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QM/MM Study of the Reaction Mechanism of the Carboxyl Transferase Domain of Pyruvate Carboxylase from Staphylococcus aureus | |
Sheng, Xiang ; Liu, Yongjun | |
2014-07-15 | |
发表期刊 | BIOCHEMISTRY
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摘要 | Pyruvate carboxylase (PC) catalyzes the carboxylation of pyruvate to produce oxaloacetate. Its activity is directly related to insulin release and thus PC has recently attracted great interest as a potential target for diabetes treatment. In this article, the catalytic mechanism of the carboxyl transferase domain of PC from Staphylococcus aureus was investigated by using a combined quantum-mechanical/molecular-mechanical approach. Our calculation results indicate that the catalytic reaction starts from the decarboxylation of carboxybiotin to generate an enol-BTI intermediate, followed by two consecutive proton-transfer processes (from T908 to enol-BTI and from PYR to T908). During the catalytic reaction, the main-chain amide of T908 plays a key role in catching CO2 and preventing its diffusion from the active center. A triad of residues, R571, Q575, and K741, contributes both to substrate binding and enol-pyruvate stabilization. The oxyanion hole, consisting of the side-chain hydroxyl of S911 and the side-chain amino of Q870, plays an important role in stabilizing the hydroxyl anion of BTI. The coordination of the metal cation by pyruvate is a second sphere, rather than an inner sphere, interaction, and the metal cation stabilizes the species through the medium of residue K741. The decarboxylation of carboxybiotin corresponds to the highest free energy barrier of 21.7 kcal/mol. Our results may provide useful information for both the regulation of enzyme activity and the development of related biocatalytic applications.; Pyruvate carboxylase (PC) catalyzes the carboxylation of pyruvate to produce oxaloacetate. Its activity is directly related to insulin release and thus PC has recently attracted great interest as a potential target for diabetes treatment. In this article, the catalytic mechanism of the carboxyl transferase domain of PC from Staphylococcus aureus was investigated by using a combined quantum-mechanical/molecular-mechanical approach. Our calculation results indicate that the catalytic reaction starts from the decarboxylation of carboxybiotin to generate an enol-BTI intermediate, followed by two consecutive proton-transfer processes (from T908 to enol-BTI and from PYR to T908). During the catalytic reaction, the main-chain amide of T908 plays a key role in catching CO2 and preventing its diffusion from the active center. A triad of residues, R571, Q575, and K741, contributes both to substrate binding and enol-pyruvate stabilization. The oxyanion hole, consisting of the side-chain hydroxyl of S911 and the side-chain amino of Q870, plays an important role in stabilizing the hydroxyl anion of BTI. The coordination of the metal cation by pyruvate is a second sphere, rather than an inner sphere, interaction, and the metal cation stabilizes the species through the medium of residue K741. The decarboxylation of carboxybiotin corresponds to the highest free energy barrier of 21.7 kcal/mol. Our results may provide useful information for both the regulation of enzyme activity and the development of related biocatalytic applications. |
文献类型 | 期刊论文 |
条目标识符 | http://210.75.249.4/handle/363003/47537 |
专题 | 中国科学院西北高原生物研究所 |
推荐引用方式 GB/T 7714 | Sheng, Xiang,Liu, Yongjun. QM/MM Study of the Reaction Mechanism of the Carboxyl Transferase Domain of Pyruvate Carboxylase from Staphylococcus aureus[J]. BIOCHEMISTRY, Sheng, X; Liu, YJ.QM/MM Study of the Reaction Mechanism of the Carboxyl Transferase Domain of Pyruvate Carboxylase from Staphylococcus aureus,BIOCHEMISTRY,2014,53(27):4455,2014. |
APA | Sheng, Xiang,&Liu, Yongjun.(2014).QM/MM Study of the Reaction Mechanism of the Carboxyl Transferase Domain of Pyruvate Carboxylase from Staphylococcus aureus.BIOCHEMISTRY. |
MLA | Sheng, Xiang,et al."QM/MM Study of the Reaction Mechanism of the Carboxyl Transferase Domain of Pyruvate Carboxylase from Staphylococcus aureus".BIOCHEMISTRY (2014). |
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