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Chemical Compound Review

TOSYLLYSINE CHLOROMETHYL KETONE     N-[(3S)-7-amino-1-chloro-2- oxo-heptan-3...

Synonyms: Tosyl-K-CMK, Tosyl-Lys-CMK, Tos-Lys-CH2Cl, Lopac-T-7254, CHEMBL466465, ...
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  • In hepatoma 7777, TLCK (2.5 mg/100 g body wt) exerted a greater inhibitory effect on incorporation when administered 60 minutes before [3H]leucine injection than when injected simultaneously [1].
  • In the present study we evaluated the effect of TLCK or TPCK treatment on the immortalization of primary keratinocytes by transfected HPV-18 DNA [2].
  • Pre-incubation with the NFkappaB pathway inhibitors, N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK) or pyrrolidine dithiocarbamate (PDTC), or infection with adenovirus encoding IkappaBalpha, blocked both IRF-1 induction and NFkappaB DNA-binding activity [3].
  • The protection from soman toxicity by chemically distinct protease inhibitors such as suramin and TLCK suggests a role for pathological proteolytic pathways in soman intoxication [4].
  • Tosyl-L-lysine chloromethyl ketone (TLCK) and pentamidine isethionate, potent trypsin inhibitors, also dose-dependently inhibited the growth of E. coli and the DNA synthesis [5].



Chemical compound and disease context of TOSYLLYSINE CHLOROMETHYL KETONE

  • Ethanol-induced apoptosis in hepatoma cells proceeds via intracellular Ca(2+) elevation, activation of TLCK-sensitive proteases, and cytochrome c release [9].





Associations of TOSYLLYSINE CHLOROMETHYL KETONE with other chemical compounds

  • The protease inhibitors N alpha-tosylphenylalanyl chloromethyl ketone (TPCK) and N alpha-tosyl-L-lysine chloromethyl ketone (TLCK) block activation of NF-kappa B/Rel proteins by preventing degradation of I kappa B alpha [18].
  • PMSF, diisopropylfluorophosphate, and N alpha-tosyl-L-lysyl-chloromethylketone were, again, inhibiting Fc gamma RII-mediated binding dose-dependently, whereas several inhibitors of metal, aspartic, or thiol proteases proved ineffective [19].
  • Incubation of CEM cells with N alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) indicates that ETS proteins can be modified in their cellular context and that pretreatment of the cells with N-ethylmaleimide (NEM) protects ETS1 proteins from TLCK modification [20].
  • Moreover, the enzymatic activity(ies) in T. denticola responsible for glutathione breakdown was inactivated by trypsin or proteinase K, by heating (56 degrees C) and freezing (-20 degrees C), by sonication, and by exposure to N alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) [21].
  • Site-specific mutagenesis demonstrated that the E7 Rb-binding core (Leu-X-Cys-X-Glu) contained a cysteine residue which was essential for this modification and that the TLCK/TPCK-dependent alteration of the E7 protein abolished its ability to bind Rb [22].


  • The TNF stimulated A549 cell culture supernatant had significantly (P < 0.05) greater chemotactic ability than control supernatant, while aprotinin and TLCK significantly (P < 0.05) reduced this chemotactic ability [23].
  • Pyrrolidine dithiocarbamate (PDTC) and N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK), two inhibitors of NF-kappaB activation, as well as the specific proteasome inhibitor MG132, blocked leptin-induced iNOS [24].
  • Inhibitors of I-kappaB degradation, MG132 and N(alpha)-p-tosyl-L-lysine chloromethyl ketone (TLCK), suppressed the further increase by gamma-irradiation in IFN-gamma-induced NO production, showing that gamma-irradiation induced NO production via NF-kappaB activation [25].
  • Induction of COX-2 activity along with the induction of COX-2 mRNA and protein by LPS was attenuated by the serine protease inhibitors N-alpha-tosyl-L-phenylalanine chloromethyl ketone (TPCK) and N-alpha-tosyl-L-lysine chloromethyl ketone (TLCK) [26].
  • The ETS1.PEA3 complex formed with TLCK-modified ETS1 has a slower mobility than the complex formed with unmodified ETS1 [20].

Analytical, diagnostic and therapeutic context of TOSYLLYSINE CHLOROMETHYL KETONE

  • The rAd effect correlated with a rapid increase (1 h) in the NF-kappaB-DNA binding activity detected by electrophoretic mobility shift assays. rAd-induced DC maturation was blocked by the proteasome inhibitor Nalpha-p-tosyl-L-lysine chloromethyl ketone (TLCK) or by infection with rAd-IkappaB, an rAd-encoding the dominant-negative form of IkappaB [27].
  • RESULTS: TLCK prolonged hepatic allograft survival [28].
  • Thrombin inactivated with Tos-Lys-CH2Cl also showed two peaks of radioactivity on gel filtration, one peak which was excluded from the column and the other peak with an elution volume that was consistent with the position of native thrombin [29].
  • In vitro, TLCK suppressed interleukin-2 production and [(3)H]thymidine incorporation into an allogeneic mixed lymphocyte reaction [28].
  • Preincubation of eggs before fertilization with 100 microM TPCK, but not TLCK, resulted in inhibition of fertilization [30].


  1. Selective effects of two chloromethyl ketones on amino acid and phosphate uptake in rat liver and tumors. Lea, M.A., Koch, M.R. J. Natl. Cancer Inst. (1979) [Pubmed]
  2. The serine protease inhibitors TLCK and TPCK inhibit the in vitro immortalization of primary human keratinocytes by HPV-18 DNA. Stöppler, H., Koval, D., Schlegel, R. Oncogene (1996) [Pubmed]
  3. Nuclear factor kappa B is involved in lipopolysaccharide-stimulated induction of interferon regulatory factor-1 and GAS/GAF DNA-binding in human umbilical vein endothelial cells. Liu, L., Paul, A., MacKenzie, C.J., Bryant, C., Graham, A., Plevin, R. Br. J. Pharmacol. (2001) [Pubmed]
  4. Protective action of the serine protease inhibitor N-tosyl-L-lysine chloromethyl ketone (TLCK) against acute soman poisoning. Cowan, F.M., Broomfield, C.A., Lenz, D.E., Shih, T.M. Journal of applied toxicology : JAT. (2001) [Pubmed]
  5. Effects of synthetic trypsin inhibitors on the growth of Escherichia coli. Kato, M., Irisawa, T., Muramatu, M. Biol. Pharm. Bull. (1993) [Pubmed]
  6. Protective role of nuclear factor kappa B against nitric oxide-induced apoptosis in J774 macrophages. D'Acquisto, F., de Cristofaro, F., Maiuri, M.C., Tajana, G., Carnuccio, R. Cell Death Differ. (2001) [Pubmed]
  7. Fas aggregation does not correlate with Fas-mediated apoptosis. Lee , Y., Shacter, E. J. Immunol. (2001) [Pubmed]
  8. Chloromethyl ketones block induction of nitric oxide synthase in murine macrophages by preventing activation of nuclear factor-kappa B. Kim, H., Lee, H.S., Chang, K.T., Ko, T.H., Baek, K.J., Kwon, N.S. J. Immunol. (1995) [Pubmed]
  9. Ethanol-induced apoptosis in hepatoma cells proceeds via intracellular Ca(2+) elevation, activation of TLCK-sensitive proteases, and cytochrome c release. Nakayama, N., Eichhorst, S.T., Müller, M., Krammer, P.H. Exp. Cell Res. (2001) [Pubmed]
  10. The effect of TLCK on transcription and its role in modifying cell growth. Noonan, N.E., Noonan, K.D. J. Cell. Physiol. (1977) [Pubmed]
  11. Trichomonas vaginalis surface proteinase activity is necessary for parasite adherence to epithelial cells. Arroyo, R., Alderete, J.F. Infect. Immun. (1989) [Pubmed]
  12. Differential sensitivity of anti-IgM-induced and NaF-induced inositol phospholipid metabolism to serine protease inhibitors in BAL17 B lymphoma cells. Mizuguchi, J., Utsunomiya, N., Nakanishi, M., Arata, Y., Fukazawa, H. Biochem. J. (1989) [Pubmed]
  13. Involvement of TLCK-sensitive serine protease in colchicine-induced cell death of sympathetic neurons in culture. Mitsui, C., Sakai, K., Ninomiya, T., Koike, T. J. Neurosci. Res. (2001) [Pubmed]
  14. Effect of cyclooxygenase inhibitors and protease inhibitors on phorbol-induced stimulation of oxygen consumption and superoxide production by rat pulmonary macrophages. Hoffman, M., Autor, A.P. Biochem. Pharmacol. (1982) [Pubmed]
  15. Characterization of distinct tyrosine-specific protein kinases in B and T lymphocytes. Earp, H.S., Austin, K.S., Gillespie, G.Y., Buessow, S.C., Davies, A.A., Parker, P.J. J. Biol. Chem. (1985) [Pubmed]
  16. Effects of N alpha-tosyl-L-lysyl-chloromethylketone on the activity of cytotoxic T lymphocytes. Chang, T.W., Eisen, H.N. J. Immunol. (1980) [Pubmed]
  17. Targeted disruption of fibronectin-integrin interactions in human gingival fibroblasts by the RI protease of Porphyromonas gingivalis W50. Scragg, M.A., Cannon, S.J., Rangarajan, M., Williams, D.M., Curtis, M.A. Infect. Immun. (1999) [Pubmed]
  18. Protease inhibitors block lipopolysaccharide induction of tissue factor gene expression in human monocytic cells by preventing activation of c-Rel/p65 heterodimers. Mackman, N. J. Biol. Chem. (1994) [Pubmed]
  19. Effect of protease inhibitors on human monocyte IgG Fc receptor II. Evidence that serine esterase activity is essential for Fc gamma RII-mediated binding. van de Winkel, J.G., Jansze, M., Capel, P.J. J. Immunol. (1990) [Pubmed]
  20. Human ETS1 oncoprotein. Purification, isoforms, -SH modification, and DNA sequence-specific binding. Fisher, R.J., Koizumi, S., Kondoh, A., Mariano, J.M., Mavrothalassitis, G., Bhat, N.K., Papas, T.S. J. Biol. Chem. (1992) [Pubmed]
  21. Role of glutathione metabolism of Treponema denticola in bacterial growth and virulence expression. Chu, L., Dong, Z., Xu, X., Cochran, D.L., Ebersole, J.L. Infect. Immun. (2002) [Pubmed]
  22. The serine protease inhibitors TLCK and TPCK react with the RB-binding core of HPV-18 E7 protein and abolish its RB-binding capability. Stöppler, H., Stöppler, M.C., Adduci, A., Koval, D., Schlegel, R. Virology (1996) [Pubmed]
  23. Aprotinin reduces interleukin-8 production and lung neutrophil accumulation after cardiopulmonary bypass. Hill, G.E., Pohorecki, R., Alonso, A., Rennard, S.I., Robbins, R.A. Anesth. Analg. (1996) [Pubmed]
  24. Leptin induces nitric oxide synthase type II in C6 glioma cells. Role for nuclear factor-kappaB in hormone effect. Mattace Raso, G., Esposito, E., Iacono, A., Pacilio, M., Coppola, A., Bianco, G., Diano, S., Di Carlo, R., Meli, R. Neurosci. Lett. (2006) [Pubmed]
  25. gamma-Irradiation-induced DNA damage enhances NO production via NF-kappaB activation in RAW264.7 cells. Ibuki, Y., Mizuno, S., Goto, R. Biochim. Biophys. Acta (2003) [Pubmed]
  26. Lipopolysaccharide-induced expression of cyclooxygenase-2 in mouse macrophages is inhibited by chloromethylketones and a direct inhibitor of NF-kappa B translocation. Abate, A., Oberle, S., Schröder, H. Prostaglandins Other Lipid Mediat. (1998) [Pubmed]
  27. Recombinant adenovirus induces maturation of dendritic cells via an NF-kappaB-dependent pathway. Morelli, A.E., Larregina, A.T., Ganster, R.W., Zahorchak, A.F., Plowey, J.M., Takayama, T., Logar, A.J., Robbins, P.D., Falo, L.D., Thomson, A.W. J. Virol. (2000) [Pubmed]
  28. A serine protease inhibitor, N-alpha-tosyl-l-lysine chloromethyl ketone, prolongs rat hepatic allograft survival. Zhang, J.L., Yamaguchi, Y., Mori, K., Okabe, K., Hidaka, H., Ohshiro, H., Uchino, S., Ishihara, K., Furuhashi, T., Yamada, S., Ogawa, M. J. Surg. Res. (2001) [Pubmed]
  29. Correlation of in vivo and in vitro inhibition of thrombin by plasma inhibitors. Vogel, C.N., Kingdon, H.S., Lundblad, R.L. J. Lab. Clin. Med. (1979) [Pubmed]
  30. Effects of proteinase inhibitors on fertilization in sea lamprey (Petromyzon marinus). Dabrowski, K., Glogowski, J., Ciereszko, A. Comp. Biochem. Physiol. B, Biochem. Mol. Biol. (2004) [Pubmed]
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