Nucleotides are the building blocks of nucleic acids such as DNA and RNA. They also serve as energy carriers, enzyme cofactors, and signaling molecules in the cell. The biosynthesis of nucleotides involves a complex set of biochemical reactions that occur in different compartments of the cell. In this chapter, we will discuss the biosynthesis of nucleotides, including the de novo synthesis of purines and pyrimidines, salvage pathways, and the regulation of nucleotide biosynthesis.
De novo synthesis of purines: The de novo synthesis of purines occurs through a series of 10 enzymatic reactions that take place in the cytoplasm of the cell. The first step is the formation of 5-phosphoribosyl-1-pyrophosphate (PRPP) from ribose-5-phosphate, which is catalyzed by the enzyme PRPP synthetase. PRPP is then used as a substrate for the synthesis of inosine monophosphate (IMP), which is the precursor for all other purine nucleotides. The synthesis of IMP occurs in a multi-step process involving the enzymes adenylosuccinate synthetase, adenylosuccinate lyase, and IMP dehydrogenase.
De novo synthesis of pyrimidines: The de novo synthesis of pyrimidines occurs through a series of six enzymatic reactions that take place in the cytoplasm of the cell. The first step is the formation of carbamoyl phosphate from glutamine and bicarbonate, which is catalyzed by the enzyme carbamoyl phosphate synthetase II. Carbamoyl phosphate is then condensed with aspartate to form carbamoyl aspartate, which is then converted to dihydroorotate by the enzyme dihydroorotase. Dihydroorotate is then oxidized to orotate by the enzyme dihydroorotate dehydrogenase, and orotate is finally converted to uridine monophosphate (UMP) through a series of enzymatic reactions.
Salvage pathways: In addition to de novo synthesis, cells can also obtain nucleotides through salvage pathways. Salvage pathways involve the recycling of pre-formed nucleotides from degradation of nucleic acids or other cellular components. For example, adenosine can be salvaged from the degradation of RNA and converted to AMP through the action of the enzyme adenosine kinase. Similarly, hypoxanthine and guanine can be salvaged and converted to IMP and GMP, respectively.
Regulation of nucleotide biosynthesis: The biosynthesis of nucleotides is tightly regulated to ensure that the cell has sufficient amounts of nucleotides for DNA and RNA synthesis, while avoiding the accumulation of toxic intermediates. Regulation occurs at multiple levels, including transcriptional regulation of the genes encoding the enzymes involved in nucleotide biosynthesis, feedback inhibition of key enzymes, and allosteric regulation of enzyme activity by metabolites such as ATP and GTP.
In summary, the biosynthesis of nucleotides involves the de novo synthesis of purines and pyrimidines, salvage pathways, and tight regulation of nucleotide biosynthesis to ensure that the cell has sufficient amounts of nucleotides for DNA and RNA synthesis.