Chemical Synthesis of an Enzyme Containing an Artificial Catalytic Apparatus*
Vladimir Torbeev A B and Stephen B. H. Kent A CA Department of Chemistry, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
B Current address: Laboratory of Protein Chemistry, Institut de Science et d’Ingénierie Supramoléculaires, Université de Strasbourg, 8 Allée Gaspard Monge, BP 70028, 67083 Strasbourg (Cedex), France.
C Corresponding author. Email: skent@uchicago.edu
Australian Journal of Chemistry 73(4) 321-326 https://doi.org/10.1071/CH19460
Submitted: 18 September 2019 Accepted: 11 October 2019 Published: 11 December 2019
Abstract
With the goal of investigating electronic aspects of the catalysis of peptide bond hydrolysis, an analogue of HIV-1 protease was designed in which a non-peptide hydroxy-isoquinolinone artificial catalytic apparatus replaced the conserved Asp25–Thr26–Gly27 sequence in each 99-residue polypeptide chain of the homodimeric enzyme molecule. The enzyme analogue was prepared by total chemical synthesis and had detectable catalytic activity on known HIV-1 protease peptide substrates. Compared with uncatalyzed hydrolysis, the analogue enzyme increased the rate of peptide bond hydrolysis by ∼108-fold. Extensions of this unique approach to the study of enzyme catalysis in HIV-1 protease are discussed.
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