Schistosome egg production is dependent upon the activities of two developmentally regulated tyrosinases
Schistosome egg production is dependent upon the activities of two developmentally regulated tyrosinases
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DOI：
10.1096/fj.06-7314com
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发表时间：
2007-03-01
期刊：
影响因子：
4.8
通讯作者：
Hoffmann, Karl F.
中科院分区：
文献类型：
--
作者：
Fitzpatrick, Jennifer M.;Hirai, Yuriko;Hoffmann, Karl F.
卵的产生是负责血吸虫病的生命周期进展和宿主免疫病理学，相关的寄生虫分子正在研究作为潜在的新的化疗靶点。在这里，我们表征两个曼氏血吸虫的产品，酪氨酸酶I和酪氨酸酶2（SmTYR 1/SmTYR 2），并表明它们的二酚氧化酶的酶活性是蛋壳形成和生产的关键。编码这些双功能酶（单酚和二酚氧化酶）的基因来自可能发生在物种形成之前的复制事件，并作为多个拷贝存在于寄生虫的基因组中，这些拷贝与4号和W号染色体相连并定位。SmTYR 1/SmTYR 2的转录和双酚氧化酶的作用是发育调节与大多数酶的活性定位到卵壳生产细胞内所载的成年雌性蠕虫的卵黄。重要的是，曲酸介导的抑制（IC 50 =0.5 μ M）的SmTYR 1/SmTYR 2的双酚氧化酶活性在体外培养的性成熟蠕虫导致在生产表型正常的鸡蛋显着减少。因此，我们的数据表明，SmTYR 1/2抑制代表了一种新的和潜在的有效的战略，用于打击血吸虫病，此外，它可能指向新的方法组合控制免疫病理学和卵传播过程中的扁形虫感染。
Egg production is responsible for life cycle progression and host immunopathology during schistosomiasis, with the associated parasite molecules being investigated as potential novel chemotherapeutic targets. Here, we characterize two Schistosoma mansoni products, tyrosinase I and tyrosinase 2 (SmTYR1/SmTYR2) and show that their diphenol oxidase enzyme activities are critical for eggshell formation and production. The genes encoding these bifunctional enzymes (monophenol and diphenol oxidases) result from a duplication event that likely occurred before speciation and exist in the parasite's genome as multiple copies, which are linked and localized to chromosomes 4 and W. SmTYR1/SmTYR2 transcription and diphenol oxidase action are developmentally regulated with most enzyme activity localized to the eggshell-producing cells contained within the vitellaria of adult female worms. Importantly, kojic-acid mediated inhibition (IC50=0.5 mu M) of SmTYR1/SmTYR2's diphenol oxidase activity during in vitro culture of sexually mature adult worms resulted in a significant decrease in the production of phenotypically normal eggs. Therefore our data suggest that SmTYR1/2 inhibition represents a novel and potentially effective strategy for combating schistosomiasis and furthermore, it may point to new methods for combinatorial control of immunopathology and egg transmission during platyhelminth infection.