Potent Inhibition of 3-Deoxy-d-arabinoheptulosonate-7-phosphate (DAHP) Synthase by DAHP Oxime, a Phosphate Group Mimic
| Autor: | Maren Heimhalt, Paul J. Berti, Murray S. Junop, Derek J. Wilson, Frederick To, Naresh Balachandran, Peter Liuni |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Stereochemistry Dimer DAHP synthase Crystallography X-Ray Biochemistry 03 medical and health sciences chemistry.chemical_compound Protein Domains Tetrahedral carbonyl addition compound Oximes Escherichia coli Shikimate pathway 3-Deoxy-7-Phosphoheptulonate Synthase 030102 biochemistry & molecular biology biology ATP synthase Molecular Structure Escherichia coli Proteins Deuterium Exchange Measurement Sugar Acids Oxime Kinetics 030104 developmental biology chemistry Erythrose biology.protein Biocatalysis Protein Multimerization Phosphoenolpyruvate carboxykinase Algorithms Protein Binding |
| Zdroj: | Biochemistry. 55(48) |
| ISSN: | 1520-4995 |
| Popis: | 3-Deoxy-d-arabinoheptulosonate-7-phosphate (DAHP) synthase catalyzes the first step in the shikimate pathway. It catalyzes an aldol-like reaction of phosphoenolpyruvate (PEP) with erythrose 4-phosphate (E4P) to form DAHP. The kinetic mechanism was rapid equilibrium sequential ordered ter ter, with the essential divalent metal ion, Mn2+, binding first, followed by PEP and E4P. DAHP oxime, in which an oxime group replaces the keto oxygen, was a potent inhibitor, with Ki = 1.5 ± 0.4 μM, though with residual activity at high inhibitor concentrations. It displayed slow-binding inhibition with a residence time, tR, of 83 min. The crystal structure revealed that the oxime functional group, combined with two crystallographic waters, bound at the same location in the catalytic center as the phosphate group of the tetrahedral intermediate. DAHP synthase has a dimer-of-dimers homotetrameric structure, and DAHP oxime bound to only one subunit of each tight dimer. Inhibitor binding was competitive with respect to all ... |
| Databáze: | OpenAIRE |
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