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The design of substrates for Cathepsin X

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The design of substrates for Cathepsin X

Devanathan, Gopal (2003) The design of substrates for Cathepsin X. Masters thesis, Concordia University.

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Abstract

Cysteine proteases constitute an important group of enzymes involved in a number of physiological processes. As these enzymes have been linked to diseases such as arthritis, Alzheimer's, and cancer, they are attractive targets for inhibitor design. Cathepsin X is a cysteine protease that was only recently discovered. The primary structure of cathepsin X contains several unique features that clearly distinguish it from the other human cysteine proteases. The aim of this study is to perform a systematic study on the S2, S1, and S1 ' subsites of the cathepsin X active site and to gain a detailed understanding of the enzyme's substrate specificity. Three libraries of compounds have been synthesized based on the parent compound 2-Abz-Phe-Arg-Phe(4NO 2 ). In each library, the 20 natural amino acids were substituted into P2, P1, and P1 ' sites respectively, while keeping the other positions fixed. In reference to the parent compound, P2 is occupied by Phe, P1 by Arg, and P1 ' by Phe(NO 2 ). All 59 compounds were purified and analyzed using RP-HPLC and MS. The catalytic efficiency values for P2 and P1 variants were assessed kinetically by analyzing progress curves using a fluorescent substrate analogue while P1 ' variants were analyzed by discontinuous assay using RP-HPLC. Molecular modeling studies were also performed by docking 2-Abz-Phe-Arg-Phe(4NO 2 ) and analogues to the cathepsin X active site in order to gain a detailed understanding of factors underlying substrate specificity. Knowledge obtained from this study will aid in the development of specific inhibitors useful as research tools to investigate the physiological and potential pathological roles of this novel enzyme

Divisions:Concordia University > Faculty of Arts and Science > Chemistry and Biochemistry
Item Type:Thesis (Masters)
Authors:Devanathan, Gopal
Pagination:xii, 90 leaves : ill. ; 29 cm.
Institution:Concordia University
Degree Name:Theses (M.Sc.)
Program:Chemistry and Biochemistry
Date:2003
Thesis Supervisor(s):Turnbull, Joanne
ID Code:2239
Deposited By:Concordia University Libraries
Deposited On:27 Aug 2009 13:26
Last Modified:08 Dec 2010 10:25
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