Functional role of R462 in the degradation of hyaluronan catalyzed by hyaluronate lyase from Streptococcus pneumoniae

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• 作者：Fengxue Li ; Dingguo Xu
• 关键词：Enzymatic catalysis ; Hyaluronan lyase ; Molecular dynamics ; QM/MM ; Reaction mechanism ; Site ; directed mutagenesis
• 刊名：Journal of Molecular Modeling
• 出版年：2015
• 出版时间：August 2015
• 年：2015
• 卷：21
• 期：8
• 全文大小：1,201 KB
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• 作者单位：Fengxue Li (1)
  Dingguo Xu (1)
  
  1. MOE Key Laboratory of Green Chemistry, College of Chemistry, Sichuan University, Chengdu, Sichuan, 610064, People’s Republic of China
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Computer Applications in Chemistry
  Biomedicine
  Molecular Medicine
  Health Informatics and Administration
  Life Sciences
  Computer Application in Life Sciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：0948-5023

文摘

Hyaluronan lyase from Streptococcus pneumoniae can degrade hyaluronic acid, which is one of the major components in the extracellular matrix. Hyaluronan can regulate water balance, osmotic pressure, and act as an ion exchange resin. Followed by our recent work on the catalytic reaction mechanism and substrate binding mode, we in this work further investigate the functional role of active site arginine residue, R462, in the degradation of hyaluronan. The site directed mutagenesis simulation of R462A and R462Q were modeled using a combined quantum mechanical and molecular mechanical method. The overall substrate binding features upon mutations do not have significant changes. The energetic profiles for the reaction processes are essentially the same as that in wild type enzyme, but significant activation barrier height changes can be observed. Both mutants were shown to accelerate the overall enzymatic activity, e.g., R462A can reduce the barrier height by about 2.8?kcal mol-, while R462Q reduces the activation energy by about 2.9?kcal mol-. Consistent with the active site model calculated using density functional theory, our results can support that the positive charge on R462 guanidino side chain group plays a negative role in the catalysis. Finally, the functional role of R462 was proposed to facilitate the formation of initial enzyme-substrate complex, but not in the subsequent catalytic degradation reaction.