Experimentally calibrated computational chemistry of tryptophan hydroxylase: Trans influence, hydrogen-bonding, and 18-electron rule govern O2-activation
| Autor: | Jane Boesen, Hans Erik Mølager Christensen, Kasper P. Jensen, Lærke T. Haahr |
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| Rok vydání: | 2010 |
| Předmět: |
Models
Molecular Stereochemistry Trans effect Molecular Conformation Electrons Tryptophan Hydroxylase Biochemistry Peroxide Catalysis Substrate Specificity Inorganic Chemistry chemistry.chemical_compound Catalytic Domain Animals Humans Molecule Computer Simulation Molecular Structure Hydrogen bond Tryptophan Transition state Protein Structure Tertiary Oxygen Kinetics Models Chemical chemistry Calibration Thermodynamics Valence electron |
| Zdroj: | Journal of Inorganic Biochemistry. 104:136-145 |
| ISSN: | 0162-0134 |
| DOI: | 10.1016/j.jinorgbio.2009.10.010 |
| Popis: | Insight into the nature of oxygen activation in tryptophan hydroxylase has been obtained from density functional computations. Conformations of O(2)-bound intermediates have been studied with oxygen trans to glutamate and histidine, respectively. An O(2)-adduct with O(2)trans to histidine (O(his)) and a peroxo intermediate with peroxide trans to glutamate (P(glu)) were found to be consistent (0.57-0.59mm/s) with experimental Mössbauer isomer shifts (0.55mm/s) and had low computed free energies. The weaker trans influence of histidine is shown to give rise to a bent O(2) coordination mode with O(2) pointing towards the cofactor and a more activated O-O bond (1.33A) than in O(glu) (1.30A). It is shown that the cofactor can hydrogen bond to O(2) and activate the O-O bond further (from 1.33 to 1.38A). The O(his) intermediate leads to a ferryl intermediate (F(his)) with an isomer shift of 0.34mm/s, also consistent with the experimental value (0.25mm/s) which we propose as the structure of the hydroxylating intermediate, with the tryptophan substrate well located for further reaction 3.5A from the ferryl group. Based on the optimized transition states, the activation barriers for the two paths (glu and his) are similar, so a two-state scenario involving O(his) and P(glu) is possible. A structure of the activated deoxy state which is high-spin implies that the valence electron count has been lowered from 18 to 16 (glutamate becomes bidentate), giving a "green light" that invites O(2)-binding. Our mechanism of oxygen activation in tryptophan hydroxylase does not require inversion of spin, which may be an important observation. |
| Databáze: | OpenAIRE |
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