bis(triethylammonium) UDP-[2-F]Galp

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷酸
• 英文名称: bis(triethylammonium) UDP-[2-F]Galp
• 英文别名: UDP-2-fluoro-2-deoxy-α-D-galactose bis(triethylamine)；N,N-diethylethanamine;[[(2R,3S,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2R,3R,4S,5R,6R)-3-fluoro-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl] hydrogen phosphate
• 化学式: 2C₆H₁₅N*C₁₅H₂₃FN₂O₁₆P₂
• 分子量: 770.681
• InChiKey: KQBPORIGNMEOHT-AMKQWFBQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.47
• 重原子数：
  43
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  275
• 氢给体数：
  8
• 氢受体数：
  18

反应信息

• 作为反应物：
  描述：

  bis(triethylammonium) UDP-[2-F]Galp 在 sodium dithionite 、 potassium phosphate buffer 、 UDP-Galp mutase 作用下， 生成 bis(triethylammonium) UDP-[2-F]Galf
  参考文献：
  名称：

  Mechanistic Investigation of UDP-Galactopyranose Mutase from Escherichia coli Using 2- and 3-Fluorinated UDP-Galactofuranose as Probes

  摘要：

  The galactofuranose moiety found in many surface constituents of microorganisms is derived from UDP-D-galactopyranose (UDP-Galp) via a unique ring contraction reaction catalyzed by UDP-Galp mutase. This enzyme, which has been isolated from several bacterial sources, is a flavoprotein. To study this catalysis, the cloned Escherichia coli mutase was purified and two fluorinated analogues, UDP-[2-F]Galf(9) and UDP-[3-F]Galf(10), were chemically synthesized. These two compounds were found to be substrates for the reduced UDP-Galp mutase with the K-m values determined to be 65 and 861 muM for 9 and 10, respectively, and the corresponding k(cat) values estimated to be 0.033 and 5.7 s(-1). Since the fluorine substituent is redox inert, a mechanism initiated by the oxidation of 2-OH or 3-OH on the galactose moiety can thus be firmly ruled out. Furthermore, both 9 and 10 are poorer substrates than UDP-Galf, and the rate reduction for 9 is especially significant. This finding may be ascribed to the inductive effect of the 2-F substituent that is immediately adjacent to the anomeric center, and is consistent with a mechanism involving formation of oxocarbenium intermediates or transition states during turnover. Interestingly, under nonreducing conditions, compounds 9 and 10 are not substrates, but instead are inhibitors for the mutase. The inactivation by 10 is time-dependent, active-site-directed. and irreversible with a K-I of 270 muM and a k(inact) of 0.19 min(-1). Since the K-I value is similar to K-m, the observed inactivation is unlikely a result of tight binding. To our surprise, the inactivated enzyme could be regenerated in the presence of dithionite, and the reduced enzyme is resistant to inactivation by these fluorinated analogues. It is possible that reduction of the enzyme-bound FAD may induce a conformational change that facilitates the breakdown of the putative covalent enzyme-inhibitor adduct to reactivate the enzyme. It is also conceivable that the reduced flavin bears a higher electron density at N-1, which may play a role in preventing the formation of the covalent adduct or facilitating its breakdown by charge stabilization of the oxocarbenium intermediates/transition states. Clearly, this study has led to the identification of a potent inactivator (10) for this enzyme, and study of its inactivation has also shed light on the possible mechanism of this mutase.

  DOI：

  10.1021/ja010473l
• 作为产物：
  描述：

  bis(triethylammonium) UDP-[2-F]Galf 在 sodium dithionite 、 potassium phosphate buffer 、 UDP-Galp mutase 作用下， 生成 bis(triethylammonium) UDP-[2-F]Galp
  参考文献：
  名称：

  Mechanistic Investigation of UDP-Galactopyranose Mutase from Escherichia coli Using 2- and 3-Fluorinated UDP-Galactofuranose as Probes

  摘要：

  The galactofuranose moiety found in many surface constituents of microorganisms is derived from UDP-D-galactopyranose (UDP-Galp) via a unique ring contraction reaction catalyzed by UDP-Galp mutase. This enzyme, which has been isolated from several bacterial sources, is a flavoprotein. To study this catalysis, the cloned Escherichia coli mutase was purified and two fluorinated analogues, UDP-[2-F]Galf(9) and UDP-[3-F]Galf(10), were chemically synthesized. These two compounds were found to be substrates for the reduced UDP-Galp mutase with the K-m values determined to be 65 and 861 muM for 9 and 10, respectively, and the corresponding k(cat) values estimated to be 0.033 and 5.7 s(-1). Since the fluorine substituent is redox inert, a mechanism initiated by the oxidation of 2-OH or 3-OH on the galactose moiety can thus be firmly ruled out. Furthermore, both 9 and 10 are poorer substrates than UDP-Galf, and the rate reduction for 9 is especially significant. This finding may be ascribed to the inductive effect of the 2-F substituent that is immediately adjacent to the anomeric center, and is consistent with a mechanism involving formation of oxocarbenium intermediates or transition states during turnover. Interestingly, under nonreducing conditions, compounds 9 and 10 are not substrates, but instead are inhibitors for the mutase. The inactivation by 10 is time-dependent, active-site-directed. and irreversible with a K-I of 270 muM and a k(inact) of 0.19 min(-1). Since the K-I value is similar to K-m, the observed inactivation is unlikely a result of tight binding. To our surprise, the inactivated enzyme could be regenerated in the presence of dithionite, and the reduced enzyme is resistant to inactivation by these fluorinated analogues. It is possible that reduction of the enzyme-bound FAD may induce a conformational change that facilitates the breakdown of the putative covalent enzyme-inhibitor adduct to reactivate the enzyme. It is also conceivable that the reduced flavin bears a higher electron density at N-1, which may play a role in preventing the formation of the covalent adduct or facilitating its breakdown by charge stabilization of the oxocarbenium intermediates/transition states. Clearly, this study has led to the identification of a potent inactivator (10) for this enzyme, and study of its inactivation has also shed light on the possible mechanism of this mutase.

  DOI：

  10.1021/ja010473l

文献信息

• Synthesis of Nonnatural Nucleoside Diphosphate Sugars
  作者：Saskia Wolf、Rosmirt Molina Berrio、Chris Meier

  DOI：10.1002/ejoc.201100906

  日期：2011.11

  an efficient chemical method for the synthesis of a variety of naturally occurring nucleoside diphosphate (NDP) sugars. This method, which is based on the cycloSal approach, can also be used, in principle, for the preparation of rare or even nonnatural NDP sugars. Herein, the syntheses of sulfoquinovose-, glucose-6-sulfate-, L-galactose-, and 2-fluoroglycopyranoside-containing NDP sugars are presented

  最近，我们报道了一种合成多种天然核苷二磷酸 (NDP) 糖的有效化学方法。这种基于 cycloSal 方法的方法原则上也可用于制备稀有甚至非天然 NDP 糖。在此，介绍了含有磺基奎诺糖、葡萄糖-6-硫酸盐、L-半乳糖和 2-氟吡喃糖苷的 NDP 糖的合成，以及具有非天然核苷的 NDP 糖的合成。所描述的反应以高产率和短反应时间提供立体异构定义的 NDP 糖。