Nucleic Acid Metabolism

Nucleotides are required for a wide variety of biological processes and are constantly synthesized denovo in all cells. When cells proliferate, increased nucleotide synthesis is necessary for DNA replication and for RNA production to support protein synthesis at different stages of the cell cycle, during which these events are regulated at multiple levels. Therefore the synthesis of the precursor nucleotides is also strongly regulated at multiple levels. Nucleotide synthesis is an energy intensive process that uses multiple metabolic pathways across different cell compartments and several sources of carbon and nitrogen. The processes are regulated at the transcription level by a set of master transcription factors but also at the enzyme level by allosteric regulation and feedback inhibition.

The different parts of the nucleotides derive from various carbon and nitrogen sources in the cell, and the assembly of the mature rNTPs has a high metabolic demand. The numbers of nucleoside triphosphate (NTP) equivalents (number of phosphates released from ATP and GTP) needed to make one molecule each of the four rNTPs. Thus starting from glucose, three ATP equivalents are needed to make the activated ribose-5’-phosphoribosepyrophosphate (PRPP), which is produced by the reaction of 5’-phosphoribose with ATP, driven by the release of the good leaving group 5’-AMP. 5-phosphoribose-1-pyrophosphate (PRPP) is the activated form of ribose used for nucleotide biosynthesis and is derived from ribose-5-phosphate from the pentose phosphate pathway (PPP).Ribose-5-phosphate is produced via both oxidative and non-oxidative branches of the PPP. The oxidative branch also generates two NADPH. The oxidative branch comprises the reactions catalyzed by G6PD, PGLS and PGD. The non-oxidative branch interconverts five carbon sugars with four and six carbon sugars using the transaldolase (TA) and transketolase (TK) reactions.