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Enzyme‐Specific Activation versus Leaving Group Ability
Author(s) -
de Beer Roseri J. A. C.,
Bögels Berry,
Schaftenaar Gijs,
Zarzycka Barbara,
Quaedflieg Peter J. L. M.,
van Delft Floris L.,
Nabuurs Sander B.,
Rutjes Floris P. J. T.
Publication year - 2012
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201200227
Subject(s) - dipeptide , chemistry , peptide , protease , combinatorial chemistry , enzyme , docking (animal) , stereochemistry , substrate (aquarium) , leaving group , trypsin , biochemistry , catalysis , biology , medicine , ecology , nursing
Abstract Enzyme‐specific activation and the substrate mimetics strategy are effective ways to circumvent the limited substrate recognition often encountered in protease‐catalyzed peptide synthesis. A key structural element in both approaches is the guanidinophenyl (OGp) ester, which enables important interactions for affinity and recognition by the enzyme—at least, this is usually the explanation given for its successful application. In this study we show that leaving group ability is of equal or even greater importance. To this end we used both experimental and computational methods: 1) synthesis of close analogues of OGp, and their evaluation in a dipeptide synthesis assay with trypsin, 2) molecular docking studies to provide insights into the binding mode, and 3) ab initio calculations to evaluate their electronic properties.