| Nucleotides are synthesized primarily from amino acid precursors and phosphoribosylpyrophosphate by complex, multistep pathways. Not surprisingly therefore, salvage pathways therefore play a prominent role in nucleotide metabolism. De novo nucleotide metabolism is required for cell proliferation. Both classes of nucleotides (purines and pyrimidines) are synthesized as precursors (IMP, UMP), which are then converted into the DNA precursors (dATP, dGTP, dCTP, TTP). With the exception of TTP, ribonucleotides are converted to deoxyribonucleotides by ribonucleotide reductase. TTP is synthesized from dUMP by a special pathway involving folates. The salvage pathways have proven useful for the activation of pharmaceutical agents, while the uniqueness of the pathway for synthesis of TTP has provided a special target for chemotherapeutic inhibition of DNA synthesis and cell division in cancer cells.
|
- Compare the roles of de novo synthesis and salvage pathways of nucleotide synthesis in various cell types, e.g. erythrocytes, lymphocytes, muscle and liver.
- In addition to its activity as a xanthine oxidase inhibitor, what other activities of allopurinol
 might contribute to its efficacy for treatment of gout? - Discuss the use of thymidylate synthetase inhibitors for treatment of diseases other than cancer, e.g. arthritis and Crohn's disease.
|
Rott KT, Agudelo CA. Gout. JAMA 2003;289:2857-2860.
Full article
|
| Huennekens FM. The methotrexate story: a paradigm for development of cancer chemotherapeutic agents. Adv Enz Reg 1994;34:379-419.
|
| Kinsella AR, Smith D, Pickard M. Resistance to chemotherapeutic antimetabolites: a function of the salvage pathway involvement and cellular response to DNA damage. Br J Cancer 1997;75:935-945.
|
| Nyhan WL. The recognition of Lesch-Nyhan syndrome as an inborn error of purine metabolism. J Inherited Metab Dis 1997;20:171-178.
Full article
|
| Rustum YM, Harstrick A, Cao S, Vanhoefer U, Yin M, Wilke H, Seeber S. Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors. J Clin Oncol 1997:15:389-400.
Full article
|
| Sigoillot FD, Berkowski JA, Sigoillot SM, Kotsis DH, Guy HI. Cell cycle-dependent regulation of pyrimidine biosynthesis. J Biol Chem 2003;278:3403-3409.
Full article
|
| Aiuti A. Advances in gene therapy for ADA-deficient SCID. Curr Opin Mol Ther 2002;4:515-522.
|
| Purine and pyrimidine disorders: www.amg.gda.pl/~essppmm/index.html;
|
| Gout: www.nlm.nih.gov/medlineplus/goutandpseudogout.html;
|
| www.niams.nih.gov/hi/topics/gout/gout.htm; ww.nhsdirect.nhs.uk/en.asp?TopicID=221
|
| Lesch Nyhan Syndrome: www.icondata.com/health/pedbase/files/LESCH-NY.HTM;
|
| www.emedicine.com/neuro/topic630.htm
|
| page 423 |  | | page 424 |
|
