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Purine and pyrimidine nucleotides are synthesized by both de novo and salvage pathways (Figures 46-1 and 46-2). The de novo pathways create these complex phosphorylated molecules from simple precursors, such as CO2, glycine, and glutamine, in stepwise fashion, whereas the salvage pathways serve the reuse of purine and pyrimidine bases of metabolic and dietary sources. In purine metabolism, inosinic acid (inosine monophosphate [IMP]) is the central product of both pathways and is central to the interconversion to adenine and purine nucleotides (Figure 46-1). Phosphoribosyl-pyrophosphate (PRPP) synthetase catalyzes the first step in the pathway of de novo purine synthesis; the next step, the amidotransferase reaction, is the first committed step. Purine salvage is catalyzed by the enzymes adenine phosphoribosyltransferase (APRT), adenosine kinase, and hypoxanthine–guanine phosphoribosyl transferase (HPRT). Other important interrelations include the conversion of adenosine monophosphate (AMP) to IMP, catalyzed by adenosine myoadenylate deaminase (AMPDA) and the adenylosuccinate lyase (ASL) reactions in which IMP is converted to AMP via adenylosuccinate (AMPS). The latter enzyme also catalyzes the conversion of 5-phosphoribosyl-5-amino-4-imidazole-succinylcarboxamide (SAICAMP) to 5-phosphoribosyl-5-amino-4-imidazole-carboxamide (AICAMP). Adenosine is converted to inosine in the reaction catalyzed by adenosine deaminase (ADA). Purine nucleoside phosphorylase (PNP) catalyzes the conversion inosine to hypoxanthine; it also catalyzes the conversion of guanosine and the deoxy analogues to their bases. The conversion of hypoxanthine to xanthine and their conversion to uric acid is catalyzed by xanthine oxidase (XO). Uric acid is the endpoint of purine metabolism in humans.

FIGURE 46-1.

Normal purine metabolism. Pathways of synthesis, salvage, interrelations, and degradation of purine nucleotides. The enzymatic steps in the boxes indicate the sites of the commonly encountered disorders of purine metabolism. Abbreviations include the hypoxanthine:guanine phosphoribosyl transferase (HPRT) reaction. This enzyme is the molecular defect in Lesch–Nyhan disease. ATP, adenosine triphosphate; ASL, adenylosuccinate lyase, APRT, adenine phosphoribosyltransferase; HPRT, hypoxanthine–guanine phosphoribosyl transferase; AICAMP, (AICAR, AICA ribotide, ZMP); SAICAMP, (SAICAR, succinyl-AICAR); ADA, adenosine deaminase; PNP, purine nucleoside phosphorylase; AMPDA, adenylate deaminase; XO, xanthine oxidase.

FIGURE 46-2.

Pathways of pyrimidine nucleotide synthesis and degradation. CPS II, carbamylphosphate synthetase II; ATP, adenosine triphosphate; ATC, aspartate transcarbamylase; DHO, dihydroorotase; DHODH, dihydroorotate dehydrogenase; OPRT, orotic acid phosphoribosyltransferase; ODC, orotidine 5-phosphate decarboxylase; UMH, UMP hydrolase; DHP, dihydropyrimidinase. UMP, uridine monophosphate; DPD, dihydropyrimidine dehydrogenase.

De novo synthesis of pyrimidines begins with a carbamylphosphate synthetase 2 reaction. It is catalyzed by a different synthetase than the one involved in the urea cycle, but when carbamylphosphate accumulates as in ornithine transcarbamyl synthetase deficiency and other disorders of the urea cycle, pyrimidine synthesis accelerates, and orotic acid and uracil accumulate. The last two steps of the pyrimidine de novo pathway are catalyzed by uridine 5′-monophosphate (UMP) synthase (UMPS), which contains two catalytic activities, orotic acid phosphoribosyltransferase (OPRT) and orotidine monophosphate ...

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