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• W2782546825 endingPage "3190" @default.
• W2782546825 startingPage "3176" @default.
• W2782546825 abstract "Cruzain, an important drug target for Chagas disease, is a member of clan CA of the cysteine proteases. Understanding the catalytic mechanism of cruzain is vital to the design of new inhibitors. To this end, we have determined pH-rate profiles for substrates and affinity agents and solvent kinetic isotope effects in pre-steady-state and steady-state modes using three substrates: Cbz-Phe-Arg-AMC, Cbz-Arg-Arg-AMC, and Cbz-Arg-Ala-AMC. The pH-rate profile of kcat/ Km for Cbz-Arg-Arg-AMC indicated p K1 = 6.6 (unprotonated) and p K2 ∼ 9.6 (protonated) groups were required for catalysis. The temperature dependence of the p K = 6.2-6.6 group exhibited a Δ Hion value of 8.4 kcal/mol, typical of histidine. The pH-rate profile of inactivation by iodoacetamide confirmed that the catalytic cysteine possesses a p Ka of 9.8. Normal solvent kinetic isotope effects were observed for both D2O kcat (1.6-2.1) and D2O kcat/ Km (1.1-1.4) for all three substrates. Pre-steady-state kinetics revealed exponential bursts of AMC production for Cbz-Phe-Arg-AMC and Cbz-Arg-Arg-AMC, but not for Cbz-Arg-Ala-AMC. The overall solvent isotope effect on kcat can be attributed to the solvent isotope effect on the deacylation step. Our results suggest that cruzain is unique among papain-like cysteine proteases in that the catalytic cysteine and histidine have neutral charges in the free enzyme. The generation of the active thiolate of the catalytic cysteine is likely preceded (and possibly triggered) by a ligand-induced conformational change, which could bring the catalytic dyad into the proximity to effect proton transfer." @default.
• W2782546825 created "2018-01-26" @default.
• W2782546825 creator A5006496354 @default.
• W2782546825 creator A5047649241 @default.
• W2782546825 date "2018-01-16" @default.
• W2782546825 modified "2023-10-17" @default.
• W2782546825 title "Catalytic Mechanism of Cruzain from <i>Trypanosoma cruzi</i> As Determined from Solvent Kinetic Isotope Effects of Steady-State and Pre-Steady-State Kinetics" @default.
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• W2782546825 doi "https://doi.org/10.1021/acs.biochem.7b01250" @default.
• W2782546825 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29336553" @default.
• W2782546825 hasPublicationYear "2018" @default.
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