革兰氏阴性菌血红素转运系统结构及功能特点

铁是大多数生物包括细菌生存的必需营养元素．对于感染宿主的致病细菌,血红素(heme/haem)可作为一种主要的铁来源．血红素转运系统在革兰氏阴性菌和革兰氏阳性菌中均有发现和鉴定,其转运机制在革兰氏阴性菌中有较为深入研究．革兰氏阴性菌血红素转运系统主要由分泌于细胞外的血红素载体(hemophore)、血红素受体、TonB ExbB ExbD复合物、ABC转运体、血红素降解蛋白和调控蛋白等结构单元组成．对参与该系统的各个蛋白结构特点以及它们之间的相互作用机制的讨论,有助于对病原菌致病机制的深入研究和抗菌新药的研发．     

铁摄取调节蛋白Fur功能和作用模式的研究进展

铁是大多数生物必需的微量元素,在健康和疾病,尤其是宿主-病原菌互作过程中发挥着至关重要的作用.细菌胞内铁离子浓度的高低不仅是调节自身高亲和力铁运输系统表达的信号,更是病原菌产生毒素和其他必要毒力因子的关键调控因素.而另一方面,超负荷的铁也会导致致命的细胞毒性.因此,生物体内铁稳态的维持受到严格控制,其中以铁摄取调节蛋白(ferric uptake regulator,Fur)的作用最为显著,其调控网络涵盖了细菌生命活动的各个方面.本综述将基于Fur的生物学功能,围绕其家族分类、结构特点和差异、调控网络和调控机制等方面进行总结和分析,以期为Fur和铁稳态调节等研究提供参考.     

革兰氏阳性菌群体感应系统研究进展

细菌利用群体感应系统进行细菌间以及细菌与宿主间的交流,革兰氏阳性与阴性菌的群体感应系统差异显著,阳性菌的群体感应系统主要由寡肽类信号分子和受体蛋白组成,对细菌致病性等相关生理特性具有重要作用。就常见的革兰氏阳性菌：蜡样芽孢杆菌、枯草芽孢杆菌、金黄色葡萄球菌和肺炎链球菌的群体感应系统的基因组成、信号分子及其调控机制特点的研究进行了总结,对群体感应系统在细菌营养吸收、生物膜形成、毒力因子和孢子产生等重要生理活动的调节机制进行了重点阐述,为革兰氏阳性菌群体感应的相关研究提供了有益参考。     

鸭疫里默氏杆菌铁离子代谢机制研究进展

铁离子是大多数细菌生存所必需的一种营养物质,但过多的铁离子会通过芬顿反应产生的活性氧对细菌造成损伤。因此,细菌通过摄取、调控、螯合、外排等机制维持体内铁离子的稳态。鸭疫里默氏杆菌(Riemerella anatipestifer)是一种最新被归类于威克斯菌科里氏杆菌属的革兰氏阴性菌。该菌主要感染禽类,参与该菌的铁离子代谢基因具有特别之处。本文对鸭疫里默氏杆菌铁离子代谢机制研究进展进行了系统总结和阐述,包括该菌的TonB系统、TonB依赖性受体、Fur蛋白及Dps蛋白等在铁离子转运、调控、螯合中的功能,以及以上蛋白在鸭疫里默氏杆菌致病中的作用,以期更全面地理解鸭疫里默氏杆菌铁代谢机制,并为进一步深入研究该菌铁离子代谢提供理论依据和参考。     

细菌金属离子外排系统及金属稳态调控

铁、铜、锌、锰等金属离子是各类生物体生存和增殖所必需的微量元素,可影响生物体内蛋白酶活性、免疫反应、生理过程和抗感染机制。细菌感染过程中,宿主可通过限制或提高体内环境中金属离子的浓度来抑制细菌增殖,与此同时,细菌进化出各种转运系统以适应宿主体内金属离子水平的变化。由于不同细菌的金属离子外排系统在结构和生化特性上存在变异,它们呈现出独特的金属离子外排模式。本文根据现有文献报道及本团队研究结果,对铁、铜、锌和锰离子的细菌外排系统进行讨论和总结,旨在综述目前对细菌金属离子稳态调控机制研究进展的认识,为深入理解细菌金属稳态调控相关机制提供参考。     

低氧与铁代谢相关蛋白

氧和铁这两种元素对生命活动十分重要. 低氧诱导因子(hypoxia-inducible factors, HIFs)作为转录因子,参与一系列靶基因的表达调控以适应低氧. 铁参与 DNA合成、氧气运输、代谢反应等多种细胞活动,过量游离铁会通过Haber-Weiss或 Fenton反应产生毒性自由基. 细胞通过与铁吸收、存储和利用有关的多种铁代谢相 关蛋白之间的协同作用来维持铁稳态. 与铁稳态相关的一些基因是HIFs的靶基因或 者间接受低氧调控,包括转铁蛋白、转铁蛋白受体、二价金属转运体1、铁调素、膜 铁转运蛋白、血浆铜蓝蛋白、铁蛋白等,而胞内铁浓度的改变能影响HIFs的表达. 本文就低氧与铁代谢相关蛋白的关系,尤其是低氧对铁代谢相关蛋白的调节作一综 述.     

革兰氏阴性菌脂蛋白Lol系统转运蛋白的功能及表面展示分泌机制

细菌脂蛋白是细胞膜的重要组成成分,在革兰氏阴性菌的生理及致病性中扮演着重要的角色。革兰氏阴性菌中已知负责胞内脂蛋白转运的是Lol(Localization of lipoprotein)系统。该系统识别成熟脂蛋白的分泌信号,将外膜脂蛋白转运并定位于细胞外膜内侧。近年来的研究发现,跨细胞外膜进行表面展示的脂蛋白实际上在革兰氏阴性菌中广泛存在,其分泌机制开始成为研究热点。为了对革兰氏阴性菌中脂蛋白分泌机制的研究现状有一个系统全面的了解,本文概述了脂蛋白转运过程中Lol系统5个转运蛋白的功能与保守性、不同细菌中脂蛋白分泌信号的差异以及表面展示脂蛋白可能的分泌机制。     

白念珠菌铁稳态调控网络研究进展

铁是绝大多数生物生长和代谢过程中必需的营养元素。尽管自然界中铁元素含量非常丰富,但是其生物可利用性却很低。作为一种人体常见的条件致病真菌,白念珠菌在漫长的进化过程中形成了复杂的铁稳态调控网络,能够应答环境中铁浓度的变化,增强菌株对环境的适应力。结合课题组研究工作,简要综述近几年关于铁代谢表达调控途径的研究进展,主要关注白念珠菌在环境铁匮乏条件下铁获得和调控策略,揭示白念珠菌体内铁离子摄取、转运、储存和利用机制。     

膜铁转运蛋白1，铁调素的靶分子？

膜铁转运蛋白1是重要的跨膜铁输出分子,主要分布于十二指肠和单核巨噬系统的细胞膜上,参与机体的肠铁吸收和巨噬细胞对铁的再循环等过程。铁调素是调节机体铁代谢平衡的激素,机体通过肝脏分泌的铁调素对铁转运相关蛋白的表达进行调控,从而实现机体自身的铁稳态。最新研究显示,铁调素的靶分子可能是膜铁转运蛋白1,它通过直接的作用引起膜铁转运蛋白1的内化(internalization)、降解,从而调节其在细胞膜上的表达量,进而控制肠铁吸收和巨噬细胞对铁的再循环过程,以维持机体的铁稳态。     

Hepcidin与疾病关系和其临床意义的研究进展

铁是人体必需的微量元素,是血红蛋白、肌红蛋白及多种酶的重要组成成分,广泛地参与氧气输运、氧化还原反应、细胞增殖与分化、基因表达调控等基本生命过程。机体铁稳态对生命体新陈代谢的平衡起着至关重要的作用。铁稳态依赖铁吸收、转运和储存、再循环利用等代谢过程共同调节。铁调素（Hepcidin）是铁代谢调节中最关键的调节分子,成熟的铁调素是一个由25个氨基酸组成的功能性小肽类激素,可以通过调节小肠上皮细胞和巨噬细胞表面的相关铁转运蛋白来调控机体内铁的储存和利用。铁调素同时受到机体铁水平的反馈,免疫应答和红细胞生成等因素的共同调节。许多铁代谢疾病、炎症和各种原因引起的贫血与铁调素的异常表达相关。因此,对于铁调素的检测不但可以反映机体的铁代谢状况,结合其他临床指标还能够辅助诊断和有针对性地检测相关疾病的治疗效果。     

Anaerobic and aerobic oxidation of ferrous iron at neutral pH by chemoheterotrophic nitrate-reducing bacteria

Nine out of ten anaerobic enrichment cultures inoculated with sediment samples from various freshwater, brackish-water, and marine sediments exhibited ferrous iron oxidation in mineral media with nitrate and an organic cosubstrate at pH 7.2 and 30° C. Anaerobic nitrate-dependent ferrous iron oxidation was a biological process. One strain isolated from brackish-water sediment (strain HidR2, a motile, nonsporeforming, gram-negative rod) was chosen for further investigation of ferrous iron oxidation in the presence of acetate as cosubstrate. Strain HidR2 oxidized between 0.7 and 4.9 mM ferrous iron aerobically and anaerobically at pH 7.2 and 30° C in the presence of small amounts of acetate (between 0.2 and 1.1 mM). The strain gained energy for growth from anaerobic ferrous iron oxidation with nitrate, and the ratio of iron oxidized to acetate provided was constant at limiting acetate supply. The ability to oxidize ferrous iron anaerobically with nitrate at approximately pH 7 appears to be a widespread capacity among mesophilic denitrifying bacteria. Since nitrate-dependent iron oxidation closes the iron cycle within the anoxic zone of sediments and aerobic iron oxidation enhances the reoxidation of ferrous to ferric iron in the oxic zone, both processes increase the importance of iron as a transient electron carrier in the turnover of organic matter in natural sediments. Received: 24 April 1997 / Accepted: 22 September 1997     

The influence of lactoferrin, orally administered, on systemic iron homeostasis in pregnant women suffering of iron deficiency and iron deficiency anaemia

Iron is a fundamental element for humans as it represents an essential component of many proteins and enzymes. However, this element can also be toxic when present in excess because of its ability to generate reactive oxygen species. This dual nature imposes a tight regulation of iron concentration in the body. In humans, systemic iron homeostasis is mainly regulated at the level of intestinal absorption and, until now, no regulated pathways for the excretion of iron have been found. The regulation and maintenance of systemic iron homeostasis is critical to human health. Excessive iron absorption leads to iron-overload in parenchyma, while low iron absorption leads to plasma iron deficiency, which manifests as hypoferremia (iron deficiency, ID) and ID anaemia (IDA). ID and IDA are still a major health problem in pregnant women. To cure ID and IDA, iron supplements are routinely prescribed. The preferred treatment of ID/IDA, consisting in oral administration of iron as ferrous sulphate, often fails to exert significant effects on hypoferremia and may also cause adverse effects. Lactoferrin (Lf), an iron-binding glycoprotein abundantly found in exocrine secretions of mammals, is emerging as an important regulator of systemic iron homeostasis. Recent data suggest that this natural compound, capable of interacting with the most important components of iron homeostasis, may represent a valuable alternative to iron supplements in the prevention and cure of pregnancy-associated ID and IDA. In this review, recent advances in the molecular circuits involved in the complex cellular and systemic iron homeostasis will be summarised. The role of Lf in curing ID and IDA in pregnancy and in the maintenance of iron homeostasis will also be discussed. Understanding these mechanisms will provide the rationale for the development of novel therapeutic alternatives to ferrous sulphate oral administration in the prevention and cure of ID and IDA.     

The ‘Checkmate’ for Iron Between Human Host and Invading Bacteria: Chess Game Analogy

Iron is an essential nutrient for all living organisms with critical roles in many biological processes. The mammalian host maintains the iron requirements by dietary intake, while the invading pathogenic bacteria compete with the host to obtain those absorbed irons. In order to limit the iron uptake by the bacteria, the human host employs numerous iron binding proteins and withholding defense mechanisms that capture iron from the microbial invaders. To counteract, the bacteria cope with the iron limitation imposed by the host by expressing various iron acquisition systems, allowing them to achieve effective iron homeostasis. The armamentarium used by the human host and invading bacteria, leads to the dilemma of who wins the ultimate war for iron.     

Interplay between ferritin metabolism, reactive oxygen species and nitric oxide

 The biological relevance of each of the three inorganic species – iron, oxygen, and nitric oxide (NO) – is crucial. Moreover, their metabolic pathways cross each other and thus create a complex network of connections responsible for the regulation of many essential biological processes. The iron storage protein ferritin, one of the main regulators of iron homeostasis, influences oxygen and NO metabolism. Here, examples are given of the biological interactions of the ferritin molecule (ferritin iron and ferritin shell) with reactive oxygen species (ROS) and NO. The focus is the regulation of ferritin expression by ROS and NO. From these data, ferritin emerges as an important cytoprotective component of the cellular response to ROS and NO. Also, by its ability to alter the amount of intracellular "free" iron, ferritin may affect the metabolism of ROS and NO. It is proposed that this putative activity of ferritin may constitute a missing link in the regulatory loop between iron, ROS, and NO. Received: 2 January 1997 / Accepted: 9 June 1997     

抗生素诱导革兰阴性菌外膜囊泡产生及发挥生理作用的机制

外膜囊泡是革兰阴性菌分泌的一种球形纳米颗粒,由外膜及其所含成分组成,是细菌在外界压力条件下分泌的具有生理活性的特殊结构。外界压力如抗生素、缺氧等可触发细菌释放外膜囊泡,甚至在正常生长周期中,一些革兰阴性菌也会释放囊泡。外膜囊泡与细菌的多种生理过程相关,如应激反应、毒素传递、致病、细胞间通讯、免疫调节、基因水平转移及维持微生物群稳态等。在使用抗生素治疗过程中,尤其是当人体微生物群处于低剂量抗生素环境时,细菌会大量分泌外膜囊泡。在肠道中,外膜囊泡释放后会通过多种机制刺激肠道而引发多种炎症。本文综述了外膜囊泡的产生、结构及生理作用,提出抗生素治疗不但会破坏人体正常菌群而导致菌群失调,还会诱导细菌产生大量外膜囊泡而引发慢性炎症。噬菌体治疗不破坏正常菌群,特异性杀灭细菌时也不引起外膜囊泡的产生,因此开发使用噬菌体靶向治疗细菌感染将大大减少不良反应。     

Molecular and cellular characterization of transferrin receptor 2

Iron is an essential component of many biological processes. However, an excess of iron in the body is also toxic; thus, the levels of this element are tightly regulated. Our knowledge of the mechanism by which iron levels are maintained has been bolstered by the dramatic increase in the discovery of novel molecules implicated in iron homeostasis. The transferrin receptor-transferrin pathway is the main mechanism by which cells take up iron. The recently identified homolog of transferrin receptor, its characterization and its role in iron metabolism is the subject of this review.     

铁摄取调节子在细菌铁离子代谢中的调节及其机制

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。     

细菌铁离子摄取系统与宿主免疫

铁是绝大多数细菌生存所必需的营养物质,参与了许多重要的生命过程。病原菌为了在宿主体内生长繁殖建立感染,进化出了多种从宿主体内摄取铁元素的机制。但过量的铁也会通过Fenton反应对细胞产生毒性,所以铁的摄取必须受到严格的调控。宿主为抵抗感染采取多种手段限制病原菌对于自身铁的利用,同时铁摄取系统也可以作为抗菌治疗的靶点。     

Nitric oxide, nitrosyl iron complexes, ferritin and frataxin: A well equipped team to preserve plant iron homeostasis

Iron is a key element in plant nutrition. Iron deficiency as well as iron overload results in serious metabolic disorders that affect photosynthesis, respiration and general plant fitness with direct consequences on crop production.More than 25% of the cultivable land possesses low iron availability due to high pH (calcareous soils). Plant biologists are challenged by this concern and aimed to find new avenues to ameliorate plant responses and keep iron homeostasis under control even at wide range of iron availability in various soils. For this purpose, detailed knowledge of iron uptake, transport, storage and interactions with cellular compounds will help to construct a more complete picture of its role as essential nutrient. In this review, we summarize and describe the recent findings involving four central players involved in keeping cellular iron homeostasis in plants: nitric oxide, ferritin, frataxin and nitrosyl iron complexes. We attempt to highlight the interactions among these actors in different scenarios occurring under iron deficiency or iron overload, and discuss their counteracting and/or coordinating actions leading to the control of iron homeostasis.