Multi-copper oxidase mediated iron uptake in Ps. aeruginosa and other pathogenic bacteria: mechanism and role in disease

多铜氧化酶介导的 Ps 铁吸收。

• 批准号: nhmrc : 252885
• 负责人: Prof Alastair Mcewan
• 金额: $ 4.9万
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2003
• 资助国家: 澳大利亚
• 起止时间: 2003-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/multi-copper-oxidase-role-disease/81392
• 关键词: Multi; copper; oxidase; mediated; iron

Iron is essential for the growth of bacteria. One of the mechanisms used by humans (and other animals) to defend against bacteria that cause disease is to trap iron by binding it to a set of iron binding proteins eg. transferrin. In this way there is no free iron in the system, so bacteria that survive in humans have had to evolve specific mechanisms to remove the iron form these host proteins. The mechanisms of iron uptake in pathogenic bacteria have been studied extensively, and the iron uptake systems are considered to be important of virulence factors (bacterial factors essential for causing disease). Humans and other higher organisms like Yeast have an iron uptake system that uses multi copper oxidase proteins (MCOs). These proteins have a ferroxidase activity, which converts iron from a protein bound insoluable form Fe (III) to a soluble form Fe(II), allowing it to be released from iron binding proteins. We have searched the genomes of many bacteria for a similar system and have discovered that many bacteria have MCOs. We wanted to test the idea that the bacteria MCOs we have identified may be involved in iron uptkae. If so, it would represent a huge step forward in understanding this important process and could lead to products for prevention or better treatment of infectious disease. We chose the disease causing bacterium Pseudomonas aeruginosa for our study. We have shown that the MCO has ferroxidase activity (Fe(III)>Fe(II), we have made a mutation in the MCO gene had have shown that the bacterium lacking MCO will not grow under certain conditions. These conditions are consistent with a defect in iron uptake. We have identified but not characterised several other key compnents of this iron uptake system. In the proposed work we wish to investigate all of the components of this iron uptake system in this important pathogen, and to initiate studies in other bacteria pathogens.

铁对细菌的生长是必不可少的。人类(和其他动物)用来抵御致病细菌的机制之一是通过将铁与一系列铁结合蛋白结合来捕获铁。转铁蛋白。通过这种方式，系统中不存在游离铁，因此在人类体内生存的细菌必须进化出特定的机制来从这些宿主蛋白中去除铁。病原菌的铁摄取机制已被广泛研究，而铁摄取系统被认为是致病细菌致病因子(毒力因子)的重要组成部分。人类和其他高等生物，如酵母，有一个铁吸收系统，使用多个铜氧化酶蛋白(MCO)。这些蛋白质具有铁氧合酶活性，可以将铁从蛋白质结合的不溶性铁(III)转化为可溶性的铁(II)，从而使铁从铁结合蛋白中释放出来。我们已经在许多细菌的基因组中搜索了类似的系统，并发现许多细菌都有MCO。我们想要测试的想法是，我们已经确定的细菌MCOs可能参与了铁中毒。如果是这样的话，这将是在理解这一重要过程方面向前迈出的一大步，并可能导致产生预防或更好地治疗传染病的产品。我们选择了致病细菌铜绿假单胞菌作为研究对象。我们已经证明了MCO具有铁氧合酶活性(Fe(III)&GT；Fe(II))，我们对MCO基因进行了突变，表明缺乏MCO的细菌在一定条件下不会生长。这些情况与铁摄取缺陷是一致的。我们已经确定了这个铁摄取系统的其他几个关键成分，但没有描述。在拟议的工作中，我们希望调查这种重要病原体中这一铁摄取系统的所有组件，并启动对其他细菌病原体的研究。