Theoretical studies of manganese and iron superoxide dismutases: Superoxide binding and superoxide oxidation
Theoretical studies of manganese and iron superoxide dismutases: Superoxide binding and superoxide oxidation
复制标题
DOI：
10.1021/jp052368u
复制
发表时间：
2005-12-29
影响因子：
3.3
通讯作者：
Cabelli, DE
中科院分区：
文献类型：
--
作者：
Abreu, IA;Rodriguez, JA;Cabelli, DE
密度泛函计算表明，锰和铁超氧化物歧化酶（MnSODs和FeSODs）金属中心周围的第二配位球在O-2（-）的结合中起重要作用。在这些体系中，O-2倾向于以端对端构型与Mn或Fe结合。对于人类和大肠杆菌的mnsod，结合的O-2（-）在第二配位球中与酪氨酸和谷氨酰胺氨基酸残基形成氢键。在大肠杆菌和T.细长FeSODs的情况下，氢键发生在结合的O-2（-）和酪氨酸氨基酸之间，只是因为谷氨酰胺距离太远，无法有效地相互作用。在MnSODs和FeSODs中，O-2（-）与金属中心结合的方式可以影响后续质子化的速率，并决定H2O2的形成机制。含锰和含铁的超氧化物歧化酶都含有一个金属结合的溶剂分子，该分子被认为参与了金属中心还原时H+的吸收[Bull， C.；费，J. A. J. Anz。化学。社会科学学报。1985,107,3295；米勒,A.-F。Padmakumar k;索金博士；Karapetian, a;万斯，C. K. J.。生物化学学报，2003,19(3):371 - 371。利用密度泛函理论，我们证实了这一建议，并显示了第二个协调领域在这一过程中的参与。我们发现，含锰或含铁的超氧化物歧化酶对超氧化物的氧化是由超氧化物结合、氢氧根与金属结合的质子化以及电子从超氧化物分子转移到被氧化金属之间的协同作用促成的。特别是，质子通过酪氨酸-34的转移在没有结合的超氧化物的情况下是上坡的，而一旦超氧化物结合，能垒就会降低。正是这种屏障可能使酶的静息状态（Mn(III)SOD）与氢氧化物结合，而不是水。本研究为超氧化物在锰和FeSODs中与氧化态金属的反应机理提供了一个模型。
Density-functional calculations indicate that the second sphere of coordination around the metal centers of manganese and iron superoxide dismutases (MnSODs and FeSODs) plays an important role in the binding of O-2(-). In these systems, O-2 prefers to bind to Mn or Fe in end-on configurations. For human and E. coli MnSODs, the bound O-2(-) forms hydrogen bonds with tyrosine and glutamine amino acids residues in the second sphere of coordination. In the cases of E. coli and T. elongates FeSODs, hydrogen bonding occurs between the bound O-2(-) and the tyrosine amino acid only because the glutamine is too far away for an effective bonding interaction. The manner in which the O-2(-) binds to the metal center in MnSODs and FeSODs can affect the rate of subsequent protonation and determine the mechanism for the formation of H2O2. Both Mn- and Fe-containing superoxide dismutases contain a metal-bound solvent molecule that has been suggested to be involved in the uptake of a H+ upon reduction of the metal center [Bull, C.; Fee, J. A. J. Anz. Chem. Soc. 1985, 107, 3295; Miller, A.-F.; Padmakumar, K.; Sorkin, D. L.; Karapetian, A.; Vance, C. K. J. Inorg. Biochem. 2003, 93, 71]. Using density-functional theory, we confirm this suggestion and show the involvement of the second sphere of coordination in the process. We show that the oxidation of superoxide by Mn- or Fe-containing superoxide dismutases is facilitated by a cooperative effect between superoxide binding, protonation of the OH- bound to the metal, and electron transfer from the superoxide molecule to the oxidized metal. In particular, proton transfer through tyrosine-34 on the absence of a bound superoxide is uphill while, once superoxide is bound, the energetic barrier is lowered. It is this barrier that likely keeps the resting state (Mn(III)SOD) of the enzyme with a bound hydroxide, instead of a water. This work provides a model for the mechanism of reaction of superoxide with the oxidized form of the metal within Mn- and FeSODs.