2-epi-5-epi-valiolone | 244195-43-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-epi-5-epi-valiolone
• 英文别名: (2S,3S,4S,5R)-2,3,4,5-tetrahydroxy-5-(hydroxymethyl)cyclohexan-1-one
• CAS: 244195-43-5
• 化学式: C₇H₁₂O₆
• 分子量: 192.169
• InChiKey: JCZFNXYQGNLHDQ-MVIOUDGNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  118
• 氢给体数：
  5
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-epi-5-epi-valiolone 在 Val D protein, 51.8 kDa, His₆-tagged 作用下， 以 water-d2 为溶剂， 生成 5-epi-valiolone
  参考文献：
  名称：

  Alternative Epimerization in C7N-Aminocyclitol Biosynthesis Is Catalyzed by ValD, A Large Protein of the Vicinal Oxygen Chelate Superfamily

  摘要：

  Gene valD, encodes a large vicinal oxygen chelate (VOC) superfamily protein, has been identified in the validamycin biosynthetic gene cluster. Inactivation of valD significantly reduced validamycin A production, which was fully restored with the full-length valD and partially restored with either N-terminal or C-terminal half by complementation. Heterologously expressed ValD catalyzed the epimerization of 2-epi-5-epi-valiolone to 5-epi-valiolone. This metalloenzyme is a homodimer with a metal ion-binding ratio of 0.73 mol/mole protein toward Fe2+, Mn2+, Ni2+, and Zn2+. Individual and combined site-directed mutations of eight putative active site residues revealed that the N-terminal H44/E107 and the C-terminal H315/E366 are more critical for the activity than the internal H130, E183, H229, and E291. Our data have established ValD as one of the largest proteins of the VOC superfamily, catalyzing an alternative epimerization for C7N-aminocyclitol biosynthesis.

  DOI：

  10.1016/j.chembiol.2009.04.006
• 作为产物：
  描述：

  (2,3,4,5,7-五羟基-6-氧代庚基)磷酸二氢酯 在 potassium fluoride 、 6XHis-(Nonomuraea spiralis IMC A‑0156 2-epi-5-epi-valiolone synthase PrlA) fusion protein 、 β-烟酰胺腺嘌呤二核苷酸 、 cobalt(II) chloride 作用下， 以 aq. phosphate buffer 为溶剂， 反应 2.0h， 生成 2-epi-5-epi-valiolone
  参考文献：
  名称：

  Genetic Insights into Pyralomicin Biosynthesis in Nonomuraea spiralis IMC A-0156

  摘要：

  The biosynthetic gene duster for the pyralomicin antibiotics has been cloned and sequenced from Nonomuraea spiralis IMC A-0156. The 41 kb gene duster contains 27 ORFs predicted to encode all of the functions for pyralomicin biosynthesis. This includes nonribosomal peptide synthetases (NAPS) and polyketide synthases (PKS) required for the formation of the benzopyranopyrrole core unit, as well as a suite of tailoring enzymes (e.g., four halogenases, an O-methyltransferase, and an N-glycosyltransferase) necessary for further modifications of the core structure. The N-glycosyltransferase is predicted to transfer either glucose or a pseudosugar (cyclitol) to the aglycone. A gene cassette encoding C-7-cyclitol biosynthetic enzymes was identified upstream of the benzopyranopyrrole-specific ORFs. Targeted disruption of the gene encoding the N-glycosyltransferase, prlH, abolished pyralomicin production, and recombinant expression of PrlA confirms the activity of this enzyme as a sugar phosphate cyclase involved in the formation of the C-7-cyclitol moiety.

  DOI：

  10.1021/np400159a

文献信息

• Synthesis of 5-<i>epi</i>-[6-²H₂]Valiolone and Stereospecifically Monodeuterated 5-<i>epi</i>-Valiolones:  Exploring the Steric Course of 5-<i>epi</i>-Valiolone Dehydratase in Validamycin A Biosynthesis
  作者：Taifo Mahmud、Jun Xu、Young Ung Choi

  DOI：10.1021/jo0101003

  日期：2001.7.1

  C-6 to yield valienone. To probe the dehydration mechanism of 5-epi-valiolone to valienone, stereospecifically 6alpha- and 6beta-monodeuterated 5-epi-valiolones were synthesized. The key step in the synthesis was desulfurization of the tetrabenzyl-6,6-bis(methylthio)-5-epi-valiolone and introduction of the deuterium utilizing Zn, NiCl(2), ND(4)Cl/D(2)O, and THF. Extensive studies using various combinations

  在有效霉素A和阿卡波糖的生物合成中，缬氨酸胺和有效胺部分最终衍生自C（7）糖七庚糖7-磷酸酯，其通过环化酶环化成2-epi-5-epi-valiolone通过脱氢奎宁（DHQ）合酶样机制运作。首先在C-2上将2-epi-5-epi-Valiolone异构化，得到5-epi-valiolone，然后在C-5和C-6之间脱水得到缬氨酸。为了探讨5-表缬草酮对缬氨酸的脱水机理，合成了立体定向的6α-和6β-单十二烷基醚化的5-表缬草酮。合成中的关键步骤是对六苄基-6,6-双（甲硫基）-5-表缬草酮进行脱硫并使用Zn，NiCl（2），ND（4）Cl / D（2）O引入氘和THF。广泛使用蛋白质和氘代反应剂和溶剂的组合进行的研究探讨了还原性脱硫的机理，这对于制备立体特异性单氘化的5-表-缬氨酸是至关重要的。在有效霉素A生产菌株Streptomyces hygroscopicus var中与标记前体的
• ValC, a New Type of C7-Cyclitol Kinase Involved in the Biosynthesis of the Antifungal Agent Validamycin A
  作者：Kazuyuki Minagawa、Yirong Zhang、Takuya Ito、Linquan Bai、Zixin Deng、Taifo Mahmud

  DOI：10.1002/cbic.200600528

  日期：2007.4.16

  thus suggesting a critical function of valC in validamycin biosynthesis. In vitro characterization of ValC revealed a new type of C7-cyclitol kinase, which phosphorylates valienone and validone--but not 2-epi-5-epi-valiolone, 5-epi-valiolone, or glucose--to afford their 7-phosphate derivatives. The results provide new insights into the activity of this enzyme and also confirm the existence of two

  在有效霉素A生物合成基因簇中鉴定出了基因valC，该基因编码与阿卡波糖生物合成途径的2-epi-5-epi-valiolone激酶（AcbM）同源的酶。valC的失活导致突变体缺乏产生有效霉素的能力。带有全长valC的复制质粒的互补实验恢复了有效霉素A的产生，因此表明valC在有效霉素的生物合成中具有关键作用。ValC的体外表征揭示了一种新型的C7-环糖醇激酶，可磷酸化瓦伦酮和有效酮，而不是2-epi-5-epi-valiolone，5-epi-valiolone或葡萄糖，以提供其7-磷酸酯衍生品。结果提供了对该酶活性的新见解，并证实了导致相同终产物的两种不同途径的存在：
• 2-epi-5-epi-Valiolone synthase activity is essential for maintaining phycobilisome composition in the cyanobacterium Anabaena variabilis ATCC 29413 when grown in the presence of a carbon source
  作者：Edward Spence、Samantha J. Bryan、Mohamed Lisfi、John Cullum、Walter C. Dunlap、J. Malcolm Shick、Conrad W. Mullineaux、Paul F. Long

  DOI：10.1007/s11120-013-9886-2

  日期：2013.9

  The cyclase 2-epi-5-epi-valiolone synthase (EVS) is reported to be a key enzyme for biosynthesis of the mycosporine-like amino acid shinorine in the cyanobacterium Anabaena variabilis ATCC 29413. Subsequently, we demonstrated that an in-frame complete deletion of the EVS gene had little effect on in vivo production of shinorine. Complete segregation of the EVS gene deletion mutant proved difficult and was achieved only when the mutant was grown in the dark and in a medium supplemented with fructose. The segregated mutant showed a striking colour change from native blue-green to pale yellow-green, corresponding to substantial loss of the photosynthetic pigment phycocyanin, as evinced by combinations of absorbance and emission spectra. Transcriptional analysis of the mutant grown in the presence of fructose under dark or light conditions revealed downregulation of the cpcA gene that encodes the alpha subunit of phycocyanin, whereas the gene encoding nblA, a protease chaperone essential for phycobilisome degradation, was not expressed. We propose that the substrate of EVS (sedoheptulose 7-phosphate) or possibly lack of its EVS-downstream products, represses transcription of cpcA to exert a hitherto unknown control over photosynthesis in this cyanobacterium. The significance of this finding is enhanced by phylogenetic analyses revealing horizontal gene transfer of the EVS gene of cyanobacteria to fungi and dinoflagellates. It is also conceivable that the EVS gene has been transferred from dinoflagellates, as evident in the host genome of symbiotic corals. A role of EVS in regulating sedoheptulose 7-phosphate concentrations in the photophysiology of coral symbiosis is yet to be determined.

  据报道，2-epi-5-epi-valiolone synthase（EVS）环化酶是蓝藻 Anabaena variabilis ATCC 29413 中生物合成类似霉菌素的氨基酸 shinorine 的关键酶。随后，我们证实，EVS 基因的框架内完全缺失对体内霞糠酸的产生几乎没有影响。事实证明，EVS 基因缺失突变体的完全分离非常困难，只有在黑暗和添加果糖的培养基中生长时才能实现。分离出的突变体显示出明显的颜色变化，从原生蓝绿色变为淡黄绿色，这与光合色素藻蓝蛋白的大量损失有关，吸光度和发射光谱组合也证明了这一点。在有果糖存在的黑暗或光照条件下生长的突变体的转录分析显示，编码藻蓝蛋白α亚基的 cpcA 基因下调，而编码藻蓝蛋白降解所必需的蛋白酶伴侣蛋白 nblA 的基因没有表达。我们认为，EVS 的底物（7-磷酸色酮糖）或可能缺乏其 EVS 下游产物，抑制了 cpcA 的转录，从而对这种蓝藻的光合作用实施了迄今未知的控制。系统发生学分析表明，蓝藻的 EVS 基因可水平转移到真菌和甲鞭毛藻，这进一步增强了这一发现的意义。也可以想象，EVS 基因是从甲藻转移过来的，这在共生珊瑚的宿主基因组中很明显。在珊瑚共生的光生理学过程中，EVS 在调节 7-磷酸沉降七酮糖浓度方面的作用尚有待确定。
• Biosynthesis of the C7-cyclitol Moiety of Acarbose inActinoplanes Species SE50/110
  作者：Chang-Sheng Zhang、Ansgar Stratmann、Oliver Block、Ralph Brückner、Michael Podeschwa、Hans-Josef Altenbach、Udo F. Wehmeier、Wolfgang Piepersberg

  DOI：10.1074/jbc.m202375200

  日期：2002.6

  We have previously demonstrated that the biosynthesis of the C-7-cyclitol, called valienol (or valienamine), of the a-glucosidase inhibitor acarbose starts from the cyclization of sedo-heptulose 7-phosphate to 2-epi-5-epivaliolone (Stratmann, A., Mahmud, T., Lee, S., Distler, J., Floss, H. G., and Piepersberg, W. (1999) J. Biol. Chem. 274, 10889-10896). Synthesis of the intermediate 2-epi-5-epi-valiolone is catalyzed by the cyclase AcbC encoded in the biosynthetic (acb) gene cluster of Actinoplanes sp. SE50/110. The acbC gene lies in a possible transcription unit, acbKLMNOC, cluster encompassing putative biosynthetic genes for cyclitol conversion. All genes were heterologously expressed in strains of Streptomyces lividans 66 strains 1326, TK23, and TK64. The AcbK protein was identified as the acarbose 7-kinase, which had been described earlier (Drepper, A., and Pape, H. (1996) J. Antibiot. (Tokyo) 49, 664-668). The multistep conversion of 2-epi-5-epi-valiolone to the final cyclitol moiety was studied by testing enzymatic mechanisms such as dehydration, reduction, epimerization, and phosphorylation. Thus, a phosphotransferase activity was identified modifying 2-epi-5-epi-valiolone by ATP-dependent phosphorylation. This activity could be attributed to the AcbM protein by verifying this activity in S. lividans strain TK64/pCW4123M, expressing His-tagged AcbM. The His-tagged AcbM protein was purified and subsequently characterized as a 2-epi-5-epi-valiolone 7-kinase, presumably catalyzing the first enzyme reaction in the biosynthetic route, leading to an activated form of the intermediate 1-epi-valienol. The AcbK protein could not catalyze the same reaction nor convert any of the other C-7-cyclitol monomers tested. The 2-epi-5-epi-valiolone 7-phosphate was further converted by the AcbO protein to another isomeric and phosphorylated intermediate, which was likely to be the 2-epimer 5-epi-valiolone 7-phosphate. The products of both enzyme reactions were characterized by mass spectrometric methods. The product of the AcbM-catalyzed reaction, 2-epi-5-epi-valiolone 7-phosphate, was purified on a preparative scale and identified by NAIR spectroscopy. A biosynthetic pathway for the pseudodisaccharidic acarviosyl moiety of acarbose is proposed on the basis of these data.
• Alternative Epimerization in C7N-Aminocyclitol Biosynthesis Is Catalyzed by ValD, A Large Protein of the Vicinal Oxygen Chelate Superfamily
  作者：Hui Xu、Yirong Zhang、Jongtae Yang、Taifo Mahmud、Linquan Bai、Zixin Deng

  DOI：10.1016/j.chembiol.2009.04.006

  日期：2009.5

  Gene valD, encodes a large vicinal oxygen chelate (VOC) superfamily protein, has been identified in the validamycin biosynthetic gene cluster. Inactivation of valD significantly reduced validamycin A production, which was fully restored with the full-length valD and partially restored with either N-terminal or C-terminal half by complementation. Heterologously expressed ValD catalyzed the epimerization of 2-epi-5-epi-valiolone to 5-epi-valiolone. This metalloenzyme is a homodimer with a metal ion-binding ratio of 0.73 mol/mole protein toward Fe2+, Mn2+, Ni2+, and Zn2+. Individual and combined site-directed mutations of eight putative active site residues revealed that the N-terminal H44/E107 and the C-terminal H315/E366 are more critical for the activity than the internal H130, E183, H229, and E291. Our data have established ValD as one of the largest proteins of the VOC superfamily, catalyzing an alternative epimerization for C7N-aminocyclitol biosynthesis.