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

铁对细菌的生长至关重要。人类（和其他动物）用来防御致病细菌的机制之一是通过将铁与一组铁结合蛋白结合来捕获铁。转铁蛋白这样，系统中就没有游离铁，因此在人类中生存的细菌必须进化出特定的机制来从这些宿主蛋白质中去除铁。病原菌的铁吸收机制已被广泛研究，铁吸收系统被认为是致病因子（致病的细菌因子）的重要组成部分。人类和其他高等生物（如酵母）具有使用多铜氧化酶蛋白（MCO）的铁吸收系统。这些蛋白质具有铁氧化酶活性，其将铁从蛋白质结合的不溶性形式Fe（III）转化为可溶性形式Fe（II），使其从铁结合蛋白中释放。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。我们想测试我们已经确定的细菌MCO可能与铁uptkae有关的想法。如果是这样的话，这将是理解这一重要过程的一个巨大进步，并可能导致预防或更好地治疗传染病的产品。我们选择致病细菌铜绿假单胞菌进行研究。我们已经证明MCO具有铁氧化酶活性（Fe（III）Fe（II）），我们已经在MCO基因中进行了突变，已经表明缺乏MCO的细菌在某些条件下不会生长。这些情况与铁吸收缺陷一致。我们已经确定，但没有表征其他几个关键成分的铁吸收系统。在拟议的工作中，我们希望研究这种重要病原体中铁吸收系统的所有组成部分，并开始在其他细菌病原体中的研究。

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.