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Cytochrome bd and Gaseous Ligands in Bacterial Physiology. 细胞色素bd和气体配体在细菌生理中的作用。
2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-01-01 Epub Date: 2017-07-10 DOI: 10.1016/bs.ampbs.2017.05.002
Elena Forte, Vitaliy B Borisov, João B Vicente, Alessandro Giuffrè

Cytochrome bd is a unique prokaryotic respiratory terminal oxidase that does not belong to the extensively investigated family of haem-copper oxidases (HCOs). The enzyme catalyses the four-electron reduction of O2 to 2H2O, using quinols as physiological reducing substrates. The reaction is electrogenic and cytochrome bd therefore sustains bacterial energy metabolism by contributing to maintain the transmembrane proton motive force required for ATP synthesis. As compared to HCOs, cytochrome bd displays several distinctive features in terms of (i) metal composition (it lacks Cu and harbours a d-type haem in addition to two haems b), (ii) overall three-dimensional structure, that only recently has been solved, and arrangement of the redox cofactors, (iii) lesser energetic efficiency (it is not a proton pump), (iv) higher O2 affinity, (v) higher resistance to inhibitors such as cyanide, nitric oxide (NO) and hydrogen sulphide (H2S) and (vi) ability to efficiently metabolize potentially toxic reactive oxygen and nitrogen species like hydrogen peroxide (H2O2) and peroxynitrite (ONOO-). Compelling evidence suggests that, beyond its bioenergetic role, cytochrome bd plays multiple functions in bacterial physiology and affords protection against oxidative and nitrosative stress. Relevant to human pathophysiology, thanks to its peculiar properties, the enzyme has been shown to promote virulence in several bacterial pathogens, being currently recognized as a target for the development of new antibiotics. This review aims to give an update on our current understanding of bd-type oxidases with a focus on their reactivity with gaseous ligands and its potential impact on bacterial physiology and human pathophysiology.

细胞色素bd是一种独特的原核呼吸末端氧化酶,不属于广泛研究的血红铜氧化酶(HCOs)家族。该酶以喹啉为生理还原底物,催化O2的四电子还原为2H2O。该反应是电致的,因此细胞色素bd通过维持ATP合成所需的跨膜质子动力来维持细菌的能量代谢。与HCOs相比,细胞色素bd在以下方面表现出几个独特的特征:(i)金属组成(它缺乏Cu,除了两个血红素b之外还有一个d型血红素),(ii)整体三维结构(直到最近才被解决)和氧化还原辅助因子的排列,(iii)较低的能量效率(它不是质子泵),(iv)更高的O2亲和力,(v)对氰化物等抑制剂的抵抗力更高。一氧化氮(NO)和硫化氢(H2S)以及(vi)有效代谢潜在有毒活性氧和氮的能力,如过氧化氢(H2O2)和过氧亚硝酸盐(ONOO-)。令人信服的证据表明,除了其生物能量作用,细胞色素bd在细菌生理中发挥多种功能,并提供抗氧化和亚硝化应激的保护。与人类病理生理学相关,由于其特殊的性质,该酶已被证明可以促进几种细菌病原体的毒力,目前被认为是开发新抗生素的目标。这篇综述旨在更新我们目前对bd型氧化酶的理解,重点关注它们与气体配体的反应性及其对细菌生理和人类病理生理的潜在影响。
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引用次数: 44
Mechanism and Role of Globin-Coupled Sensor Signalling. 珠蛋白耦合传感器信号传导的机制和作用。
2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-01-01 Epub Date: 2017-07-06 DOI: 10.1016/bs.ampbs.2017.05.003
Johnnie A Walker, Shannon Rivera, Emily E Weinert

The discovery of the globin-coupled sensor (GCS) family of haem proteins has provided new insights into signalling proteins and pathways by which organisms sense and respond to changing oxygen levels. GCS proteins consist of a sensor globin domain linked to a variety of output domains, suggesting roles in controlling numerous cellular pathways, and behaviours in response to changing oxygen concentration. Members of this family of proteins have been identified in the genomes of numerous organisms and characterization of GCS with output domains, including methyl accepting chemotaxis proteins, kinases, and diguanylate cyclases, have yielded an understanding of the mechanism by which oxygen controls activity of GCS protein output domains, as well as downstream proteins and pathways regulated by GCS signalling. Future studies will expand our understanding of these proteins both in vitro and in vivo, likely demonstrating broad roles for GCS in controlling oxygen-dependent microbial physiology and phenotypes.

血红素蛋白的珠蛋白偶联传感器(GCS)家族的发现为生物体感知和响应变化的氧水平的信号蛋白和途径提供了新的见解。GCS蛋白由一个与多种输出结构域相连的传感珠蛋白结构域组成,表明其在控制多种细胞通路和响应氧浓度变化的行为中发挥作用。该蛋白家族的成员已经在许多生物体的基因组中被鉴定出来,并且具有输出结构域的GCS的表征,包括甲基接受趋化蛋白、激酶和二胍酸环化酶,已经产生了氧气控制GCS蛋白输出结构域活性的机制,以及由GCS信号调节的下游蛋白和途径。未来的研究将扩大我们对这些蛋白质在体外和体内的理解,可能会证明GCS在控制氧依赖的微生物生理和表型方面的广泛作用。
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引用次数: 19
Manganese in Marine Microbiology. 海洋微生物学中的锰。
2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-01-01 Epub Date: 2017-03-14 DOI: 10.1016/bs.ampbs.2017.01.005
Colleen M Hansel

The importance of manganese in the physiology of marine microbes, the biogeochemistry of the ocean and the health of microbial communities of past and present is emerging. Manganese is distributed widely throughout the global ocean, taking the form of an essential antioxidant (Mn2+), a potent oxidant (Mn3+) and strong adsorbent (Mn oxides) sequestering disproportionately high levels of trace metals and nutrients in comparison to the surrounding seawater. Manganese is, in fact, linked to nearly all other elemental cycles and intricately involved in the health, metabolism and function of the ocean's microbiome. Here, we briefly review the diversity of microbes and pathways responsible for the transformation of Mn within the three Mn pools and their distribution within the marine environment. Despite decades of interrogation, we still have much to learn about the players, mechanisms and consequences of the Mn cycle, and new and exciting discoveries are being made at a rapid rate. What is clear is the dynamic and ever-inspiring complexity of reactions involving Mn, and the acknowledgement that microorganisms are the catalytic engine driving the Mn cycle.

锰在海洋微生物生理学、海洋生物地球化学以及过去和现在微生物群落健康方面的重要性正在显现。锰广泛分布在全球海洋中,以必需的抗氧化剂(Mn2+)、强氧化剂(Mn3+)和强吸附剂(Mn氧化物)的形式存在,与周围海水相比,它们隔离了不成比例的高水平微量金属和营养物质。事实上,锰与几乎所有其他元素循环都有联系,并且与海洋微生物群的健康、新陈代谢和功能有着复杂的关系。在此,我们简要回顾了三个锰池中负责锰转化的微生物多样性和途径及其在海洋环境中的分布。尽管经过了几十年的探索,我们对锰循环的参与者、机制和后果仍有很多需要了解的地方,新的令人兴奋的发现正在迅速出现。清楚的是,涉及Mn的反应是动态的、令人鼓舞的复杂性,并且承认微生物是驱动Mn循环的催化引擎。
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引用次数: 44
Preface. 前言。
2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-01-01 DOI: 10.1016/S0065-2911(17)30018-8
Robert K Poole
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引用次数: 0
Metal-Based Combinations That Target Protein Synthesis by Fungi. 以真菌合成蛋白质为目标的金属基组合。
2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-01-01 Epub Date: 2017-02-11 DOI: 10.1016/bs.ampbs.2017.01.001
Cindy Vallières, Simon V Avery

A wide range of fungicides (or antifungals) are used in agriculture and medicine, with activities against a spectrum of fungal pathogens. Unfortunately, the evolution of fungicide resistance has become a major issue. Therefore, there is an urgent need for new antifungal treatments. Certain metals have been used for decades as efficient fungicides in agriculture. However, concerns over metal toxicity have escalated over this time. Recent studies have revealed that metals like copper and chromate can impair functions required for the fidelity of protein synthesis in fungi. This occurs through different mechanisms, based on targeting of iron-sulphur cluster integrity or competition for uptake with amino acid precursors. Moreover, chromate at least acts synergistically with other agents known to target translation fidelity, like aminoglycoside antibiotics, causing dramatic and selective growth inhibition of several fungal pathogens of humans and plants. As such synergy allows the application of decreased amounts of metals for effective inhibition, it lessens concerns about nonspecific toxicity and opens new possibilities for metal applications in combinatorial fungicides targeting protein synthesis.

广泛的杀菌剂(或抗真菌剂)用于农业和医学,具有对抗真菌病原体的活性。不幸的是,杀菌剂耐药性的演变已成为一个主要问题。因此,迫切需要新的抗真菌治疗方法。某些金属作为高效的杀菌剂已经在农业中使用了几十年。然而,在这段时间里,对金属毒性的担忧已经升级。最近的研究表明,铜和铬酸盐等金属会损害真菌中蛋白质合成保真度所需的功能。这通过不同的机制发生,基于铁硫簇完整性的靶向或与氨基酸前体的摄取竞争。此外,铬酸盐至少与其他已知的靶向翻译保真度的药物协同作用,如氨基糖苷类抗生素,对人类和植物的几种真菌病原体产生显著的选择性生长抑制。由于这种协同作用允许使用较少数量的金属进行有效抑制,它减少了对非特异性毒性的担忧,并为金属在靶向蛋白质合成的组合杀菌剂中的应用开辟了新的可能性。
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引用次数: 7
Copper and Antibiotics: Discovery, Modes of Action, and Opportunities for Medicinal Applications. 铜和抗生素:发现、作用方式和医药应用机会。
2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-01-01 Epub Date: 2017-03-18 DOI: 10.1016/bs.ampbs.2017.01.007
Alex G Dalecki, Cameron L Crawford, Frank Wolschendorf

Copper is a ubiquitous element in the environment as well as living organisms, with its redox capabilities and complexation potential making it indispensable for many cellular functions. However, these same properties can be highly detrimental to prokaryotes and eukaryotes when not properly controlled, damaging many biomolecules including DNA, lipids, and proteins. To restrict free copper concentrations, all bacteria have developed mechanisms of resistance, sequestering and effluxing labile copper to minimize its deleterious effects. This weakness is actively exploited by phagocytes, which utilize a copper burst to destroy pathogens. Though administration of free copper is an unreasonable therapeutic antimicrobial itself, due to insufficient selectivity between host and pathogen, small-molecule ligands may provide an opportunity for therapeutic mimicry of the immune system. By modulating cellular entry, complex stability, resistance evasion, and target selectivity, ligand/metal coordination complexes can synergistically result in high levels of antibacterial activity. Several established therapeutic drugs, such as disulfiram and pyrithione, display remarkable copper-dependent inhibitory activity. These findings have led to development of new drug discovery techniques, using copper ions as the focal point. High-throughput screens for copper-dependent inhibitors against Mycobacterium tuberculosis and Staphylococcus aureus uncovered several new compounds, including a new class of inhibitors, the NNSNs. In this review, we highlight the microbial biology of copper, its antibacterial activities, and mechanisms to discover new inhibitors that synergize with copper.

铜是环境和生物体中普遍存在的元素,其氧化还原能力和络合潜力使其对许多细胞功能不可或缺。然而,如果控制不当,这些相同的特性可能对原核生物和真核生物非常有害,破坏许多生物分子,包括DNA、脂质和蛋白质。为了限制游离铜的浓度,所有细菌都发展出了抵抗、螯合和释放不稳定铜的机制,以最大限度地减少其有害影响。吞噬细胞积极利用这一弱点,利用铜爆发摧毁病原体。尽管游离铜本身是一种不合理的治疗性抗菌药物,但由于宿主和病原体之间的选择性不足,小分子配体可能为免疫系统的治疗模拟提供了机会。通过调节细胞进入、复合物稳定性、耐药性逃避和靶向选择性,配体/金属配位复合物可以协同产生高水平的抗菌活性。一些已建立的治疗药物,如双硫仑和吡啶硫酮,显示出显著的铜依赖性抑制活性。这些发现推动了以铜离子为焦点的新药发现技术的发展。针对结核分枝杆菌和金黄色葡萄球菌的铜依赖性抑制剂的高通量筛选发现了几种新化合物,包括一类新的抑制剂NNSN。在这篇综述中,我们重点介绍了铜的微生物生物学、其抗菌活性,以及发现与铜协同作用的新抑制剂的机制。
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引用次数: 77
Haem-Based Sensors of O2: Lessons and Perspectives. 基于血液的O2传感器:经验教训和观点。
2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-01-01 Epub Date: 2017-07-06 DOI: 10.1016/bs.ampbs.2017.05.001
Eduardo H S Sousa, Marie-Alda Gilles-Gonzalez

Haem-based sensors have emerged during the last 15 years as being a large family of proteins that occur in all kingdoms of life. These sensors are responsible mainly for detecting binding of O2, CO and NO and reporting the ligation status to an output domain with an enzymatic or macromolecule-binding property. A myriad of biological functions have been associated with these sensors, which are involved in vasodilation, bacterial symbiosis, chemotaxis and biofilm formation, among others. Here, we critically review several bacterial systems for O2 sensing that are extensively studied in many respects, focusing on the lessons that are important to advance the field.

在过去的15年里,以血液为基础的传感器作为一大家族蛋白质出现在所有生命领域。这些传感器主要负责检测O2, CO和NO的结合,并将连接状态报告给具有酶或大分子结合特性的输出域。无数的生物功能与这些传感器有关,包括血管舒张、细菌共生、趋化性和生物膜形成等。在这里,我们批判性地回顾了在许多方面被广泛研究的几种细菌O2传感系统,重点关注对推进该领域至关重要的经验教训。
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引用次数: 13
Metal Resistance and Its Association With Antibiotic Resistance. 金属耐药性及其与抗生素耐药性的关系。
2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-01-01 Epub Date: 2017-04-03 DOI: 10.1016/bs.ampbs.2017.02.001
Chandan Pal, Karishma Asiani, Sankalp Arya, Christopher Rensing, Dov J Stekel, D G Joakim Larsson, Jon L Hobman

Antibiotic resistance is recognised as a major global threat to public health by the World Health Organization. Currently, several hundred thousand deaths yearly can be attributed to infections with antibiotic-resistant bacteria. The major driver for the development of antibiotic resistance is considered to be the use, misuse and overuse of antibiotics in humans and animals. Nonantibiotic compounds, such as antibacterial biocides and metals, may also contribute to the promotion of antibiotic resistance through co-selection. This may occur when resistance genes to both antibiotics and metals/biocides are co-located together in the same cell (co-resistance), or a single resistance mechanism (e.g. an efflux pump) confers resistance to both antibiotics and biocides/metals (cross-resistance), leading to co-selection of bacterial strains, or mobile genetic elements that they carry. Here, we review antimicrobial metal resistance in the context of the antibiotic resistance problem, discuss co-selection, and highlight critical knowledge gaps in our understanding.

抗生素耐药性被世界卫生组织认定为对公共卫生的主要全球威胁。目前,每年有数十万人死于耐抗生素细菌感染。抗生素耐药性发展的主要驱动因素被认为是在人类和动物中使用、误用和过度使用抗生素。非抗生素化合物,如抗菌杀菌剂和金属,也可能通过共选择促进抗生素耐药性。当抗生素和金属/杀菌剂的耐药基因在同一细胞中共存(共耐药),或单一耐药机制(如外排泵)同时对抗生素和杀菌剂/金属产生耐药性(交叉耐药),导致细菌菌株或它们携带的可移动遗传元件的共同选择时,就可能发生这种情况。在这里,我们回顾了抗生素耐药性问题背景下的抗微生物金属耐药性,讨论了共同选择,并强调了我们理解中的关键知识空白。
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引用次数: 231
Nutritional Immunity and Fungal Pathogenesis: The Struggle for Micronutrients at the Host-Pathogen Interface. 营养免疫和真菌发病机制:在宿主-病原体界面争夺微量营养素。
2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-01-01 Epub Date: 2017-02-16 DOI: 10.1016/bs.ampbs.2017.01.006
Dhara Malavia, Aaron Crawford, Duncan Wilson

All living organisms require certain micronutrients such as iron, zinc, manganese and copper for cellular function and growth. For human pathogens however, the maintenance of metal ion homeostasis is particularly challenging. This is because the mammalian host actively enforces extremes of micronutrient availability on potential microbial invaders-processes collectively termed nutritional immunity. The role of iron sequestration in controlling microbial infections is well established and, more recently, the importance of other metals including zinc, manganese and copper has been recognised. In this chapter, we explore the nutritional immune mechanisms that defend the human body against fungal infections and the strategies that these important pathogens exploit to counteract nutritional immunity and thrive in the infected host.

所有生物体都需要某些微量营养素,如铁、锌、锰和铜,以实现细胞功能和生长。然而,对于人类病原体来说,维持金属离子稳态尤其具有挑战性。这是因为哺乳动物宿主在潜在的微生物入侵过程中积极地强化微量营养素的极端可用性,统称为营养免疫。铁固存在控制微生物感染中的作用已经得到了很好的证实,最近,锌、锰和铜等其他金属的重要性也得到了认可。在本章中,我们探讨了保护人体免受真菌感染的营养免疫机制,以及这些重要病原体用来抵消营养免疫并在感染宿主中茁壮成长的策略。
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引用次数: 40
Transition Metal Homeostasis in Streptococcus pyogenes and Streptococcus pneumoniae. 化脓性链球菌和肺炎链球菌的过渡金属稳态。
2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2017-01-01 Epub Date: 2017-02-20 DOI: 10.1016/bs.ampbs.2017.01.002
Andrew G Turner, Cheryl-Lynn Y Ong, Mark J Walker, Karrera Y Djoko, Alastair G McEwan

Trace metals such as Fe, Mn, Zn and Cu are essential for various biological functions including proper innate immune function. The host immune system has complicated and coordinated mechanisms in place to either starve and/or overload invading pathogens with various metals to combat the infection. Here, we discuss the roles of Fe, Mn and Zn in terms of nutritional immunity, and also the roles of Cu and Zn in metal overload in relation to the physiology and pathogenesis of two human streptococcal species, Streptococcus pneumoniae and Streptococcus pyogenes. S. pneumoniae is a major human pathogen that is carried asymptomatically in the nasopharynx by up to 70% of the population; however, transition to internal sites can cause a range of diseases such as pneumonia, otitis media, meningitis and bacteraemia. S. pyogenes is a human pathogen responsible for diseases ranging from pharyngitis and impetigo, to severe invasive infections. Both species have overlapping capacity with respect to metal acquisition, export and regulation and how metal homeostasis relates to their virulence and ability to invade and survive within the host. It is becoming more apparent that metals have an important role to play in the control of infection, and with further investigations, it could lead to the potential use of metals in novel antimicrobial therapies.

微量金属如铁、锰、锌和铜是多种生物功能所必需的,包括适当的先天免疫功能。宿主免疫系统具有复杂而协调的机制,可以用各种金属来饥饿和/或超载入侵的病原体来对抗感染。在此,我们讨论了铁、锰和锌在营养免疫方面的作用,以及铜和锌在两种人类链球菌——肺炎链球菌和化脓性链球菌的生理和发病机制中的金属超载作用。肺炎链球菌是一种主要的人类病原体,高达70%的人群无症状地在鼻咽部携带;然而,转移到内部部位可引起一系列疾病,如肺炎、中耳炎、脑膜炎和菌血症。化脓性链球菌是一种人类病原体,可引起从咽炎和脓疱疮到严重侵袭性感染等疾病。这两个物种在金属获取、出口和调节方面具有重叠的能力,以及金属稳态如何与它们的毒力和入侵和在宿主内生存的能力相关。越来越明显的是,金属在控制感染方面发挥着重要作用,随着进一步的研究,它可能导致金属在新型抗菌疗法中的潜在应用。
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引用次数: 25
期刊
Advances in Microbial Physiology
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