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首页> 外文期刊>The journal of physical chemistry, A. Molecules, spectroscopy, kinetics, environment, & general theory >Why Do Cysteine Dioxygenase Enzymes Contain a 3-His Ligand Motif Rather than a 2His/1Asp Motif Like Most Nonheme Dioxygenases?
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Why Do Cysteine Dioxygenase Enzymes Contain a 3-His Ligand Motif Rather than a 2His/1Asp Motif Like Most Nonheme Dioxygenases?

机译：为什么半胱氨酸双加氧酶比大多数非血红素双加氧酶包含3-His配体基元，而不是2His / 1Asp基序？

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Density functional theory calculations on the oxygen activation process in cysteine dioxygenase (CDO) and three active site mutants whereby one histidine group is replaced by a carboxylic acid group are reported.The calculations predict an oxygen activation mechanism that starts from an FeIII-O-O complex that has close lying singlet, triplet, and quintet spin states. A subsequent spin state crossing to the quintet spin state surfaces leads to formation of a ring-structure whereby an O-S bond is formed. This weakens the central O-O bond, which is subsequently broken to give sulfoxide and an iron-oxo complex. The second oxygen atom is transferred to the substrate after a rotation of the sulfoxide group. A series of calculations were performed on cysteine dioxygenase mutants with a 2His/1Asp motif rather than a 3His motif. These calculations focused on the differences in catalytic and electronic properties of nonheme iron systems with a 3His ligand system versus a 2His/1Asp motif, such as taurine/R-ketoglutarate dioxygenase (TauD), and predict why CDO has a 3His ligand system while TauD and other dioxygenases share a 2His/1Asp motif. One mutant (H86D) had the ligand trans to the dioxygen group replaced by acetate, while in another set of calculations the ligand trans to the sulfur group of cysteinate was replaced by acetate (H88D). The calculations show that the ligands influence the spin state ordering of the dioxygen bound complexes considerably and in particular stabilize the quintet spin state more so that the oxygen activation step should encounter a lower energetic cost in the mutants as compared to WT. Despite this, the mutant structures require higher O-O bond breaking energies. Moreover, the mutants create more stable iron-oxo complexes than the WT, but the second oxygen atom transfer to the substrate is accomplished with much higher reaction barriers than the WT system. In particular,a ligand trans to the sulfur atom of cysteine that pushes electrons to the iron will weaken the Fe-S bond and lead to dissociation of this bond in an earlier step in the catalytic cycle than the WT structure. On the other hand, replacement of the ligand trans to the dioxygen moiety has minor effects on cysteinate binding but enhances the barriers for the second oxygen transfer process. These studies have given insight into why cysteine dioxygenase enzymes contain a 3His ligand motif rather than 2His/1Asp and show that the ligand system is essential for optimal dioxygenation activity of the substrate. In particular, CDO mutants with a 2His/1Asp motif may give sulfoxides as byproduct due to incomplete dioxygenation processes.
机译：报道了半胱氨酸双加氧酶（CDO）和三个活性位点突变体中一个组氨酸基团被一个羧酸基团取代的氧激活过程的密度泛函理论计算，这些计算预测了一个氧激活机制从FeIII-OO配合物开始具有紧密的单重态，三重态和五重态自旋状态。随后的与五重态自旋态表面相交的自旋态导致形成环结构，由此形成O-S键。这削弱了中央O-O键，该键随后被断裂以产生亚砜和铁-氧配合物。亚砜基旋转后，第二个氧原子被转移到基底上。对具有2His / 1Asp基序而不是3His基序的半胱氨酸双加氧酶突变体进行了一系列计算。这些计算着眼于具有3His配体系统与2His / 1Asp基序的非血红素铁系统（如牛磺酸/ R-酮戊二酸双加氧酶（TauD））的催化和电子性质的差异，并预测为什么CDO具有ThiD的3His配体系统其他双加氧酶具有2His / 1Asp基序。一个突变体（H86D）的配体反式向双氧基团被乙酸酯替代，而在另一组计算中，半胱氨酸酯的反式至半胱氨酸硫基团被配体转化为乙酸酯（H88D）。计算表明，配体显着影响双氧键合复合物的自旋态有序性，特别是使五重体自旋态更稳定，因此与WT相比，氧活化步骤在突变体中的能量成本较低。尽管如此，突变体结构需要更高的O-O键断裂能。此外，该突变体比WT产生更稳定的铁-氧配合物，但是第二个氧原子转移到底物上的反应势垒比WT系统高得多。特别地，与半胱氨酸的硫原子反式的配体将电子推向铁将削弱Fe-S键并导致该键在比WT结构更早的催化循环步骤中解离。另一方面，将反式配体替换为双氧部分对半胱氨酸的结合影响较小，但增强了第二次氧气转移过程的阻隔性。这些研究深入了解了半胱氨酸双加氧酶为什么包含3His配体基序而不是2His / 1Asp，并表明配体系统对于底物的最佳双加氧活性至关重要。特别是，具有2His / 1Asp基序的CDO突变体可能由于不完全的双加氧过程而产生亚砜作为副产物。

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