期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 32, 页码 24439-24446出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.131193
关键词
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资金
- Fondo di Ateneo per la Ricerca
- National Institutes of Health [NIH P41-RR005969]
Molecular dynamics simulations and implicit ligand sampling methods have identified trajectories and sites of high affinity for O-2 in the protein framework of the flavoprotein D-amino-acid oxidase (DAAO). A specific dynamic channel for the diffusion of O-2 leads from solvent to the flavin Si-side ( amino acid substrate and product bind on the Re-side). Based on this, amino acids that flank the putative O-2 high affinity sites have been exchanged with bulky residues to introduce steric constraints. In G52V DAAO, the valine side chain occupies the site that in wild-type DAAO has the highest O-2 affinity. In this variant, the reactivity of the reduced enzyme with O-2 is decreased >= 100-fold and the turnover number approximate to 1000-fold thus verifying the concept. In addition, the simulations have identified a chain of three water molecules that might serve in relaying a H+ from the product imino acid +NH2+ group bound on the flavin Reside to the developing peroxide on the Si-side. This function would be comparable with that of a similarly located histidine in the flavoprotein glucose oxidase.
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