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首页> 外文期刊>Journal of Molecular Biology >The structural basis of chain length control in Rv1086.
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The structural basis of chain length control in Rv1086.

机译：Rv1086中链长控制的结构基础。

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摘要

In Mycobacterium tuberculosis, two related Z-prenyl diphosphate synthases, E,Z-farnesyl diphosphate synthase (Rv1086) and decaprenyl diphosphate synthase (Rv2361c), work in series to synthesize decaprenyl phosphate (C(50)) from isopentenyl diphosphate and E-geranyl diphosphate. Decaprenyl phosphate plays a central role in the biosynthesis of essential mycobacterial cell wall components, such as the mycolyl-arabinogalactan-peptidoglycan complex and lipoarabinomannan; thus, its synthesis has attracted considerable interest as a potential therapeutic target. Rv1086 is a unique prenyl diphosphate synthase in that it adds only one isoprene unit to geranyl diphosphate, generating the 15-carbon product (E,Z-farnesyl diphosphate). Rv2361c then adds a further seven isoprene units to E,Z-farnesyl diphosphate in a processive manner to generate the 50-carbon prenyl diphosphate, which is then dephosphorylated to generate a carrier for activated sugars. The molecular basis for chain-length discrimination by Rv1086 during synthesis is unknown. We also report the structure of apo Rv1086 with citronellyl diphosphate bound and with the product mimic E,E-farnesyl diphosphate bound. We report the structures of Rv2361c in the apo form, with isopentenyl diphosphate bound and with a substrate analogue, citronellyl diphosphate. The structures confirm the enzymes are very closely related. Detailed comparison reveals structural differences that account for chain-length control in Rv1086. We have tested this hypothesis and have identified a double mutant of Rv1086 that makes a range of longer lipid chains.
机译：在结核分枝杆菌中，两个相关的Z-异戊二烯基二磷酸合酶E，Z-法呢基二磷酸合酶（Rv1086）和癸二烯基二磷酸合酶（Rv2361c）串联工作，由异戊烯基二磷酸酯和E-香叶基壬烯合成磷酸癸二烯酯（C（50））。二磷酸。磷酸癸二烯酯在必需的分枝杆菌细胞壁成分如菌丝基-阿拉伯半乳聚糖-肽聚糖复合物和脂质阿拉伯糖甘露聚糖的生物合成中起着核心作用。因此，其合成作为潜在的治疗靶标引起了广泛的关注。 Rv1086是独特的异戊二烯基二磷酸合酶，因为它仅向二磷酸香叶基酯中添加一个异戊二烯单元，生成15个碳的产物（E，Z-法呢基二磷酸酯）。然后，Rv2361c以加工方式向E，Z-法呢基二磷酸酯中添加另外七个异戊二烯单元以生成50碳的异戊二烯基二磷酸酯，然后将其脱磷酸以生成活性糖的载体。合成过程中Rv1086识别链长的分子基础是未知的。我们还报告了载脂蛋白二磷酸结合的载脂蛋白Rv1086的结构，以及与产品模仿的E，E-法呢基二磷酸结合的产物。我们报告载脂蛋白形式的Rv2361c的结构，与异戊烯基二磷酸结合，并与底物类似物，香茅基二磷酸。结构证实了这些酶是非常紧密相关的。详细的比较揭示了结构差异，这些差异解释了Rv1086中的链长控制。我们已经验证了这一假设，并确定了Rv1086的双突变体，该双突变体可形成一系列更长的脂质链。

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