Mechanisms for the deamination reaction of 8-oxoguanine catalyzed by 8-oxoguanine deaminase: A combined QM/MM molecular dynamics study
Autor: | Xinli Duan, Yirong Mo, Zexing Cao, Hui N. Zhang, Yuan Zhao, Xin Zhang |
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Rok vydání: | 2016 |
Předmět: |
Alanine
biology 010405 organic chemistry Stereochemistry Hydrogen bond Guanine Deamination Active site 010402 general chemistry 01 natural sciences 0104 chemical sciences Computer Science Applications Enzyme catalysis QM/MM chemistry.chemical_compound Computational Theory and Mathematics chemistry biology.protein Isocytosine Physical and Theoretical Chemistry |
Zdroj: | Journal of Theoretical and Computational Chemistry. 15:1650066 |
ISSN: | 1793-6888 0219-6336 |
Popis: | The deamination reaction of 8-oxoguanine (8-oxoG) catalyzed by 8-oxoguanine deaminase (8-oxoGD) plays a critically important role in the DNA repair activity for oxidative damage. In order to elucidate the complete enzymatic catalysis mechanism at the stages of 8-oxoguanine binding, departure of 2-hydroxy-1H-purine-6,8(7H,9H)-dione from the active site, and formation of 8-oxoxanthine, extensive combined QM(PM3)/MM molecular dynamics simulations have been performed. Computations show that the rate-limiting step corresponds to the nucleophilic attack from zinc-coordinate hydroxide group to free 8-oxoguanine. Through conformational analyses, we demonstrate that Trp115, Trp123 and Leu119 connect to O8@8-oxoguanine with hydrogen bonds, and we suggest that mutations of tryptophan (115 and 123) to histidine or phenylalanine and mutation of leucine (119) to alanine could potentially lead to a mutant with enhanced activity. On this ground, a proton transfer mechanism for the formation of 8-oxoxanthine was further discussed. Both Glu218 and water molecule could be used as proton shuttles, and water molecule plays a major role in proton transfer in substrate. On the other hand, comparative simulations on the deamination of guanine and isocytosine reveal that, for the helping of hydrogen bonds between O8@8-oxoguanine and enzyme, O8@8-oxoguanine is the fastest to be deaminated among the three substrates which are also supported by the experimental kinetic constants. |
Databáze: | OpenAIRE |
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