供需——Apicomplexa 的血红素合成、回收和利用。,The FEBS Journal

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供需——Apicomplexa 的血红素合成、回收和利用。
The FEBS Journal ( IF 5.5 ) Pub Date : 2020-06-12 , DOI: 10.1111/febs.15445
Joachim Kloehn ₁ , Clare R Harding ₂ , Dominique Soldati-Favre ₁

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Apicomplexa 门将导致严重疾病的重要人类和动物病原体分组，包括疟疾、弓形体病和隐孢子虫病。与大多数生物一样，顶复体依赖血红素作为多种酶的辅因子，包括电子传递链的细胞色素。这种血红素来源于从头合成和/或吸收机制的发展，以从宿主中清除血红素。最近的研究表明，血红素合成对弓形虫速殖子以及疟原虫的蚊子和肝脏阶段至关重要属相比之下，疟疾寄生虫的红细胞阶段依赖于从宿主红细胞中清除血红素。Apicomplexa 中不寻常的血红素合成途径跨越三个细胞区室，包含不同祖先来源的酶，提供了有希望的药物靶点。值得注意的是，考虑到对血红素的需求，刚地弓形虫可以以高适应度成本耐受几种血红素合成酶的损失，而亚铁螯合酶对于生存至关重要。这些发现表明，刚地弓形虫能够从宿主中挽救血红素前体。此外，血红素与关键抗疟药物青蒿素的激活有关。最近的研究结果表明，血红素可用性的降低对应于青蒿素敏感性降低T. gondii和Plasmodium falciparum，提供了对联合疗法的可能发展的见解，以解决 apicomplexan 寄生虫。这篇综述描述了 Apicomplexa 中血红素的微观经济学，从从头合成或清除的供应到代谢途径的需求，包括电子传递链。

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Supply and demand-heme synthesis, salvage and utilization by Apicomplexa.

The Apicomplexa phylum groups important human and animal pathogens that cause severe diseases, encompassing malaria, toxoplasmosis, and cryptosporidiosis. In common with most organisms, apicomplexans rely on heme as cofactor for several enzymes, including cytochromes of the electron transport chain. This heme derives from de novo synthesis and/or the development of uptake mechanisms to scavenge heme from their host. Recent studies have revealed that heme synthesis is essential for Toxoplasma gondii tachyzoites, as well as for the mosquito and liver stages of Plasmodium spp. In contrast, the erythrocytic stages of the malaria parasites rely on scavenging heme from the host red blood cell. The unusual heme synthesis pathway in Apicomplexa spans three cellular compartments and comprises enzymes of distinct ancestral origin, providing promising drug targets. Remarkably given the requirement for heme, T. gondii can tolerate the loss of several heme synthesis enzymes at a high fitness cost, while the ferrochelatase is essential for survival. These findings indicate that T. gondii is capable of salvaging heme precursors from its host. Furthermore, heme is implicated in the activation of the key antimalarial drug artemisinin. Recent findings established that a reduction in heme availability corresponds to decreased sensitivity to artemisinin in T. gondii and Plasmodium falciparum, providing insights into the possible development of combination therapies to tackle apicomplexan parasites. This review describes the microeconomics of heme in Apicomplexa, from supply, either from de novo synthesis or scavenging, to demand by metabolic pathways, including the electron transport chain.

更新日期：2020-06-12

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