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Chemical Compound Review

AGN-PC-0095TP     2-amino-4-[[5-(6-aminopurin- 9-yl)-3,4...

Synonyms: SureCN12436336, CHEBI:340409, AR-1D8273, AC1L18OR, AC1Q5S8Q, ...
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Disease relevance of S-adenosylhomocysteine

  • Impaired ability to catabolize AdoHcy may have contributed to the cytolytic responses to dCF and ara-A, as well as to hepatic and central nervous system toxicity associated with their combined use [1].
  • The crystal structures of Escherichia coli MTA/AdoHcy nucleosidase complexed with the transition state analog, formycin A (FMA), and the nonhydrolyzable substrate analog, 5'-methylthiotubercidin (MTT) have been solved to 2.2- and 2.0-A resolution, respectively [2].
  • When the methylation of VSV mRNA was measured in assays carried out with permeabilized virions at the AdoHcy and AdoMet concentrations found in interferon-treated cells, a preferential inhibition of the viral (guanine-7-)methyltransferase activity was observed [3].
  • Accumulation of adenosylhomocysteine results in a fall in the adenosylmethionine:adenosylhomocysteine methylation ratio, and this change is believed to cause defective methylation and demyelination in the nervous system [4].
  • In the present study, we have investigated the influence of hypoxia and inhibition of AdoHcy hydrolase on MP in HepG2 cells [5].

High impact information on S-adenosylhomocysteine


Chemical compound and disease context of S-adenosylhomocysteine


Biological context of S-adenosylhomocysteine

  • It is evident, therefore, that increased cellular levels of AdoHcy or c3AdoHcy can affect cellular physiology via perturbation of cyclic AMP metabolism as well as via inhibition of S-adenosylmethionine-dependent methylation reactions [15].
  • These metabolic effects were associated with a rapid inactivation of AdoHcy hydrolase, but a fraction of the enzyme activity (about 8% in liver) was not or only slowly inactivated [16].
  • Thus, the combined treatment with these two types of mechanistically different methylation inhibitors resulted in significantly enhanced interference with nucleic acid methylation and cell growth, both of which correlated directly with unprecedented increases in the AdoHcy/AdoMet ratio [17].
  • Comparisons of the inhibitor complexes to the adenine-bound MTA/AdoHcy nucleosidase (Lee, J. E., Cornell, K. A., Riscoe, M. K., and Howell, P. L. (2001) Structure (Camb.) 9, 941-953) structure provide evidence for a ligand-induced conformational change in the active site and the substrate preference of the enzyme [2].
  • Both hydrolysis of AdoHcy and the inhibition of the hydrolysis of AdoHcy by 3-deazaadenosine are the same in sonicates of the two macrophage cell lines [18].

Anatomical context of S-adenosylhomocysteine


Associations of S-adenosylhomocysteine with other chemical compounds


Gene context of S-adenosylhomocysteine

  • Adenosylhomocysteine hydrolase-like protein 1 (AHCYL1) is a novel intracellular protein with approximately 50% protein identity to adenosylhomocysteine hydrolase (AHCY), an important enzyme for metabolizing S-adenosyl-l-homocysteine, the by-product of S-adenosyl-l-homomethionine-dependent methylation [24].
  • Because changes in the AdoMet/AdoHcy ratio could potentially alter the overall excitatory state of the brain, this effect may play a role in the progressive epilepsy seen in the Pcmt1-/- mice [25].
  • RESULTS: Two ternary structures of human HNMT have been determined: the Thr105 variant complexed with its substrate histamine and reaction product AdoHcy and the Ile105 variant complexed with an inhibitor (quinacrine) and AdoHcy [26].
  • Here we describe the crystal structure of rat PRMT1 in complex with the reaction product AdoHcy and a 19 residue substrate peptide containing three arginines [27].
  • GNMT is believed to play a role in monitoring the AdoMet/AdoHcy ratio, and hence the cellular methylation capacity, but regulation of the enzyme itself is not well understood [28].

Analytical, diagnostic and therapeutic context of S-adenosylhomocysteine


  1. S-adenosylhomocysteine catabolism and basis for acquired resistance during treatment of T-cell acute lymphoblastic leukemia with 2'-deoxycoformycin alone and in combination with 9-beta-D-arabinofuranosyladenine. Hershfield, M.S., Kredich, N.M., Koller, C.A., Mitchell, B.S., Kurtzberg, J., Kinney, T.R., Falletta, J.M. Cancer Res. (1983) [Pubmed]
  2. Structure of Escherichia coli 5'-methylthioadenosine/ S-adenosylhomocysteine nucleosidase inhibitor complexes provide insight into the conformational changes required for substrate binding and catalysis. Lee, J.E., Cornell, K.A., Riscoe, M.K., Howell, P.L. J. Biol. Chem. (2003) [Pubmed]
  3. Increase in S-adenosylhomocysteine concentration in interferon-treated HeLa cells and inhibition of methylation of vesicular stomatitis virus mRNA. de Ferra, F., Baglioni, C. J. Biol. Chem. (1983) [Pubmed]
  4. Cobalamin deficiency and the pathogenesis of nervous system disease. Metz, J. Annu. Rev. Nutr. (1992) [Pubmed]
  5. Influence of an altered methylation potential on mRNA methylation and gene expression in HepG2 cells. Hermes, M., Osswald, H., Mattar, J., Kloor, D. Exp. Cell Res. (2004) [Pubmed]
  6. Enzymatic methyl esterification of erythrocyte membrane proteins is impaired in chronic renal failure. Evidence for high levels of the natural inhibitor S-adenosylhomocysteine. Pema, A.F., Ingrosso, D., Zappia, V., Galletti, P., Capasso, G., De Santo, N.G. J. Clin. Invest. (1993) [Pubmed]
  7. Crystal structure of the conserved core of protein arginine methyltransferase PRMT3. Zhang, X., Zhou, L., Cheng, X. EMBO J. (2000) [Pubmed]
  8. S-Adenosylhomocysteine hydrolase as a target for intracellular adenosine action. Kloor, D., Osswald, H. Trends Pharmacol. Sci. (2004) [Pubmed]
  9. S-adenosylhomocysteine hydrolase deficiency in a human: a genetic disorder of methionine metabolism. Baric, I., Fumic, K., Glenn, B., Cuk, M., Schulze, A., Finkelstein, J.D., James, S.J., Mejaski-Bosnjak, V., Pazanin, L., Pogribny, I.P., Rados, M., Sarnavka, V., Scukanec-Spoljar, M., Allen, R.H., Stabler, S., Uzelac, L., Vugrek, O., Wagner, C., Zeisel, S., Mudd, S.H. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  10. Transcription initiation by RNA polymerase II is inhibited by S-adenosylhomocysteine. Jove, R., Manley, J.L. Proc. Natl. Acad. Sci. U.S.A. (1982) [Pubmed]
  11. Selective inhibition of avian sarcoma virus protein synthesis in 3-deazaadenosine-treated infected chicken embryo fibroblasts. Stoltzfus, C.M., Montgomery, J.A. J. Virol. (1981) [Pubmed]
  12. Tissue levels of S-adenosylhomocysteine in the rat kidney: effects of ischemia and homocysteine. Kloor, D., Delabar, U., Mühlbauer, B., Luippold, G., Osswald, H. Biochem. Pharmacol. (2002) [Pubmed]
  13. Crystallization and preliminary X-ray analysis of human placental S-adenosylhomocysteine hydrolase. Turner, M.A., Dole, K., Yuan, C.S., Hershfield, M.S., Borchardt, R.T., Howell, P.L. Acta Crystallogr. D Biol. Crystallogr. (1997) [Pubmed]
  14. Neplanocin A inhibition of S-adenosylhomocysteine hydrolase in Alcaligenes faecalis has no effect on growth of the microorganism. Fisher, E.W., Decedue, C.J., Keller, B.T., Borchardt, R.T. J. Antibiot. (1987) [Pubmed]
  15. Modulation of cyclic AMP metabolism by S-adenosylhomocysteine and S-3-deazaadenosylhomocysteine in mouse lymphocytes. Zimmerman, T.P., Schmitges, C.J., Wolberg, G., Deeprose, R.D., Duncan, G.S., Cuatrecasas, P., Elion, G.B. Proc. Natl. Acad. Sci. U.S.A. (1980) [Pubmed]
  16. S-adenosylhomocysteine and S-adenosylhomocysteine hydrolase in various tissues of mice given injections of 9-beta-D-arabinofuranosyladenine. Helland, S., Ueland, P.M. Cancer Res. (1983) [Pubmed]
  17. Combined modulation of S-adenosylmethionine biosynthesis and S-adenosylhomocysteine metabolism enhances inhibition of nucleic acid methylation and L1210 cell growth. Kramer, D.L., Porter, C.W., Borchardt, R.T., Sufrin, J.R. Cancer Res. (1990) [Pubmed]
  18. Inhibition of chemotaxis by S-3-deazaadenosylhomocysteine in a mouse macrophage cell line. Aksamit, R.R., Falk, W., Cantoni, G.L. J. Biol. Chem. (1982) [Pubmed]
  19. Inactivation of S-adenosylhomocysteine hydrolase by 9-beta-D-arabinofuranosyladenine in intact cells. Helland, S., Ueland, P.M. Cancer Res. (1982) [Pubmed]
  20. Inhibition of phosphoinositide metabolism in human polymorphonuclear leukocytes by S-adenosylhomocysteine. Pike, M.C., DeMeester, C.A. J. Biol. Chem. (1988) [Pubmed]
  21. Compartmentalization of S-adenosylhomocysteine in rat liver. Determination and characterization of the in vivo protein binding. Svardal, A.M., Ueland, P.M. J. Biol. Chem. (1987) [Pubmed]
  22. Disposition of homocysteine in rat hepatocytes and in nontransformed and malignant mouse embryo fibroblasts following exposure to inhibitors of S-adenosylhomocysteine catabolism. Svardal, A.M., Djurhuus, R., Refsum, H., Ueland, P.M. Cancer Res. (1986) [Pubmed]
  23. Inactivation and reactivation of intracellular S-adenosylhomocysteinase in the presence of nucleoside analogues in rat hepatocytes. Schanche, J.S., Schanche, T., Ueland, P.M., Montgomery, J.A. Cancer Res. (1984) [Pubmed]
  24. Suppression and overexpression of adenosylhomocysteine hydrolase-like protein 1 (AHCYL1) influences zebrafish embryo development: a possible role for AHCYL1 in inositol phospholipid signaling. Cooper, B.J., Key, B., Carter, A., Angel, N.Z., Hart, D.N., Kato, M. J. Biol. Chem. (2006) [Pubmed]
  25. Altered levels of S-adenosylmethionine and S-adenosylhomocysteine in the brains of L-isoaspartyl (D-Aspartyl) O-methyltransferase-deficient mice. Farrar, C., Clarke, S. J. Biol. Chem. (2002) [Pubmed]
  26. Two polymorphic forms of human histamine methyltransferase: structural, thermal, and kinetic comparisons. Horton, J.R., Sawada, K., Nishibori, M., Zhang, X., Cheng, X. Structure (Camb.) (2001) [Pubmed]
  27. Structure of the predominant protein arginine methyltransferase PRMT1 and analysis of its binding to substrate peptides. Zhang, X., Cheng, X. Structure (Camb.) (2003) [Pubmed]
  28. Okadaic acid-induced, naringin-sensitive phosphorylation of glycine N-methyltransferase in isolated rat hepatocytes. Møller, M.T., Samari, H.R., Fengsrud, M., Strømhaug, P.E., øStvold, A.C., Seglen, P.O. Biochem. J. (2003) [Pubmed]
  29. Photoaffinity labeling of human placental S-adenosylhomocysteine hydrolase with [2-3H]8-azido-adenosine. Yuan, C.S., Borchardt, R.T. J. Biol. Chem. (1995) [Pubmed]
  30. Adenosylhomocysteine hydrolase. Crystallization of the purified enzyme and its properties. Richards, H.H., Chiang, P.K., Cantoni, G.L. J. Biol. Chem. (1978) [Pubmed]
  31. Identification of the active oligomeric state of an essential adenine DNA methyltransferase from Caulobacter crescentus. Shier, V.K., Hancey, C.J., Benkovic, S.J. J. Biol. Chem. (2001) [Pubmed]
  32. Role of S-adenosylhomocysteine hydrolase in adenosine-induced apoptosis in HepG2 cells. Hermes, M., Osswald, H., Kloor, D. Exp. Cell Res. (2007) [Pubmed]
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