Chapter 18: Nucleotide Metabolism

The chapter encompasses four major metabolic processes that maintain cellular nucleotide homeostasis. De novo purine synthesis constructs the purine ring system stepwise onto a ribose-phosphate scaffold derived from PRPP, with the pathway proceeding through ten enzymatic steps to generate inosine monophosphate, which then branches into either adenosine or guanosine nucleotides. This process is tightly regulated through feedback inhibition at the committed step catalyzed by glutamine-PRPP amidotransferase. De novo pyrimidine synthesis follows a distinct strategy, assembling the pyrimidine ring first from simple precursors before attaching the ribose-phosphate moiety, ultimately producing uridine monophosphate that serves as the precursor for all pyrimidine nucleotides. The conversion of ribonucleotides into deoxyribonucleotides for DNA synthesis depends on ribonucleotide reductase, an enzyme featuring sophisticated allosteric regulation that balances the cellular pool of all four deoxyribonucleotides. Thymidylate synthase catalyzes the critical methylation step producing deoxythymidylate and represents a major target for anticancer chemotherapy. Salvage pathways enable cells to recycle free bases released during nucleic acid turnover through phosphoribosyltransferases like HGPRT, conserving substantial metabolic energy; deficiency in HGPRT causes Lesch-Nyhan syndrome with severe neurological consequences. Finally, nucleotide catabolism degrades excess purines through oxidative pathways terminating in uric acid, whose overproduction or inadequate excretion leads to gout and can be managed with xanthine oxidase inhibitors, while pyrimidines degrade into soluble metabolites readily incorporated into central carbon metabolism.