Theoretical and experimental studies of tyrosyl hydroperoxide formation in the presence of H-bond donors.
Theoretical and experimental studies of tyrosyl hydroperoxide formation in the presence of H-bond donors.
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DOI：
10.1021/tx8001687
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发表时间：
2008-10
影响因子：
4.1
通讯作者：
Villamena, Frederick A.
中科院分区：
文献类型：
--
作者：
Field, Steven A.;Villamena, Frederick A.
脂质、蛋白质、核苷酸和糖类等生物分子的氧化损伤与多种疾病的发病机制有关。超氧阴离子(O2·−)与含酰胺N-H的硝酮的加成反应已被证明比其他硝酮更受欢迎(维拉梅纳，F.A.等人，J.Am化学。SoC.，2007,129,8177-8191)。其他人(温特伯恩，C.C.等人，Biochem)也证明了这一点。在碱性氨基存在的情况下，O2·−与酪氨酸加成形成过氧化氢是有利的，但观察到的机制仍不清楚。因此，我们推测，O2·α与N-H相互作用产生的−效应在促进过氧化氢的形成中起着至关重要的作用。了解这一现象对于阐明细胞系统中导致氧化应激的机制很重要。通过计算(PCM/B3LYP/6-31+G**//B3LYP/6-31G理论水平)和实验研究，研究了酰胺或氨基N-H对酪氨酸过氧化氢生成的促进(或稳定)作用。氨基酸与O2·−的氢键相互作用导致O2·−的自旋和电荷密度发生微扰。类似的现象也被预测到非氨基酸的氢键供体基团。利用Fox比色法，在氨基酸和非氨基酸的氢键供体的存在下，酪氨酰过氧化氢的形成被促进。进一步从理论上研究了氢键在稳定过氧化氢加合物或通过−效应促进O2·α加成反应中的作用，结果表明后者在热力学上更具优势。本研究为酪氨酰自由基氧化修饰的启动提供了新的机理见解。
Oxidative damage to biomolecules such as lipids, proteins, nucleotides and sugars has been implicated in the pathogenesis of various diseases. Superoxide radical anion (O2•−) addition to nitrones bearing an amide N-H has been shown to be more favored compared to other nitrones (Villamena, F. A., et al., J. Am. Chem. Soc., 2007, 129, 8177–8191). It has also been demonstrated by others (Winterbourn, C. C., et al., Biochem. J. 2004, 381, 241–248) that O2•− addition to tyrosine to form hydroperoxide is favored in the presence of basic amino groups but the mechanism for this observation remains obscure. We, therefore, hypothesized that the α-effect resulting from the interaction of O2•− with N-H can play a crucial role in the enhancement of hydroperoxide formation. Understanding this phenomenon is important in the elucidation of mechanisms leading to oxidative stress in cellular systems. Computational (PCM/B3LYP/6-31+G**//B3LYP/6-31G level of theory) as well as experimental studies were carried out to shed insights into the effect of amide or amino N-H on the enhancement (or stabilization) of hydroperoxide formation in tyrosine. H-bond interaction of amino acid group with O2•− results in the perturbation of the spin and charge densities of O2•−. Similar phenomenon has been predicted for non-amino acids bearing H-bond donor groups. Using FOX assay, tyrosyl hydroperoxide formation was enhanced in the presence of H-bond donors from amino acids and non-amino acids. The role of H-bonding in either stabilizing the hydroperoxide adduct, or facilitation of O2•− addition via α-effect was further theoretically investigated, and results show that the latter mechanism is more thermodynamically preferred. This study provides new mechanistic insights in the initiation of oxidative modification to tyrosyl radical.
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影响因子：
64.8
作者：
GETZOFF, ED;CABELLI, DE;HALLEWELL, RA
通讯作者：
HALLEWELL, RA
影响因子：
--
作者：
CZAPSKI, G;BIELSKI, BHJ
通讯作者：
BIELSKI, BHJ
影响因子：
4.4
作者：
BECKE, AD
通讯作者：
BECKE, AD
影响因子：
2.9
作者：
Fukuzawa, Kenji;Fujisaki, Aya;Gebicki, Janusz M.
通讯作者：
Gebicki, Janusz M.
影响因子：
3.2
作者：
Krenske, Elizabeth H.;Schiesser, Carl H.
通讯作者：
Schiesser, Carl H.