GDP-valienol

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷酸
• 英文名称: GDP-valienol
• 英文别名: GDP-valienol(2-)；[[(2R,3S,4R,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] [(1S,4R,5S,6R)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-en-1-yl] phosphate
• 化学式: C₁₇H₂₃N₅O₁₅P₂
• 分子量: 599.342
• InChiKey: SBXHHXUHVHYPDE-WPOGMVEHSA-L

计算性质

• 辛醇/水分配系数(LogP)：
  -6.7
• 重原子数：
  39
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  324
• 氢给体数：
  8
• 氢受体数：
  17

反应信息

• 作为反应物：
  描述：

  GDP-valienol 在 recombinant cyclitol nucleotidyltransferase from Streptomyces hygroscopicus subsp. limoneus KCCM 11405 、 recombinant phosphatase from Streptomyces hygroscopicus subsp. limoneus KCCM 11405 、 recombinant pseudoglycosyltransferase from Streptomyces hygroscopicus subsp. limoneus KCCM 11405 、 valienol 1-phosphate 、 validamine 7-phosphate 、 Guanosine 5'-triphosphate 、 magnesium chloride 作用下， 反应 6.0h， 生成 4-(羟基甲基)-6-[[2,3,4-三羟基-5-(羟基甲基)环己基]氨基]环己-4-烯-1,2,3-三醇
  参考文献：
  名称：

  Pseudoglycosyltransferase Catalyzes Nonglycosidic C–N Coupling in Validamycin A Biosynthesis

  摘要：

  Glycosyltransferases are ubiquitous in nature. They catalyze a glycosidic bond formation between sugar donors and sugar or nonsugar acceptors to produce oligo/polysaccharides, glycoproteins, glycolipids, glycosylated natural products, and other sugar-containing entities. However, a trehalose 6-phosphate synthase-like protein has been found to catalyze an unprecedented nonglycosidic C-N bond formation in the biosynthesis of the aminocyclitol antibiotic validamycin A. This dedicated 'pseudoglycosyltransferase' catalyzes a condensation between GDP-valienol and validamine 7-phosphate to give validoxylamine A 7'-phosphate with net retention of the 'anomeric' configuration of the donor cyclitol in the product. The enzyme operates in sequence with a phosphatase, which dephosphorylates validoxylamine A 7'-phosphate to validoxylamine A.

  DOI：

  10.1021/ja203574u
• 作为产物：
  描述：

  valienol 1-phosphate 、 Guanosine 5'-triphosphate 在 recombinant cyclitol nucleotidyltransferase from Streptomyces hygroscopicus subsp. limoneus KCCM 11405 、 magnesium chloride 作用下， 反应 2.0h， 生成 GDP-valienol
  参考文献：
  名称：

  Pseudoglycosyltransferase Catalyzes Nonglycosidic C–N Coupling in Validamycin A Biosynthesis

  摘要：

  Glycosyltransferases are ubiquitous in nature. They catalyze a glycosidic bond formation between sugar donors and sugar or nonsugar acceptors to produce oligo/polysaccharides, glycoproteins, glycolipids, glycosylated natural products, and other sugar-containing entities. However, a trehalose 6-phosphate synthase-like protein has been found to catalyze an unprecedented nonglycosidic C-N bond formation in the biosynthesis of the aminocyclitol antibiotic validamycin A. This dedicated 'pseudoglycosyltransferase' catalyzes a condensation between GDP-valienol and validamine 7-phosphate to give validoxylamine A 7'-phosphate with net retention of the 'anomeric' configuration of the donor cyclitol in the product. The enzyme operates in sequence with a phosphatase, which dephosphorylates validoxylamine A 7'-phosphate to validoxylamine A.

  DOI：

  10.1021/ja203574u

文献信息

• Nucleotidylation of unsaturated carbasugar in validamycin biosynthesis
  作者：Jongtae Yang、Hui Xu、Yirong Zhang、Linquan Bai、Zixin Deng、Taifo Mahmud

  DOI：10.1039/c0ob00475h

  日期：——

  Validamycin A is a member of microbial-derived C7N-aminocyclitol family of natural products that is widely used as crop protectant and the precursor of the antidiabetic drug voglibose. Its biosynthetic gene clusters have been identified in several Streptomyces hygroscopicus strains, and a number of genes within the clusters have been functionally analyzed. Of these genes, valB, which encodes a sugar nucleotidyltransferase, was found through inactivation study to be essential for validamycin biosynthesis, but its role was unclear. To characterize the role of ValB in validamycin biosynthesis, four carbasugar phosphate analogues were synthesized and tested as substrate for ValB. The results showed that ValB efficiently catalyzes the conversion of valienol 1-phosphate to its nucleotidyl diphosphate derivatives, whereas other unsaturated carbasugar phosphates were found to be not the preferred substrate. ValB requires Mg2+, Mn2+, or Co2+ for its optimal activity and uses the purine-based nucleotidyltriphosphates (ATP and GTP) more efficiently than the pyrimidine-based NTPs (CTP, dTTP, and UTP) as nucleotidyl donor. ValB represents the first member of unsaturated carbasugar nucleotidyltransferases involved in natural products biosynthesis. Its characterization not only expands our understanding of aminocyclitol-derived natural products biosynthesis, but may also facilitate the development of new tools for chemoenzymatic synthesis of carbohydrate mimetics.

  Validamycin A 是源自微生物的 C7N-aminocyclitol 天然产物家族中的一员，被广泛用作作物保护剂和抗糖尿病药物伏格列波糖的前体。已在多个吸水链霉菌株中发现了其生物合成基因簇，并对基因簇中的一些基因进行了功能分析。在这些基因中，通过灭活研究发现编码糖核苷酸转移酶的 ValB 是有效霉素生物合成所必需的，但其作用尚不清楚。为了确定 ValB 在有效霉素生物合成中的作用，研究人员合成了四种碳糖磷酸类似物，并将其作为 ValB 的底物进行了测试。结果表明，ValB 能有效催化缬烯醇 1- 磷酸酯向其核苷酸二磷酸衍生物的转化，而其他不饱和碳糖磷酸酯并非其首选底物。ValB 需要 Mg2+、Mn2+ 或 Co2+ 才能达到最佳活性，它使用嘌呤型核苷酸三磷酸酯（ATP 和 GTP）作为核苷酸供体的效率要高于嘧啶型 NTP（CTP、dTTP 和 UTP）。ValB 是参与天然产物生物合成的不饱和碳糖核苷酸转移酶的第一个成员。对它的鉴定不仅拓展了我们对氨环糖醇衍生天然产物生物合成的了解，还有助于开发化学合成碳水化合物模拟物的新工具。
• Mechanistic Insights into Validoxylamine A 7'-Phosphate Synthesis by VldE Using the Structure of the Entire Product Complex
  作者：Michael C. Cavalier、Young-Sun Yim、Shumpei Asamizu、David Neau、Khaled H. Almabruk、Taifo Mahmud、Yong-Hwan Lee

  DOI：10.1371/journal.pone.0044934

  日期：——

  7'-phosphate, the biosynthetic precursor of the antibiotic validamycin A. To study the molecular basis of its mechanism, the three-dimensional structures of VldE from Streptomyces hygroscopicus subsp. limoneus was determined in apo form, in complex with GDP, in complex with GDP and validoxylamine A 7'-phosphate, and in complex with GDP and trehalose. The structure of VldE with the catalytic site in both an

  假糖基转移酶 VldE 催化不饱和环醇和饱和氨基环醇之间的非糖苷 CN 偶联，保留底物的立体化学构型，形成有效的木胺 A 7'-磷酸酯，即抗生素有效霉素 A 的生物合成前体。其机制的分子基础，来自吸水链霉菌亚种的 VldE 的三维结构。limoneus 以 apo 形式、与 GDP 复合物、与 GDP 和有效木胺 A 7'-磷酸盐复合物以及与 GDP 和海藻糖复合物测定。还描述了具有“开放”和“封闭”构象的催化位点的 VldE 的结构。有了这些结构，VldE 与鸟嘌呤部分的优选结合，而不是 OtsA 中看到的尿嘧啶部分可以解释。对 VldE 结构及其全部产品的阐明提供了对内部返回机制的深入了解，通过该机制发生催化作用，并保留所提供的环醇的立体化学构型。
• Structural and Functional Analysis of Validoxylamine A 7′-phosphate Synthase ValL Involved in Validamycin A Biosynthesis
  作者：Lina Zheng、Xiang Zhou、Huaidong Zhang、Xiaofeng Ji、Lei Li、Lin Huang、Linquan Bai、Houjin Zhang

  DOI：10.1371/journal.pone.0032033

  日期：——

  Validamycin A (Val-A) is an effective antifungal agent widely used in Asian countries as crop protectant. Validoxylamine A, the core structure and intermediate of Val-A, consists of two C7-cyclitol units connected by a rare C-N bond. In the Val-A biosynthetic gene cluster in Streptomyces hygroscopicus 5008, the ORF valL was initially annotated as a validoxylamine A 7′-phosphate(V7P) synthase, whose encoded 497-aa protein shows high similarity with trehalose 6-phosphate(T6P) synthase. Gene inactivation of valL abolished both validoxylamine A and validamycin A productivity, and complementation with a cloned valL recovered 10% production of the wild-type in the mutant, indicating the involvement of ValL in validoxylamine A biosynthesis. Also we determined the structures of ValL and ValL/trehalose complex. The structural data indicates that ValL adopts the typical fold of GT-B protein family, featuring two Rossmann-fold domains and an active site at domain junction. The residues in the active site are arranged in a manner homologous to that of Escherichia coli (E.coli) T6P synthase OtsA. However, a significant discrepancy is found in the active-site loop region. Also noticeable structural variance is found around the active site entrance in the apo ValL structure while the region takes an ordered configuration upon binding of product analog trehalose. Furthermore, the modeling of V7P in the active site of ValL suggests that ValL might have a similar SNi-like mechanism as OtsA.

  有效霉素A（Val-A）是一种有效的抗真菌剂，在亚洲国家广泛用作农作物保护剂。有效霉素A的核心结构和中间体有效霉素A胺（Valoxylamine A）由两个C7-环醇单元组成，通过罕见的C-N键连接。在链霉菌5008的Val-A生物合成基因簇中，ORF valL最初被注释为有效霉素A 7'-磷酸（V7P）合成酶，其编码的497个氨基酸的蛋白与海藻糖6-磷酸（T6P）合成酶高度相似。valL基因的失活导致有效霉素A和有效霉素A胺的生产率下降，而克隆的valL的补充使突变体的产量恢复了10%，表明ValL参与了有效霉素A胺的生物合成。我们还确定了ValL和ValL/海藻糖复合物的结构。结构数据显示，ValL采用GT-B蛋白家族的典型折叠，具有两个Rossmann折叠域和一个位于域交界处的活性位点。活性位点中的残基排列方式与大肠杆菌（E.coli）T6P合成酶OtsA的残基排列方式同源。然而，在活性位点环区发现了显著的差异。在ValL的apo结构中，活性位点入口周围也发现了明显的结构差异，而在结合产物类似物海藻糖时，该区域则呈现有序结构。此外，Val