A群鏈球菌不會產生觸酶但卻可以生長在含氧的環境。Peroxide resistance protein (Dpr) 是一個與壓力相關的蛋白質，目前已知Dpr對A群鏈球菌抵禦過氧化氫很重要，但是其詳細抵禦機制仍然不清楚。Dpr 的表現是受到PerR (peroxide stress response regulator) 所調控，然而PerR調控Dpr 的詳細分子機轉仍未釐清。本研究的目標是探討dpr基因在不同壓力下的角色及 PerR 如何調節Dpr的機轉。經由同源性重組機制剔除的dpr突變株對過氧化氫非常敏感，而其互補株則可以部分回復突變株的缺失。若預先處理鐵螯合劑 (DFOM)，可以回復dpr突變株在氧化壓力下的生存能力。dpr突變株在長期靜止期及酸鹼pH壓力下的存活能力明顯比野生株低。在缺鐵的環境中，dpr突變株的存活率也比野生株低。測試A群鏈球菌在不同離子壓力的存活能力，dpr突變株對於鐵與鋅的壓力是非常敏感，但是在鎂、銅、鎳及鈣離子壓力下則無明顯差異。分析重組蛋白質的功能時，發現Dpr具有與鐵結合的能力，但是不具有與DNA結合的能力。西方點墨結果顯示Dpr 在正常培養下的表現與生長曲線呈現正相關。Dpr在鐵限制的環境會降低其表現，而外加鐵、鋅、鎳及過氧化氫則可以引起其表現，但在 perR突變株中，Dpr的表現完全不受到外界環境因子的影響。當鐵或過氧化氫的濃度增加，PerR結合在dpr promoter的能力也隨之降低。此外，構築PerRC104S和PerRC144S點突變重組蛋白，發現二者與鋅結合的能力皆降低。Dpr 在perR 互補菌株的表現是受到環境因子的調控，然而perR突變株中互補會表現PerRC104S 或 PerRC144S 的質體時，Dpr的表現則不受到環境因子調控。表現PerRC104S 或 PerRC144S 的菌株會降低其在人類全血存活的能力。這些結果推測Dpr可以避免過氧化氫經由Fenton reaction所產生的毒殺能力，也發現當PerR 感受環境因子的改變時，會直接對Dpr 進行調控。PerR 的鋅結合位點不僅是維持此功能所必需而且對A群鏈球菌存活於人類全血也是重要的。

Group A streptococcus does not produce catalase, but it can grow in aerobic environments and survive in the presence of peroxide. One stress-associated protein, peroxide resistance protein (Dpr), has been studied for its role in resistance of group A streptococcus to hydrogen peroxide, but the protective mechanism exerted by Dpr is not clear. The expression of Dpr is under perR (peroxide stress response regulator) control. However, the exact molecular mechanism of PerR regulation of Dpr is not clear. The aim of this study was to characterize the dpr gene and its role in different stresses, and to determine the regulation of Dpr by PerR. The dpr deletion mutant was constructed by double cross-over mutagenesis. The mutant was more sensitive to H2O2 and complementation could partially restore the defect in the mutant. Pretreatment with the iron-chelator DFOM rescued the survival activity of the mutant under oxidative stress. The dpr mutant also showed low survival rate in the long-term stationary phase, when treated with extreme acids, and under alkaline pH conditions when compared to the wild-type strain. The growth curve of the dpr mutant was slower than that of the wild-type strain in the iron-limiting condition. The dpr mutant showed high sensitivity to iron and zinc stress but not manganese, copper, nickel, and calcium. The recombinant Dpr protein was purified and showed iron-binding activity, whereas no DNA binding activity was found. The profile of Dpr expression performed by Western blot assay revealed growth-phase dependency under normal culture conditions. Dpr expression decreased under iron-restricted conditions, whereas iron, zinc, nickel, and hydrogen peroxide induced its expression. The perR mutant does not induce Dpr as well when exposed to environmental signals. Increased iron and hydrogen peroxide concentrations decreased PerR binding to the promoter region of the dpr gene. Moreover, site-directed mutations at predicted zinc binding sites (C104 and C144) of recombinant PerR proteins decreased their zinc-binding activities. The regulation of Dpr by environmental signals could be complemented with plasmids expressing wild-type PerR but not PerRC104S or PerRC144S in the perR mutants. Strains expressed PerRC104S or PerRC144S were also attenuated in their survival in human whole blood. Together, these data conclude that Dpr confers protection from hydrogen peroxide stress presumably by preventing the Fenton reaction. The regulation of Dpr by environmental signals is mediated by PerR directly. Furthermore, the zinc-binding site is not only necessary for PerR functions but also important for GAS survival in human whole blood.

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