Leishmania major UDP-sugar pyrophosphorylase salvages galactose for glycoconjugate biosynthesis
Leishmania major UDP-sugar pyrophosphorylase salvages galactose for glycoconjugate biosynthesis
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DOI：
10.1016/j.ijpara.2015.06.004
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发表时间：
2015-10-01
影响因子：
4
通讯作者：
Routier, Francoise H.
中科院分区：
文献类型：
--
作者：
Damerow, Sebastian;Hoppe, Carolin;Routier, Francoise H.
利什曼病是由利什曼原虫属的原生动物寄生虫引起的一组热带和亚热带疾病，其严重程度从自愈性皮肤损伤到致命的内脏感染不等。利什曼原虫合成了大量的细胞表面和分泌的糖复合物，在感染中发挥重要作用。这些糖缀合物在前鞭毛体形式中特别丰富，并且已知对于在昆虫中肠中建立感染和有效传播至哺乳动物宿主是必需的。由于它们富含半乳糖，它们的生物合成需要充足的UDP-半乳糖供应。这种核苷酸-糖来自UDP-葡萄糖的差向异构化，但也来自未表征的半乳糖补救途径。在这项研究中，我们评估了主要利什曼原虫的UDP-糖焦磷酸化酶（CUSP）在UDP-半乳糖生物合成中的作用。在USP编码基因缺失后，L. major失去了从半乳糖-1-磷酸合成UDP-半乳糖的能力，但其将葡萄糖-1-磷酸转化为UDP-葡萄糖的能力完全保持。因此，USP在UDP-半乳糖活化中起作用，但对UDP-葡萄糖的从头合成没有显著贡献。因此，USP显示在标准生长条件下生长和糖缀合物生物合成不稳定。然而，在突变体中，UDP-半乳糖的从头合成严重受损（由于UDP-葡萄糖焦磷酸化酶的缺乏），细胞外半乳糖的加入增加了细胞表面脂磷酸聚糖的生物合成。因此，在限制性条件下，如利什曼原虫在其自然栖息地中遇到的条件下，USP半乳糖补救可能在UDP-半乳糖池的生物合成中发挥重要作用。我们假设USP从昆虫中肠内的血粉中除去半乳糖，用于合成前鞭毛体糖萼，从而有助于成功的载体感染。(C)2015年澳大利亚寄生虫学会由爱思唯尔有限公司出版。保留所有权利。
Leishmaniases are a set of tropical and sub-tropical diseases caused by protozoan parasites of the genus Leishmania whose severity ranges from self-healing cutaneous lesions to fatal visceral infections. Leishmania parasites synthesise a wide array of cell surface and secreted glycoconjugates that play important roles in infection. These glycoconjugates are particularly abundant in the promastigote form and known to be essential for establishment of infection in the insect midgut and effective transmission to the mammalian host. Since they are rich in galactose, their biosynthesis requires an ample supply of UDP-galactose. This nucleotide-sugar arises from epimerisation of UDP-glucose but also from an uncharacterised galactose salvage pathway. In this study, we evaluated the role of the newly characterised UDP-sugar pyrophosphorylase CUSP) of Leishmania major in UDP-galactose biosynthesis. Upon deletion of the USP encoding gene, L. major lost the ability to synthesise UDP-galactose from galactose-1-phosphate but its ability to convert glucose-l-phosphate into UDP-glucose was fully maintained. Thus USP plays a role in UDP-galactose activation but does not significantly contribute to the de nova synthesis of UDP-glucose. Accordingly, USP was shown to be dispensable for growth and glycoconjugate biosynthesis under standard growth conditions. However, in a mutant seriously impaired in the de novo synthesis of UDP-galactose (due to deficiency of the UDP-glucose pyrophosphorylase) addition of extracellular galactose increased biosynthesis of the cell surface lipophosphoglycan. Thus under restrictive conditions, such as those encountered by Leishmania in its natural habitat, galactose salvage by USP may play a substantial role in biosynthesis of the UDP-galactose pool. We hypothesise that USP recycles galactose from the blood meal within the midgut of the insect for synthesis of the promastigote glycocalyx and thereby contributes to successful vector infection. (C) 2015 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.