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Chemical Compound Review

AC1LAHG0     3-(2-phosphonoethanoylamino) butanoic acid

Synonyms: 3-[(2-phosphonoacetyl)amino]butanoic acid
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Disease relevance of PALA


High impact information on PALA

  • Normal mammalian cells arrest primarily in G1 in response to N-(phosphonacetyl)-L-aspartate (PALA), which starves them for pyrimidine nucleotides, and do not generate or tolerate amplification of the CAD gene, which confers resistance to PALA [6].
  • Four cell lines (MP1, -4, -5, -7), isolated from baby hamster kidney cells after simultaneous selection with N-(phosphonacetyl)-L-aspartate and methotrexate, have previously been shown to amplify their DNA at an increased rate [7].
  • In an x-ray diffraction study by the isomorphous replacement method, the structure of the complex of aspartate carbamoyltransferase (EC bound to the bisubstrate analogue N-(phosphonacetyl)-L-aspartate has been solved to 2.9-A resolution (R = 0.24) [8].
  • The hybrid had a high affinity for three molecules of the bi-substrat analog, N-(phosphonacetyl)-L-aspartate, compared to the six strong binding sites in the wild-type enzyme and none in the mutant [9].
  • Similar to normal cells, "nonpermissive" REF52 cells do not develop resistance to N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of the synthesis of pyrimidine nucleotides, through amplification of cad, the target gene, but instead undergo protective, long-term, p53-dependent cell cycle arrest [10].

Chemical compound and disease context of PALA


Biological context of PALA


Anatomical context of PALA


Associations of PALA with other chemical compounds


Gene context of PALA


Analytical, diagnostic and therapeutic context of PALA


  1. Structure of DNA formed in the first step of CAD gene amplification. Giulotto, E., Saito, I., Stark, G.R. EMBO J. (1986) [Pubmed]
  2. Phase I trial of N-(phosphonacetyl)-L-aspartate. Erlichman, C., Strong, J.M., Wiernik, P.H., McAvoy, L.M., Cohen, M.H., Levine, A.S., Hubbard, S.M., Chabner, B.A. Cancer Res. (1979) [Pubmed]
  3. A phase I study of continuous infusion 5-fluorouracil plus calcium leucovorin in combination with N-(phosphonacetyl)-L-aspartate in metastatic gastrointestinal adenocarcinoma. Grem, J.L., McAtee, N., Steinberg, S.M., Hamilton, J.M., Murphy, R.F., Drake, J., Chisena, T., Balis, F., Cysyk, R., Arbuck, S.G. Cancer Res. (1993) [Pubmed]
  4. Site-specific substitutions of the Tyr-165 residue in the catalytic chain of aspartate transcarbamoylase promotes a T-state preference in the holoenzyme. Wales, M.E., Hoover, T.A., Wild, J.R. J. Biol. Chem. (1988) [Pubmed]
  5. Synergistic effect of 5-fluorouracil and N-(phosphonacetyl)-L-aspartate on cell growth and ribonucleic acid synthesis in human mammary carcinoma. Ardalan, B., Glazer, R.I., Kensler, T.W., Jayaram, H.N., Van Pham, T., Macdonald, J.S., Cooney, D.A. Biochem. Pharmacol. (1981) [Pubmed]
  6. A p53-dependent S-phase checkpoint helps to protect cells from DNA damage in response to starvation for pyrimidine nucleotides. Agarwal, M.L., Agarwal, A., Taylor, W.R., Chernova, O., Sharma, Y., Stark, G.R. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  7. BHK cell lines with increased rates of gene amplification are hypersensitive to ultraviolet light. Giulotto, E., Bertoni, L., Attolini, C., Rainaldi, G., Anglana, M. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  8. Structure at 2.9-A resolution of aspartate carbamoyltransferase complexed with the bisubstrate analogue N-(phosphonacetyl)-L-aspartate. Krause, K.L., Volz, K.W., Lipscomb, W.N. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
  9. Quaternary constraint in hybrid of aspartate transcarbamylase containing wild-type and mutant catalytic subunits. Gibbons, I., Flatgaard, J.E., Schachman, H.K. Proc. Natl. Acad. Sci. U.S.A. (1975) [Pubmed]
  10. MYC abrogates p53-mediated cell cycle arrest in N-(phosphonacetyl)-L-aspartate-treated cells, permitting CAD gene amplification. Chernova, O.B., Chernov, M.V., Ishizaka, Y., Agarwal, M.L., Stark, G.R. Mol. Cell. Biol. (1998) [Pubmed]
  11. Phase I trial of N-(phosphonacetyl)-L-aspartate, methotrexate, and 5-fluorouracil with leucovorin rescue in patients with advanced cancer. Kemeny, N., Schneider, A., Martin, D.S., Colofiore, J., Sawyer, R.C., Derby, S., Salvia, B. Cancer Res. (1989) [Pubmed]
  12. Reversal of toxicity and antitumor activity of N-(phosphonacetyl)-L-aspartate by uridine or carbamyl-DL-asparate in vivo. Johnson, R.K. Biochem. Pharmacol. (1977) [Pubmed]
  13. Biochemical modulation of tumor cell energy. IV. Evidence for the contribution of adenosine triphosphate (ATP) depletion to chemotherapeutically-induced tumor regression. Colofiore, J.R., Stolfi, R.L., Nord, L.D., Martin, D.S. Biochem. Pharmacol. (1995) [Pubmed]
  14. Enzymes of the de novo and salvage pathways for pyrimidine biosynthesis in normal colon, colon carcinoma, and xenografts. Ahmed, N.K. Cancer (1984) [Pubmed]
  15. Selective enhancement of 5-fluorouridine uptake and action in rat hepatomas in vivo following pretreatment with D-galactosamine and 6-azauridine or N-(phosphonacetyl)-L-aspartate. Anukarahanonta, T., Holstege, A., Keppler, D.O. European journal of cancer. (1980) [Pubmed]
  16. Co-amplification of rRNA genes with CAD genes in N-(phosphonacetyl)-L-aspartate-resistant Syrian hamster cells. Wahl, G.M., Vitto, L., Rubnitz, J. Mol. Cell. Biol. (1983) [Pubmed]
  17. Application of a simple competitive protein-binding assay technique to the pharmacokinetics of N-(phosphonacetyl)-L-aspartate in humans. Erlichman, C., Strong, J.M., Chabner, B.A. Cancer Res. (1980) [Pubmed]
  18. Penetration of N-(phosphonacetyl)-L-aspartate into human central nervous system and intracerebral tumor. Stewart, D.J., Leavens, M., Friedman, J., Benjamin, R.S., Moore, E.C., Bodey, G.P., Valdivieso, M., Burgess, M.A., Wiseman, C., Loo, T.L. Cancer Res. (1980) [Pubmed]
  19. Differential effect of N-(phosphonacetyl)-L-aspartate on 1-beta-D-arabinofuranosylcytosine metabolism and cytotoxicity in human leukemia and normal bone marrow progenitors. Grant, S., Rauscher, F., Cadman, E. Cancer Res. (1982) [Pubmed]
  20. Effect of uridine on response of 5-azacytidine-resistant human leukemic cells to inhibitors of de novo pyrimidine synthesis. Grant, S., Bhalla, K., Gleyzer, M. Cancer Res. (1984) [Pubmed]
  21. Gross quaternary changes in aspartate carbamoyltransferase are induced by the binding of N-(phosphonacetyl)-L-aspartate: A 3.5-A resolution study. Ladner, J.E., Kitchell, J.P., Honzatko, R.B., Ke, H.M., Volz, K.W., Kalb, A.J., Ladner, R.C., Lipscomb, W.N. Proc. Natl. Acad. Sci. U.S.A. (1982) [Pubmed]
  22. The role of an active site histidine in the catalytic mechanism of aspartate transcarbamoylase. Kleanthous, C., Wemmer, D.E., Schachman, H.K. J. Biol. Chem. (1988) [Pubmed]
  23. Proton magnetic relaxation of aspartate transcarbamylase - succinate complexes. Ireland, C.B., Schmidt, P.G. J. Biol. Chem. (1977) [Pubmed]
  24. Fibroblast growth factor mediated alterations in drug resistance, and evidence of gene amplification. Huang, A., Wright, J.A. Oncogene (1994) [Pubmed]
  25. High frequency of double drug resistance in the B16 melanoma cell line. McMillan, T.J., Kalebic, T., Stark, G.R., Hart, I.R. Eur. J. Cancer (1990) [Pubmed]
  26. Unstable and stable CAD gene amplification: importance of flanking sequences and nuclear environment in gene amplification. Meinkoth, J., Killary, A.M., Fournier, R.E., Wahl, G.M. Mol. Cell. Biol. (1987) [Pubmed]
  27. Drug resistance and gene amplification potential regulated by transforming growth factor beta 1 gene expression. Huang, A., Jin, H., Wright, J.A. Cancer Res. (1995) [Pubmed]
  28. Evidence from 13C NMR for protonation of carbamyl-P and N-(phosphonacetyl)-L-aspartate in the active site of aspartate transcarbamylase. Roberts, M.F., Opella, S.J., Schaffer, M.H., Phillips, H.M., Stark, G.R. J. Biol. Chem. (1976) [Pubmed]
  29. Comparative physiological disposition of N-(phosphonacetyl)-L-aspartate in several animal species after intravenous and oral administration. Chadwick, M., Silveira, D.M., MacGregor, J.A., Branfman, A.R., Liss, R.H., Yesair, D.W. Cancer Res. (1982) [Pubmed]
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