铁摄取调节子在细菌铁离子代谢中的调节及其机制
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摘要
铁离子是大多数细菌生存所必需的营养物质,但是过多的铁离子通过芬顿反应产生的活性氧(reactive oxygen species,ROS)对细菌造成损伤。因此,细菌必须严格控制体内铁离子浓度。铁摄取调节子(ferric uptake regulator,Fur)是细菌铁离子代谢中最重要的调节子。Fur通过抑制或者激活基因的转录,来调节与铁摄取、利用和储存相关的基因,维持胞内铁离子浓度动态平衡。此外,Fur还参与细菌的氧化应激、抗酸能力、毒力和能量代谢等多种生物过程的调节。本文对Fur参与的生物过程及调节机制进行介绍,以期为进一步研究其他细菌Fur的调节机制,以及Fur在细菌应对环境变化中所起作用提供参考。
Iron is an essential nutrient for most bacteria to survive,but excessive iron damages the bacteria through the Fenton reaction to produce reactive oxygen species( ROS). Thus,bacteria must strictly control the concentration of iron in vivo. Ferric uptake regulator( Fur) is the most important regulator of iron metabolism in bacteria. Fur regulates the genes involved in iron uptake,utilization and storage by repressing or activating gene transcription and balancing intracellular iron concentration. In addition,Fur is also involved in the regulation of various biological processes such as bacterial oxidative stress,acid resistance,virulence,energy metabolism and so on. In this review,we mainly discuss the biological processes regulated by Fur and its mechanism. It will provide a reference for further mechanistic studies on Fur and its role in the bacterial response to environmental changes.
Iron is an essential nutrient for most bacteria to survive,but excessive iron damages the bacteria through the Fenton reaction to produce reactive oxygen species( ROS). Thus,bacteria must strictly control the concentration of iron in vivo. Ferric uptake regulator( Fur) is the most important regulator of iron metabolism in bacteria. Fur regulates the genes involved in iron uptake,utilization and storage by repressing or activating gene transcription and balancing intracellular iron concentration. In addition,Fur is also involved in the regulation of various biological processes such as bacterial oxidative stress,acid resistance,virulence,energy metabolism and so on. In this review,we mainly discuss the biological processes regulated by Fur and its mechanism. It will provide a reference for further mechanistic studies on Fur and its role in the bacterial response to environmental changes.
引文
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[40]Ernst FD,Homuth G,Stoof J,et al.Iron-responsive regulation of the Helicobacter pylori iron-cofactored superoxide dismutase Sod B is mediated by Fur[J].J Bacteriol,2005,187(11):3687-3692
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[42]Hall HK,Foster JW.The role of fur in the acid tolerance response of Salmonella typhimurium is physiologically and genetically separable from its role in iron acquisition[J].J Bacteriol,1996,178(19):5683-5691
[43]Gancz H,Censini S,Merrell DS.Iron and p H homeostasis intersect at the level of Fur regulation in the gastric pathogen Helicobacter pylori[J].Infect Immun,2006,74(1):602-614
[44]Oglesby AG,Murphy ER,Iyer VR,et al.Fur regulates acid resistance in Shigella flexneri via Ryh B and yde P[J].Mol Microbiol,2005,58(5):1354-1367
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[2]Lill R.Function and biogenesis of iron-sulphur proteins[J].Nature,2009,460(7257):831-838
[3]Andrews SC,Robinson AK,Rodríguez-Qui1ones F.Bacterial iron homeostasis[J].FEMS Microbiol Rev,2003,27(2-3):215-237
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[5]Carpenter BM,Whitmire JM,Merrell DS.This is not your mother’s repressor:the complex role of Fur in pathogenesis[J].Infect Immun,2009,77(7):2590-2601
[6]李岭,刘马峰,程安春.革兰氏阴性菌血红素载体蛋白Hemophore的结构及作用机制[J].微生物学通报(Li L,Liu MF,Cheng AC.Structure and function reveal of the hemophore in Gram-negative bacteria[J].Microbiol China),2015,42(7):1358-1365
[7]Weinberg ED.Iron and susceptibility to infectious disease[J].Science,1974,184(4140):952-956
[8]Martínez D,Oyarzún R,Pontigo JP,et al.Nutritional immunity triggers the modulation of iron metabolism genes in the subantarctic notothenioid eleginops maclovinusin response to piscirickettsia salmonis[J].Front Immunol,2017,8:1153
[9]张利,刘马峰,程安春.铁载体-抗生素耦合物:一种新型的抗菌制剂[J].微生物学通报(Zhang L,Liu MF,Cheng AC.Siderophore-antibiotic conjugates:the new antimicrobial agents[J].Microbiol China),2016,43(7):1598-1604
[10]冯言,刘马峰,程安春.革兰氏阴性菌亚铁离子转运系统的组成及作用机制[J].微生物学报(Feng Y,Liu MF,Cheng AC.Component and functional mechanism of the ferrous iron acquisition system in gram-negative bacteria-A review[J].Acta Microbiol Sin),2016,56(7):1061-1069
[11]程兴军,刘马峰,程安春.革兰氏阴性菌血红素转运系统结构及功能特点[J].中国生物化学与分子生物学报(Cheng XJ,Liu MF,Cheng AC.Structure and functional properies of the heme acquistion system in Gram-negative bacteria[J].Chin J Biochem Mol Biol),2014,30(9):848-855
[12]Fenton HJH.Oxidation of tartaric acid in presence of iron[J].J Chem Soc Trans,1894,65:899-910
[13]Imlay JA,Chin SM,Linn S.Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro[J].Science,1988,240(4852):640-642
[14]Beauchene NA,Mettert EL,Moore LJ,et al.O2availability impacts iron homeostasis in Escherichia coli[J].Proc Natl Acad Sci U S A,2017,114(46):12261-12266
[15]Fillat MF.The FUR(ferric uptake regulator)superfamily:diversity and versatility of key transcriptional regulators[J].Arch Biochem Biophys,2014,546:41-51
[16]Deng Z,Wang Q,Liu Z,et al.Mechanistic insights into metal ion activation and operator recognition by the ferric uptake regulator[J].Nat Commun,2015,6:7642
[17]Yu C,Genco CA.Fur-mediated global regulatory circuits in pathogenic neisseria species[J].J Bacteriol,2012,194(23):6372-6381
[18]D’Autréaux B,Pecqueur L,Gonzalez de Peredo A,et al.Reversible redox-and zinc-dependent dimerization of the Escherichia coli fur protein[J].Biochemistry,2007,46(5):1329-1342
[19]Lewin AC,Doughty PA,Flegg L,et al.The ferric uptake regulator of Pseudomonas aeruginosa has no essential cysteine residues and does not contain a structural zinc ion[J].Microbiology,2002,148(Pt8):2449-2456
[20]Dian C,Vitale S,Leonard GA,et al.The structure of the Helicobacter pylori ferric uptake regulator Fur reveals three functional metal binding sites[J].Mol Microbiol,2011,79(5):1260-1275
[21]de Lorenzo V,Giovannini F,Herrero M,et al.Metal ion regulation of gene expression:Fur repressor-operator interaction at the promoter region of the aerobactin system of p Col V-K30[J].J Mol Biol,1988,203(4):875-884
[22]Fuangthong M,Helmann JD.Recognition of DNA by three ferric uptake regulator(Fur)homologs in Bacillus subtilis[J].J Bacteriol,2003,185(21):6348-6357
[23]Pich OQ,Carpenter BM,Gilbreath JJ,et al.Detailed analysis of Helicobacter pylori Fur-regulated promoters reveals a Fur box core sequence and novel Fur-regulated genes[J].Mol Microbiol,2012,84(5):921-941
[24]Pohl E,Haller JC,Mijovilovich A,et al.Architecture of a protein central to iron homeostasis:crystal structure and spectroscopic analysis of the ferric uptake regulator[J].Mol Microbiol,2003,47(4):903-915
[25]岳慧贤,程安春,刘马峰.部分革兰氏阴性菌胞外功能sigma因子结构与调控铁离子的利用机制[J].中国生物化学与分子生物学报(Yue HX,Cheng AC,Liu MF.The structure and regulation of ECF sigma factor in iron acquisition of some Gramnegative bacteria[J].Chin J Biochem Mol Biol),2017,33(2):108-115
[26]Porcheron G,Garénaux A,Proulx J,et al.Iron,copper,zinc,and manganese transport and regulation in pathogenic Enterobacteria:correlations between strains,site of infection and the relative importance of the different metal transport systems for virulence[J].Front Cell Infect Microbiol,2013,3:90
[27]Vanderpool CK,Armstrong SK.Integration of environmental signals controls expression of Bordetella heme utilization genes[J].J Bacteriol,2004,186(4):938-948
[28]Seo SW,Kim D,Latif H,et al.Deciphering Fur transcriptional regulatory network highlights its complex role beyond iron metabolism in Escherichia coli[J].Nat Commun,2014,5:4910
[29]Bereswill S,Greiner S,van Vliet AH,et al.Regulation of ferritin-mediated cytoplasmic iron storage by the ferric uptake regulator homolog(Fur)of Helicobacter pylori[J].J Bacteriol,2000,182(21):5948-5953
[30]Fang FC.Antimicrobial reactive oxygen and nitrogen species:concepts and controversies[J].Nat Rev Microbiol,2004,2(10):820-832
[31]Troxell B,Hassan HM.Transcriptional regulation by Ferric Uptake Regulator(Fur)in pathogenic bacteria[J].Front Cell Infect Microbiol,2013,3:59
[32]Husain M,Jones-Carson J,Liu L,et al.Ferric uptake regulatordependent antinitrosative defenses in Salmonella enterica serovar typhimurium pathogenesis[J].Infect Immun,2014,82(1):333-340
[33]Hassett DJ,Sokol PA,Howell ML,et al.Ferric uptake regulator(Fur)mutants of Pseudomonas aeruginosa demonstrate defective siderophore-mediated iron uptake,altered aerobic growth,and decreased superoxide dismutase and catalase activities[J].J Bacteriol,1996,178(14):3996-4003
[34]Gao H,Zhou D,Li Y,et al.The iron-responsive Fur regulon in Yersinia pestis[J].J Bacteriol,2008,190(8):3063-3075
[35]Hoerter JD,Arnold AA,Ward CS,et al.Reduced hydroperoxidase(HPI and HPII)activity in the Deltafur mutant contributes to increased sensitivity to UVA radiation in Escherichia coli[J].J Photochem Photobiol B,2005,79(2):151-157
[36]Vasileva D,Janssen H,H9nicke D,et al.Effect of iron limitation and fur gene inactivation on the transcriptional profile of the strict anaerobe Clostridium acetobutylicum[J].Microbiology,2012,158(Pt7):1918-1929
[37]Storz G,Opdyke JA,Zhang A.Controlling mRNA stability and translation with small,noncoding RNAs[J].Curr Opin Microbiol,2004,7(2):140-144
[38]Porcheron G,Habib R,Houle S,et al.The small RNA Ryh B contributes to siderophore production and virulence of uropathogenic Escherichia coli[J].Infect Immun,2014,82(12):5056-5068
[39]Dubrac S,Touati D.Fur-mediated transcriptional and posttranscriptional regulation of Fe SOD expression in Escherichia coli[J].Microbiology,2002,148(Pt1):147-156
[40]Ernst FD,Homuth G,Stoof J,et al.Iron-responsive regulation of the Helicobacter pylori iron-cofactored superoxide dismutase Sod B is mediated by Fur[J].J Bacteriol,2005,187(11):3687-3692
[41]Porcheron G,Dozois CM.Interplay between iron homeostasis and virulence:Fur and Ryh B as major regulators of bacterial pathogenicity[J].Vet Microbiol,2015,179(1-2):2-14
[42]Hall HK,Foster JW.The role of fur in the acid tolerance response of Salmonella typhimurium is physiologically and genetically separable from its role in iron acquisition[J].J Bacteriol,1996,178(19):5683-5691
[43]Gancz H,Censini S,Merrell DS.Iron and p H homeostasis intersect at the level of Fur regulation in the gastric pathogen Helicobacter pylori[J].Infect Immun,2006,74(1):602-614
[44]Oglesby AG,Murphy ER,Iyer VR,et al.Fur regulates acid resistance in Shigella flexneri via Ryh B and yde P[J].Mol Microbiol,2005,58(5):1354-1367
[45]Hassett DJ,Howell ML,Ochsner UA,et al.An operon containing fum C and sod A encoding fumarase C and manganese superoxide dismutase is controlled by the ferric uptake regulator in Pseudomonas aeruginosa:fur mutants produce elevated alginate levels[J].J Bacteriol,1997,179(5):1452-1459
[46]Ochsner UA,Vasil ML.Gene repression by the ferric uptake regulator in Pseudomonas aeruginosa:cycle selection of ironregulated genes[J].Proc Natl Acad Sci U S A,1996,93(9):4409-4414
[47]Yu C,Genco CA.Fur-mediated global regulatory circuits in pathogenic Neisseria species[J].J Bacteriol,2012,194(23):6372-6381
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