Su Shengchang, Panmanee Warunya, Wilson Jeffrey J, Mahtani Harry K, Li Qian, Vanderwielen Bradley D, Makris Thomas M, Rogers Melanie, McDaniel Cameron, Lipscomb John D, Irvin Randall T, Schurr Michael J, Lancaster Jack R, Kovall Rhett A, Hassett Daniel J
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, Ohio, United States of America.
Departments of Anesthesiology, Cell, Developmental and Integrative Biology, and Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
PLoS One. 2014 Mar 24;9(3):e91813. doi: 10.1371/journal.pone.0091813. eCollection 2014.
Pseudomonas aeruginosa (PA) is a common bacterial pathogen, responsible for a high incidence of nosocomial and respiratory infections. KatA is the major catalase of PA that detoxifies hydrogen peroxide (H2O2), a reactive oxygen intermediate generated during aerobic respiration. Paradoxically, PA displays elevated KatA activity under anaerobic growth conditions where the substrate of KatA, H2O2, is not produced. The aim of the present study is to elucidate the mechanism underlying this phenomenon and define the role of KatA in PA during anaerobiosis using genetic, biochemical and biophysical approaches. We demonstrated that anaerobic wild-type PAO1 cells yielded higher levels of katA transcription and expression than aerobic cells, whereas a nitrite reductase mutant ΔnirS produced ∼50% the KatA activity of PAO1, suggesting that a basal NO level was required for the increased KatA activity. We also found that transcription of the katA gene was controlled, in part, by the master anaerobic regulator, ANR. A ΔkatA mutant and a mucoid mucA22 ΔkatA bacteria demonstrated increased sensitivity to acidified nitrite (an NO generator) in anaerobic planktonic and biofilm cultures. EPR spectra of anaerobic bacteria showed that levels of dinitrosyl iron complexes (DNIC), indicators of NO stress, were increased significantly in the ΔkatA mutant, and dramatically in a ΔnorCB mutant compared to basal levels of DNIC in PAO1 and ΔnirS mutant. Expression of KatA dramatically reduced the DNIC levels in ΔnorCB mutant. We further revealed direct NO-KatA interactions in vitro using EPR, optical spectroscopy and X-ray crystallography. KatA has a 5-coordinate high spin ferric heme that binds NO without prior reduction of the heme iron (Kd ∼6 μM). Collectively, we conclude that KatA is expressed to protect PA against NO generated during anaerobic respiration. We proposed that such protective effects of KatA may involve buffering of free NO when potentially toxic concentrations of NO are approached.
铜绿假单胞菌(PA)是一种常见的细菌病原体,是医院感染和呼吸道感染高发的原因。KatA是PA的主要过氧化氢酶,可将过氧化氢(H2O2)解毒,H2O2是有氧呼吸过程中产生的一种活性氧中间体。矛盾的是,PA在厌氧生长条件下表现出升高的KatA活性,而此时KatA的底物H2O2并未产生。本研究的目的是阐明这一现象背后的机制,并使用遗传、生化和生物物理方法确定KatA在PA厌氧状态下的作用。我们证明,厌氧野生型PAO1细胞产生的katA转录和表达水平高于需氧细胞,而亚硝酸盐还原酶突变体ΔnirS产生的KatA活性约为PAO1的50%,这表明基础NO水平是KatA活性增加所必需的。我们还发现,katA基因的转录部分受主要厌氧调节因子ANR的控制。ΔkatA突变体和黏液型mucA22 ΔkatA细菌在厌氧浮游和生物膜培养中对酸化亚硝酸盐(一种NO发生器)表现出更高的敏感性。厌氧细菌的电子顺磁共振光谱表明,与PAO1和ΔnirS突变体中DNIC的基础水平相比,ΔkatA突变体中作为NO应激指标的二亚硝基铁配合物(DNIC)水平显著增加,而在ΔnorCB突变体中则急剧增加。KatA的表达显著降低了ΔnorCB突变体中的DNIC水平。我们进一步使用电子顺磁共振、光谱学和X射线晶体学在体外揭示了直接的NO-KatA相互作用。KatA具有一个五配位的高自旋铁血红素,可在不预先还原血红素铁的情况下结合NO(解离常数约为6 μM)。总的来说,我们得出结论,KatA的表达是为了保护PA免受厌氧呼吸过程中产生的NO的影响。我们提出,KatA的这种保护作用可能涉及在接近潜在有毒浓度的NO时对游离NO的缓冲。