DFT-based prediction of reactivity of short-chain alcohol dehydrogenase
| Autor: | Agnieszka Dudzik, Andrzej Skoczowski, M. Jemiola-Rzeminska, Iwona Stawoska, Kazimierz Strzałka, M. Wasylewski, Maciej Szaleniec |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Reaction mechanism short chain dehydrogenase Ketone Rhodocyclaceae Protonation Dehydrogenase Hydride transfer Photochemistry 01 natural sciences reduction of ketones Catalysis Article Chemical kinetics 03 medical and health sciences chemistry.chemical_compound Computational chemistry hydride transfer Drug Discovery Cluster Analysis Short chain dehydrogenase Reactivity (chemistry) Physical and Theoretical Chemistry chemistry.chemical_classification 010405 organic chemistry Chemistry Hydride alcohol dehydrogenase/ketoreductase Lysine Stereoisomerism Reduction of ketones Hydrogen-Ion Concentration Ketones NAD Alcohol dehydrogenase/ketoreductase 0104 chemical sciences Computer Science Applications Molecular Docking Simulation Kinetics 030104 developmental biology Alcohols PEDH (S)-1-phenylethanol dehydrogenase Quantum Theory Tyrosine Oxidoreductases Oxidation-Reduction Acetophenone |
| Zdroj: | Journal of Computer-Aided Molecular Design |
| Popis: | The reaction mechanism of ketone reduction by short chain dehydrogenase/reductase, (S)-1-phenylethanol dehydrogenase from Aromatoleum aromaticum, was studied with DFT methods using cluster model approach. The characteristics of the hydride transfer process were investigated based on reaction of acetophenone and its eight structural analogues. The results confirmed previously suggested concomitant transfer of hydride from NADH to carbonyl C atom of the substrate with proton transfer from Tyr to carbonyl O atom. However, additional coupled motion of the next proton in the proton-relay system, between O2′ ribose hydroxyl and Tyr154 was observed. The protonation of Lys158 seems not to affect the pKa of Tyr154, as the stable tyrosyl anion was observed only for a neutral Lys158 in the high pH model. The calculated reaction energies and reaction barriers were calibrated by calorimetric and kinetic methods. This allowed an excellent prediction of the reaction enthalpies (R2 = 0.93) and a good prediction of the reaction kinetics (R2 = 0.89). The observed relations were validated in prediction of log K eq obtained for real whole-cell reactor systems that modelled industrial synthesis of S-alcohols. Electronic supplementary material The online version of this article (doi:10.1007/s10822-017-0026-5) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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