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

铁对细菌的生长是必不可少的。人类（和其他动物）用来抵御引起疾病的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。通过这种方式，系统中没有游离铁，因此在人体中生存的细菌必须进化出特定的机制来去除这些宿主蛋白质中的铁。致病菌的铁摄取机制已被广泛研究，铁摄取系统被认为是重要的毒力因子（致病的细菌因子）。人类和其他高等生物如酵母有一个铁摄取系统，它使用多种铜氧化酶蛋白（MCOs）。这些蛋白质具有氧化铁酶活性，可将铁从蛋白质结合的不溶态铁（III）转化为可溶态铁（II），使其从铁结合蛋白中释放出来。我们在许多细菌的基因组中寻找类似的系统，并发现许多细菌都有MCOs。我们想要测试我们已经确定的细菌MCOs可能参与铁摄取的想法。如果是这样，它将代表着理解这一重要过程的巨大进步，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作为研究对象。我们已经证明了MCO具有铁氧化酶活性(Fe(III)>Fe(II))，我们已经对MCO基因进行了突变，已经表明缺乏MCO的细菌在某些条件下不能生长。这些情况与铁吸收缺陷相一致。我们已经确定，但没有描述这个铁摄取系统的几个其他关键组成部分。在这项工作中，我们希望研究这一重要病原体中铁摄取系统的所有组成部分，并开始对其他细菌病原体的研究。

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.