Compartmentation of redox metabolism in malaria parasites.
Compartmentation of redox metabolism in malaria parasites.
复制标题
DOI：
10.1371/journal.ppat.1001242
复制
发表时间：
2010-12-23
期刊：
影响因子：
6.7
通讯作者：
Becker K
中科院分区：
文献类型：
--
作者：
Kehr S;Sturm N;Rahlfs S;Przyborski JM;Becker K
疟疾是由顶端复合体寄生虫疟原虫引起的，仍然是对人类健康和福利的主要威胁，每年导致约100万人死亡。疟原虫是一种快速繁殖的单细胞生物体，在人和蚊子身上经历了一个复杂的发展周期--一种需要迅速适应各种环境的生活方式。为了处理高通量的活性氧物种，维持氧化还原调节过程和致病性，疟原虫依赖于足够的氧化还原平衡。通过对主要抗氧化剂和氧化还原调节蛋白亚细胞定位的系统研究，我们首次获得了恶性疟原虫氧化还原区划的完整图谱。我们证明了两个原生质膜过氧化还蛋白和一个可能的乙二醛酶系统靶向顶生质体--一种非光合体。此外，我们还获得了硫氧还蛋白和谷氧还蛋白样蛋白区隔的完整图像。值得注意的是，对于两种主要的抗氧化剂氧化还原酶-谷胱甘肽还原酶和硫氧还蛋白还原酶-疟原虫利用替代翻译启动(ATI)来实现差异靶向。受ATI影响的蛋白质的双重定位很可能也发生在其他复合体中，并可能为治疗干预开辟新的途径。单细胞寄生虫恶性疟原虫是热带疟疾的病原体，这是一种全球健康负担。为了在人类宿主和疟疾媒介按蚊中生存，疟疾寄生虫依赖于足够的抗氧化防御和有效的氧化还原调节。此外，葡萄糖-6磷酸脱氢酶缺乏症(一种保护疟疾的基因变异)表明，氧化还原平衡在寄生虫致病中起着至关重要的作用。利用绿色荧光蛋白报告基因，系统地研究了恶性疟原虫氧化还原网络的亚细胞区划。基于我们的结果和文献中的数据，我们提供了第一张完整的氧化还原分区图。最有趣的是，对于两种主要的抗氧化剂-谷胱甘肽还原酶(GR)和硫氧还蛋白还原酶(TrxR)-恶性疟原虫利用选择性翻译启动来翻译来自同一基因的不同亚细胞定位的蛋白质亚型。在Apicomplexa中，由于选择性翻译起始引起的蛋白质的双重定位可能经常发生，识别进一步进化替代翻译起始的基因可能为治疗这种毁灭性疾病提供新的治疗策略。
Malaria, caused by the apicomplexan parasite Plasmodium, still represents a major threat to human health and welfare and leads to about one million human deaths annually. Plasmodium is a rapidly multiplying unicellular organism undergoing a complex developmental cycle in man and mosquito – a life style that requires rapid adaptation to various environments. In order to deal with high fluxes of reactive oxygen species and maintain redox regulatory processes and pathogenicity, Plasmodium depends upon an adequate redox balance. By systematically studying the subcellular localization of the major antioxidant and redox regulatory proteins, we obtained the first complete map of redox compartmentation in Plasmodium falciparum. We demonstrate the targeting of two plasmodial peroxiredoxins and a putative glyoxalase system to the apicoplast, a non-photosynthetic plastid. We furthermore obtained a complete picture of the compartmentation of thioredoxin- and glutaredoxin-like proteins. Notably, for the two major antioxidant redox-enzymes – glutathione reductase and thioredoxin reductase – Plasmodium makes use of alternative-translation-initiation (ATI) to achieve differential targeting. Dual localization of proteins effected by ATI is likely to occur also in other Apicomplexa and might open new avenues for therapeutic intervention. The unicellular parasite Plasmodium falciparum is the causative agent of tropical malaria, which represents a global health burden. In order to survive in its human host and the malaria vector Anopheles, malaria parasites depend on adequate antioxidant defense and efficient redox regulation. Furthermore, as shown by glucose-6 phosphate dehydrogenase deficiency, a genetic variation protecting from malaria, redox equilibrium plays a vital role in parasite pathogenicity. Using a green fluorescent protein reporter gene, we systematically studied the subcellular compartmentation of redox networks in Plasmodium falciparum. Based on our results and data from literature, we provide the first thorough map of redox compartmentation. Most interestingly, for the two major antioxidant redox-enzymes – glutathione reductase (GR) and thioredoxin reductase (TrxR) – Plasmodium falciparum makes use of alternative translation initiation to translate protein isoforms with differing subcellular localization from one gene. Dual localization of proteins due to alternative translation initiation might occur frequently in Apicomplexa and identification of further genes that have evolved alternative translation initiation is likely to offer new therapeutic strategies against this devastating disease.
登录
查看更多内容
影响因子：
64.8
作者：
de Koning-Ward, Tania F.;Gilson, Paul R.;Boddey, Justin A.;Rug, Melanie;Smith, Brian J.;Papenfuss, Anthony T.;Sanders, Paul R.;Lundie, Rachel J.;Maier, Alexander G.;Cowman, Alan F.;Crabb, Brendan S.
通讯作者：
Crabb, Brendan S.
DOI：
10.1093/bioinformatics/btq115
发表时间：
2010-05-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Briesemeister S;Rahnenführer J;Kohlbacher O
通讯作者：
Kohlbacher O
影响因子：
1.5
作者：
Kawazu, S;Tsuji, N;Kano, S
通讯作者：
Kano, S
影响因子：
3.5
作者：
Färber, PM;Arscott, LD;Schirmer, RH
通讯作者：
Schirmer, RH
影响因子：
6.7
作者：
Pino, Paco;Foth, Bernardo Javier;Kwok, Lai-Yu;Sheiner, Lilach;Schepers, Rebecca;Soldati, Thierry;Soldati-Favre, Dominique
通讯作者：
Soldati-Favre, Dominique