Nucleic acid Synthesis

De novo pyrimidine and purine synthesis

• Several anticancer drugs target the production of dTMP (deoxythymidine monophosphate) since this nucleotide is specifically required for incorporation into DNA in rapidly dividing cells. Thus, fluorouracil inhibits thymidylate synthase, and methotrexate blocks dihydrofolate reductase.
• Reduce the dose of Xanthine Oxidase inhibitors in patients getting 6-MP

Hereditary orotic aciduria

Rare autosomal recessive disorder, characterized by a defect in uridine 5'-monophosphate (UMP) synthase

S/S

physical and mental retardation

megaloblastic anemia

elevated urinary orotic acid levels

Increased urinary orotic acid may also be seen in ornithine transcarbamylase deficiency; however, patients with this condition classically have failure to thrive and hyperammonemic encephalopathy within the first few weeks of life (due to impaired urea synthesis)

Salvage Pathways

de novo synthesis is a long and energetically expensive

Free purine bases released in the course of normal cell turnover are therefore salvaged and reused.

Two salvage enzymes (for different purines) recombine the bases with ribose phosphate, thereby reforming the nucleotide monophosphate.

1. Adenine phosphoribosyltransferase (APRT)

   salvage of adenine

   adenine + PRPP --> AMP + PPi

2. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

   catalyses the equivalent reactions for hypoxanthine and guanine