine nucleotides, the metabolism of pyrimidine nucleotides can be divided into three pathways (. Fig. 32.2). 1. The biosynthetic, de novo pathway starts with the formation of carbamoyl phosphate by cytosolic carbamoyl phosphate synthetase II (CPS II), which differs from mitochondrial CPS I, the latter catalyzing the first step of ureagenesis (7 Chap. 19). This is followed by the synthesis of uridine monophosphate (UMP) and, hence, of (deoxy)nucleoside triphosphates ((d)NTPs) used for RNA and DNA synthesis. 2. The catabolic pathway starts from CMP, UMP, and dTMP and yields β-alanine and β-aminoisobutyrate, which are converted into citric acid cycle intermediates. 3. The salvage pathway, which is composed of several kinases, converts pyrimidine nucleosides cytidine, uridine, and thymidine into their corresponding nucleotides CMP, UMP, and dTMP, respectively. This pathway also converts several pharmacological anticancer and antiviral nucleoside analogs into their active forms