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Mechanism of the Nitric Oxide Dioxygenase Reaction of Mycobacterium tuberculosis Hemoglobin N
The Journal of Physical Chemistry B ( IF 3.3 ) Pub Date : 2017-09-08 00:00:00 , DOI: 10.1021/acs.jpcb.7b06494
Lavinia A. Carabet 1 , Michel Guertin , Patrick Lagüe , Guillaume Lamoureux 1
Affiliation  

Many globins convert NO to innocuous NO3 through their nitric oxide dioxygenase (NOD) activity. Mycobacterium tuberculosis fights the oxidative and nitrosative stress imposed by its host (the toxic effects of O2•– and NO species and their OONO and NO2 derivatives) through the action of truncated hemoglobin N (trHbN), which catalyzes the NOD reaction with one of the highest rates among globins. The general NOD mechanism comprises the following steps: binding of O2 to the heme, diffusion of NO into the heme pocket and formation of peroxynitrite (OONO), isomerization of OONO, and release of NO3. Using quantum mechanics/molecular mechanics free-energy calculations, we show that the NOD reaction in trHbN follows a mechanism in which heme-bound OONO undergoes homolytic cleavage to give FeIV═O2 and the NO2 radical but that these potentially harmful intermediates are short-lived and caged by the heme pocket residues. In particular, the simulations show that Tyr33(B10) side chain is shielded from FeIV═O2 and NO2 (and protected from irreversible oxidation and nitration) by forming stable hydrogen bonds with Gln58(E11) side chain and Leu54(E7) backbone. Aromatic residues Phe46(CD1), Phe32(B9), and Tyr33(B10) promote NO3 dissociation via C–H···O bonding and provide stabilizing interactions for the anion along its egress route.

中文翻译:

结核分枝杆菌血红蛋白N一氧化氮双加氧酶反应的机理

许多球蛋白转换 NO转化成无害NO 3 -通过他们的一氧化氮双加氧酶(NOD)活动。结核分枝杆菌的战斗的氧化和通过它的主机施加亚硝化应激(毒性的O-效果2 • - NO物种及其OONO - NO 2的衍生物)通过截断血红蛋白N(trHbN),其催化的NOD的动作与球蛋白发生率最高的反应之一。一般的NOD机理包括以下步骤:O 2与血红素结合, NO扩散到血红素袋中以及形成过氧亚硝酸盐(OONO)。),OONO –的异构化和NO 3 –的释放。使用量子力学/分子力学自由能的计算,我们表明,在trHbN的NOD反应如下一种机制,其中血红素结合的OONO -经历均裂,得到的Fe IV = O 2 - NO 2基团,但是,这些潜在的有害的中间体是短命的,并被血红素口袋残留物笼罩。特别是,模拟显示,Tyr33(B10)侧链是选自Fe屏蔽IV = O 2 - NO 2(并防止不可逆的氧化和硝化作用),并与Gln58(E11)侧链和Leu54(E7)主链形成稳定的氢键。芳香族残基Phe46(CD1),Phe32(B9),和Tyr33(B10)促进NO 3 -通过C-H ... O键的解离,并为沿其流出路线的阴离子稳定的相互作用。
更新日期:2017-09-08
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