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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Parks, Jerry M. Fisher, Suzanne Zoe Wan, Qun Ostermann, Andreas Hanson, B. Leif Coates, Leighton Kovalevsky, Andrey Schrader, Tobias E. Langan, Paul Graham, David E. |
| Description | Author Affiliation: Wan Q ( Department of Physics, College of Science, Nanjing Agricultural University, Nanjing 210095, People's Republic of China); Parks JM ( University of Tennessee/Oak Ridge National Laboratory Center for Molecular Biophysics, Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831); Hanson BL ( Chemistry Department, University of Toledo, Toledo, OH 43606); Fisher SZ ( Scientific Activities Division, European Spallation Source, Lund 22100, Sweden); Ostermann A ( Heinz Maier-Leibnitz Zentrum, Technische Universität München, 85748 Garching, Germany); Schrader TE ( Jülich Centre for Neutron Science at Heinz Maier-Leibnitz Zentrum, Forschungszentrum Jülich GmbH, 85747 Garching, Germany); Graham DE ( Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831); Coates L ( Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831.); Langan P ( Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831.); Kovalevsky A ( Biology and Soft Matter Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831 kovalevskyay@ornl.gov.); |
| Abstract | Glycoside hydrolase (GH) enzymes apply acid/base chemistry to catalyze the decomposition of complex carbohydrates. These ubiquitous enzymes accept protons from solvent and donate them to substrates at close to neutral pH by modulating the pKa values of key side chains during catalysis. However, it is not known how the catalytic acid residue acquires a proton and transfers it efficiently to the substrate. To better understand GH chemistry, we used macromolecular neutron crystallography to directly determine protonation and ionization states of the active site residues of a family 11 GH at multiple pD (pD=pH+0.4) values. The general acid glutamate (Glu) cycles between two conformations, upward and downward, but is protonated only in the downward orientation. We performed continuum electrostatics calculations to estimate the pKa values of the catalytic Glu residues in both the apo- and substrate-bound states of the enzyme. The calculated pKa of the Glu increases substantially when the side chain moves down. The energy barrier required to rotate the catalytic Glu residue back to the upward conformation, where it can protonate the glycosidic oxygen of the substrate, is 4.3 kcal/mol according to free energy simulations. These findings shed light on the initial stage of the glycoside hydrolysis reaction in which molecular motion enables the general acid catalyst to obtain a proton from the bulk solvent and deliver it to the glycosidic oxygen. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 40 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-10-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Fungal Proteins Chemistry Glycoside Hydrolases Glycosides Neutrons Biocatalysis Carbohydrate Conformation Catalytic Domain Crystallography, X-Ray Metabolism Glutamic Acid Hydrogen Bonding Hydrogen-Ion Concentration Hydrolysis Models, Chemical Models, Molecular Protein Binding Protein Structure, Tertiary Protons Static Electricity Substrate Specificity Temperature Trichoderma Enzymology Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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