4- Feedback inhi bition of pyrimidine nucleotide synthesis can ..

(SSB may also protectvulnerable ssDNA segments from attack by various nucleases.) Before pol III caninitiate DNA synthesis, however, an RNA primer must be present.

We can both synthesizethem de novo and salvage and reuse those we already have.

Inosine monophosphate dehydrogenase (IMPDH) is a pivotal enzyme in the de novo pathway of guanine nucleotide biosynthesis. Inhibitors of this enzyme decrease intracellular guanine nucleotide levels by 50-80% and have potential as anti-neoplastic agents. Both mycophenolic acid (MPA) and AVN-944 are highly specific inhibitors of IMPDH that cause cell cycle arrest or apoptosis in lymphocytes and leukemic cell lines. We have examined the mechanisms by which these two agents cause cytotoxicity. Both MPA and AVN-944 inhibit the growth of K562 cells, and induce apoptosis in Raji B and CCRF-CEM T cells. Both compounds strikingly inhibit RNA synthesis within 2 h of exposure. Depletion of guanine nucleotides by MPA and AVN-944 also causes an early and near-complete reduction in levels of the 45S precursor rRNA synthesis and the concomitant translocation of nucleolar proteins including nucleolin, nucleophosmin, and nucleostemin from the nucleolus to the nucleoplasm. This efflux correlates temporally with the sustained induction of p53 in cell lines with wild-type p53. We conclude that inhibition of IMPDH causes a primary reduction in rRNA synthesis and secondary nucleolar disruption and efflux of nucleolar proteins that most likely mediate cell cycle arrest or apoptosis. The ability of AVN-944 to induce apoptosis in a number of leukemic cell lines supports its potential utility in the treatment of hematologic malignancies.

b) Denovo synthesis of pyrimidines

N2 - Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is widely used as an immunosuppressive agent. MPA selectively inhibits inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme for the de novo synthesis of guanine nucleotides, leading to depletion of the guanine nucleotide pool. Its chemotherapeutic effects have been attributed to its ability to induce cell cycle arrest and apoptosis. MPA treatment has also been shown to induce and activate p53. However, the mechanism underlying the p53 activation pathway is still unclear. Here, we show that MPA treatment results in inhibition of pre-rRNA synthesis and disruption of the nucleolus. This treatment enhances the interaction of MDM2 with L5 and L11. Interestingly, knockdown of endogenous L5 or L11 markedly impairs the induction of p53 and G1 cell cycle arrest induced by MPA. These results suggest that MPA may trigger a nucleolar stress that induces p53 activation via inhibition of MDM2 by ribosomal proteins L5 and L11.

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Second, the cellular pools of nucleotides (other than ATP) are quite small,perhaps 1% or less of the amounts required to synthesize the cell’s DNA.

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Because of the importance of these processes in dividing cells,agents that inhibit nucleotide synthesis have become particularly important tomodern medicine.

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We examine here the biosynthetic pathways of purine andpyrimidine nucleotides and their regulation, the formation of thedeoxynucleotides, and the degradation of purines and pyrimidines to uric acidand urea.

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In the third mechanism, GTP is required inthe conversion of IMP to AMP ( step 1 ), whereas ATP is required for conversionof IMP to GMP (step 4 ), a reciprocal arrangement that tends to balance thesynthesis of the two ribonucleotides.

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Relatively low levels of nucleotides result indecreased inhibition of de novo synthesis, resulting in further overload of thenon-functioning salvage pathway and increased uric acid production.