PMID: 11322895Apr 27, 2001Paper

Subsite specificity of trypanosomal cathepsin L-like cysteine proteases. Probing the S2 pocket with phenylalanine-derived amino acids

European Journal of Biochemistry
F LecailleGilles Lalmanach

Abstract

The S2 subsite of mammalian cysteine proteinases of the papain family is essential for specificity. Among natural amino acids, all these enzymes prefer bulky hydrophobic residues such as phenylalanine at P2. This holds true for their trypanosomal counterparts: cruzain from Trypanosoma cruzi and congopain from T. congolense. A detailed analysis of the S2 specificity of parasitic proteases was performed to gain information that might be of interest for the design of more selective pseudopeptidyl inhibitors. Nonproteogenic phenylalanyl analogs (Xaa) have been introduced into position P2 of fluorogenic substrates dansyl-Xaa-Arg-Ala-Pro-Trp, and their kinetic constants (Km, kcat/Km) have been determined with congopain and cruzain, and related host cathepsins B and L. Trypanosomal cysteine proteases are poorly stereoselective towards D/L-Phe, the inversion of chirality modifying the efficiency of the reaction but not the Km. Congopain binds cyclohexylalanine better than aromatic Phe derivatives. Another characteristic feature of congopain compared to cruzain and cathepsins B and L was that it could accomodate a phenylglycyl residue (kcat/Km = 1300 mM-1.s-1), while lengthening of the side chain by a methylene group only slightly impai...Continue Reading

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Citations

Jul 23, 2002·Current Opinion in Chemical Biology·Alejandro Alvarez Hernandez, William R Roush
May 3, 2008·The Journal of Biological Chemistry·Ghada Abboud-JarrousIsrael Vlodavsky
Jul 11, 2002·Biological Chemistry·Gilles LalmanachEdith Authié
Sep 16, 2006·Biological Chemistry·Martin LinkeDieter Brömme
Jun 15, 2011·Bioscience, Biotechnology, and Biochemistry·Young-Ok KimSang-Jun Lee
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Jan 22, 2005·The Journal of Biological Chemistry·Ghada Abboud-JarrousIsrael Vlodavsky
Dec 21, 2002·European Journal of Biochemistry·Claire DesmazesGilles Lalmanach
Jul 20, 2020·Protein Science : a Publication of the Protein Society·Xiaojing Shi, Yong Zhang
Oct 9, 2015·The Journal of Biological Chemistry·Jelena RajkovićBoris Turk
Dec 9, 2020·Future Medicinal Chemistry·Rafael da Fonseca LameiroCarlos Alberto Montanari
Mar 4, 2020·Journal of Medicinal Chemistry·Bala C ChennaThomas D Meek
Jun 7, 2003·The Journal of Organic Chemistry·Trevor K EllisVadim A Soloshonok

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