Pyrimidine starvation

Immune system dysfunction in ADA deficiency has also been ascribed to the inhibition of pyrimidine nucleotide synthesis by adenosine, known as pyrimidine starvation. This may arise from inhibition of conversion of orotic acid to orotidine 5 -monophosphate or from inhibition of PRPP synthesis by excessive synthesis of adenine nucleotides. 

G6. Green, H., and Chan, T.-S., Pyrimidine starvation induced by adenosine in fibroblasts and lymphoid cells Role of adenosine deaminase. Science 182, 836 (1973). 

The final steps of pyrimidine biosynthesis novo which are catalyzed by two sequential enzymes, orotate phosphoribosyltransfer-ase (OPRT) and orotidylic decarboxylase (ODC), involve the PP-ribose P dependent conversion of orotic acid to orotidine-5 -monophosphate (OMP) followed by decarboxylation at the 7 position to form uridine 5 -monophosphate (UMP) (Fig. 1). UMP is then utilized further in the synthesis of nucleic acids and co-enzymes. Defects at this site in this metabolic pathway are important for they can result in "pyrimidine starvation" from depletion of the intracellular pool of pyrimidine nucleotides. In man the rare genetic disease, orotic aciduria, involves a deficiency of both OPRT and ODC (Type 1) (Smith, Sullivan and Huguley, 1961) or, less commonly, only ODC (Type II) (Fox, 0 Sullivan and Firken, 1969). 

In addition to being synthesized or produced by the hydrolysis of dietary protein, amino acids can come from hydrolysis of tissue proteins, e.g., intestinal mucosa or, during starvation, muscle. Amino acids are used in protein synthesis (Chap. 17) they also enter gluconeogenesis and lipogenesis are degraded to provide energy and are used for synthesizing compounds such as purines, pyrimidines, porphyrins, epinephrine and creatine. 

Agarwal, M. L., Agarwal, A., Taylor, W. R., Chernova, O., Sharma, Y., Stark, G. R. (1998). A p53-dependent S-phase checkpoint helps to protect cells from DNA damage in response to starvation for pyrimidine nucleotides. Proceedings of the National Academy of Sciences of the United States of America, 95, 14775—14780. 

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