Enzymes cathepsins

Besides AT, heparin cofactor II (HCII) is an antic-oagulatory protein enhanced by heparin. HCII inactivates thrombin and the nonclotting enzymes cathepsin-G and chymotrypsin. 

Fig. 5.9 Design of the chip-based enzyme ESI-MS assay. MS instrument Ion-trap mass spectrometer (LCQ Deca, Thermo Electron). I Sample components/inhibitors injected by flow injection or eluting from capillary HPLC column. E Infusion pump delivering the enzyme cathepsin B. S infusion pump delivering the substrate Z-FR-AMC. Micro-chip design Vrije Universiteit Amsterdam. Micro-chip production Micronit Microfluidics BV (Enschede, The Netherlands).

An enzyme (cathepsin) hydrolyzes L-glutamyl-L-tyrosine to carbobenzoxy-L-glutamic acid and L-tyrosine. It has been found (Frantz and Stephenson,/. Biol. Chem., 169,359,1947) that the glutamic acid formed in the hydrolysis, inhibits (competitively) the progress of the reaction by forming a complex with cathepsin. The course of the reaction is followed by adding tyrosme decarboxylase which evolves C02. 

Levicar N, Dewey RA, Daley E, Bates TE, Davies D, Kos J, Pilkington GJ, Lah TT (2003) Selective suppression of cathepsin L by antisense cDNA impairs human brain tumor ceU invasion in vitro and promotes apoptosis. Cancer Gene Ther 10 141-151 Levicar N, Strojnik T, Kos J, Dewey RA, Pilkington GJ, Lah TT (2002) Lysosomal enzymes, cathepsins in brain tumour invasion. J Neurooncol 58 21-32 Li F, Ackermann EJ, Bennett CF (1999) Pleiotropic cell-division defects and apoptosis induced by interference with survivin function. Nat Cell Biol 1 461 66 Lopes MBS, VandenBerg SR, Scheithauer BW (1993) The World Health Organization classification of nervous system tumors in experimental neuro-oncology. In AJ Levine and HH Schmidek, eds Molecular Genetics of Nervous System Tumors. Wiley-Liss, New York, NY, pp 1-36... 

For selectivity searching, three enzymes, cathepsins K, L, and S, were targeted and cathepsin K inhibitors selective for K over L and S were used as reference molecules in order to identify new cathepsin K-selective inhibitors [43]. 

A recent successful example of amide bioisosterism can be found in the development of inhibitors of the enzyme cathepsin K, which is involved in osteoclastic bone resorption and is a target for the treatment of osteoporosis (21]. Compound... 

Qiao L, Hamamichi S, Caldwell K et al. (2008) Lysosomal enzyme cathepsin D protects against alpha-synuclein aggregation and toxicity. Mol Brain 1, 17. 

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