SURVEY AND SUMMARY Regulation of mammalian nucleotide metabolism and biosynthesis

Nucleotides are required for a wide variety of bio-logical processes and are constantly synthesized de novo in all cells. When cells proliferate, increased nucleotide synthesis is necessary for DNA replica-tion and for RNA production to support protein syn-thesis at different stages of the cell cycle, during which these events are regulated at multiple lev-els. Therefore the synthesis of the precursor nu-cleotides is also strongly regulated at multiple levels. Nucleotide synthesis is an energy intensive process that uses multiple metabolic pathways across differ-ent cell compartments and several sources of car-bon 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 reg-ulation and feedback inhibition. Here we review the cellular demands of nucleotide biosynthesis, their metabolic pathways and mechanisms of regulation during the cell cycle. The use of stable isotope trac-ers for delineating the biosynthetic routes of the mul-tiple intersecting pathways and how these are quan-titatively controlled under different conditions is also highlighted. Moreover, the importance of nucleotide synthesis for cell viability is discussed and how this may lead to potential new approaches to drug devel-opment in diseases such as cancer