The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target
The Trypanosoma brucei sphingolipid synthase, an essential enzyme and drug target
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DOI：
10.1016/j.molbiopara.2009.06.002
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发表时间：
2009-11-01
影响因子：
1.5
通讯作者：
Denny, Paul W.
中科院分区：
文献类型：
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作者：
Mina, John G.;Pan, Ssu-Ying;Denny, Paul W.
鞘脂是真核细胞膜，特别是质膜的重要组成部分，并参与多种信号转导过程。在真核生物中，形成这些脂质物质的生物合成途径在很大程度上是保守的。然而，与产生鞘磷脂（SM）的哺乳动物相反，一些病原真菌和原生动物合成肌醇磷酸神经酰胺（IPC）作为主要的磷酸鞘脂。这一过程由IPC合酶催化，IPC合酶是酵母中AUR1基因编码的抗真菌药物的公认靶标。最近，功能直系同源的AUR1 p已被确定在一组昆虫媒介传播的病原性原生动物，动质体，这是负责一系列所谓的被忽视的疾病。其中布氏锥虫是非洲许多最不发达地区人类非洲锥虫病的病原体。对这些疾病的可用治疗是有限的，降低疗效，并经常表现出严重的副作用。在此背景下，布氏锥虫鞘脂合酶，酵母AUR1 p的直向同源物，可能是一个有前途的新的抗原生动物的目标。我们的研究确定了这种蛋白质的一种同工型，作为一种新的双功能酶，能够催化IPC和SM的合成，这两种蛋白质都存在于寄生虫中。此外，合成酶是寄生虫生长所必需的，并且可以在体外被已知的抗真菌剂以低纳摩尔水平抑制。最值得注意的是，该药物显示出对培养的血流形式寄生虫的杀锥虫活性。因此，T.布鲁氏菌鞘脂合酶代表了有效的和有希望的药物靶标。(C)2009 Elsevier B.V.保留所有权利。
Sphingolipids are important components of eukaryotic membranes, particularly the plasma membrane, and are involved in a diverse array of signal transduction processes. In the Eukaryota the biosynthetic pathway for the formation of these lipid species is largely conserved. However, in contrast to mammals which produce sphingomyelin (SM), several pathogenic fungi and protozoa synthesize inositol phosphorylceramide (IPC) as the primary phosphosphingolipid. This process is catalyzed by the enzyme IPC synthase, a recognized target for anti-fungals encoded by the AUR1 gene in yeast. Recently, functional orthologues of the AUR1 p have been identified in a group of insect vector-borne pathogenic protozoa, the Kinetoplastida, which are responsible for a range of so-called neglected diseases. Of these the Trypanosoma brucei species are the causative agents of human African trypanosomiasis in many of the most under-developed regions of Africa. The available treatments for these diseases are limited, of decreasing efficacy, and often demonstrate severe side-effects. Against this background the T brucei sphingolipid synthase, an orthologue of the yeast AUR1 p, may represent a promising target for novel anti-protozoals. Our studies identify an isoform of this protein as a novel bi-functional enzyme capable of catalyzing the synthesis of both IPC and SM, both known to be present in the parasite. Furthermore, the synthase is essential for parasite growth and can be inhibited by a known anti-fungal at low nanomolar levels in vitro. Most notably this drug demonstrates trypanocidal activity against cultured bloodstream form parasites. Thus, the T. brucei sphingolipid synthase represents a valid and promising drug target. (C) 2009 Elsevier B.V. All rights reserved.