Theories on malarial pigment formation and quinoline action
Theories on malarial pigment formation and quinoline action
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DOI：
10.1016/s0020-7519(02)00193-5
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发表时间：
2002-12-04
影响因子：
4
通讯作者：
Sullivan, DJ
中科院分区：
文献类型：
--
作者：
Sullivan, DJ
血红素代谢仍然是一个脆弱的问题，红内疟原虫分解代谢血红蛋白作为一个来源的氨基酸在酸性，富氧的溶酶体样消化空泡。血红素单体能够产生氧自由基，通过形成独特的二聚体，然后结晶，转化为一种名为疟疾色素或疟原虫色素的惰性晶体。拉维兰首先描述了人类的色素体，将原生动物定义为疟疾的病原体。疟疾色素的踪迹使罗斯能够将蚊子与疟原虫的生命周期联系起来。1991年，斯莱特和塞拉米根据红外光谱和X射线光谱数据，假设在色素晶体中两个血红素之间存在独特的铁-羧酸键。此外，寄生虫提取物被证明具有“血红素聚合酶”的酶活性，因为晶体形成的过程被称为。重要的是，喹啉类，如氯喹，抑制疟原虫色素的形成。恶性疟原虫衍生的富含组氨酸的蛋白11，其结合血红素并启动疟原虫色素形成，存在于消化泡中。富含Pfhistidine的蛋白质11和富含Pfhistidine的蛋白质III是足够的，但不是形成血红素所必需的，因为缺乏这两种蛋白质的实验室克隆仍然会产生血红素晶体。还原虫、血吸虫属和变形血吸虫属也能产生疟原虫色素。最近，Bohle及其同事使用X射线衍射记录了完整的干燥寄生虫中的铁-羧酸键，并表明Fel-O 41头-尾血红素二聚体是疟原虫色素的单元构建块。疟原虫富含组氨酸的蛋白质家族成员、脂质或潜在的新蛋白质在富含蛋白质的消化泡中的大分子量血红素晶体的精确分子组装中的作用需要解决。准确的实验测定作为氯喹靶点的疟原虫色素形成和抑制的作用是确定喹啉药物作用和耐药性机制的基础。使用功能蛋白质组学工具和现有抗疟药物影响疟原虫血红素化学的机制，提高对导致疟原虫色素形成的生物合成途径的理解，将有助于设计改进的疟原虫剂。(C)2002年由Elsevier Science Ltd.代表Australian Society for Parasitology Inc.出版。
Haeme metabolism remains a vulnerable problem for the intraerythrocytic Plasmodium which catabolises haemoglobin as a source of amino acids in an acidic, oxygen-rich lysosome-like digestive vacuole. Haeme monomer, capable of generating oxygen radicals, transforms into an inert crystal named malarial pigment or haemozoin by forming unique dimers that then crystalise. Laveran first described pigmented bodies in humans to define a protozoan as the aetiologic agent of malaria. The trail of malaria pigment enabled Ross to implicate the mosquito in the life cycle of Plasmodium. In 199 1, Slater and Cerami postulated a unique iron-carboxylate bond between two haemes in haemozoin crystals based on infrared and X-ray spectroscopy data. Additionally, parasite extracts were shown to possess a 'haeme polymerase' enzymatic activity as the process of crystal formation was then termed. Importantly, the quinolines, such as choloroquine, inhibit haemozoin formation. A Plasmodium falciparum derived histidine-rich protein 11, which binds haeme and initiates haemozoin formation, is present in the digestive vacuole. Pfhistidine-rich protein 11 and Pfhistidine-rich protein III are sufficient, but not necessary for haemozoin formation as a laboratory clone lacking both still makes the haeme crystals. The reduvid bug, and the Schistosoma and Haemoproteus genera also make haemozoin. Recently, Bohle and coworkers used X-ray diffraction to document the iron-carboxylate bond in intact desiccated parasites and to show that a Fel-O41 head to tail haeme dimer is the unit building block of haemozoin. The role of the Plasmodium histidine-rich protein family members, lipids or potential novel proteins in the exact molecular assembly of the large molecular weight haeme crystals in the protein rich digestive vacuole needs to be solved. Accurate experimental determination of the role of haemozoin formation and inhibition as the target of chloroquine is fundamental to determination of the mechanism of quinoline drug action and resistance. The enhanced understanding of the biosynthetic pathway leading to haemozoin formation using functional proteomic tools and the mechanisms through which existing antimalarial drugs affect Plasmodium haeme chemistry will help design improved chaemotherapeutic agents. (C) 2002 Published by Elsevier Science Ltd. on behalf of Australian Society for Parasitology Inc.