β-1-O-methyl-ADP-ribose | 68521-69-7

• 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: β-1-O-methyl-ADP-ribose
• 英文别名: [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2R,3S,4R,5R)-3,4-dihydroxy-5-methoxyoxolan-2-yl]methyl hydrogen phosphate
• CAS: 68521-69-7
• 化学式: C₁₆H₂₅N₅O₁₄P₂
• 分子量: 573.347
• InChiKey: XNNSDOSOBTWHPT-MLCZKHQMSA-N

物化性质

• 沸点：
  934.7±75.0 °C(Predicted)
• 密度：
  2.25±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -5.6
• 重原子数：
  37
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  281
• 氢给体数：
  7
• 氢受体数：
  18

反应信息

• 作为产物：
  描述：

  甲醇 、 β-烟酰胺腺嘌呤二核苷酸 在 bovine CD₃₈/NAD⁺ glycohydrolase mutant E₁₃₈A 作用下， 以 aq. phosphate buffer 为溶剂， 生成 β-1-O-methyl-ADP-ribose
  参考文献：
  名称：

  Probing the catalytic mechanism of bovine CD38/NAD+glycohydrolase by site directed mutagenesis of key active site residues

  摘要：

  Bovine CD38/NAD(+) glycohydrolase catalyzes the hydrolysis of NAD(+) to nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose via a stepwise reaction mechanism. Our recent crystallographic study of its Michaelis complex and covalently-trapped intermediates provided insights into the modalities of substrate binding and the molecular mechanism of bCD38. The aim of the present work was to determine the precise role of key conserved active site residues (Trp118, Glu138, Asp147, Trp181 and Glu218) by focusing mainly on the cleavage of the nicotinamide-ribosyl bond. We analyzed the kinetic parameters of mutants of these residues which reside within the bCD38 subdomain in the vicinity of the scissile bond of bound NAD(+). To address the reaction mechanism we also performed chemical rescue experiments with neutral (methanol) and ionic (azide, formate) nucleophiles. The crucial role of Glu218, which orients the substrate for cleavage by interacting with the N-ribosyl 2'-OH group of NAD(+), was highlighted. This contribution to catalysis accounts for almost half of the reaction energy barrier. Other contributions can be ascribed notably to Glu138 and Asp147 via ground-state destabilization and desolvation in the vicinity of the scissile bond. Key interactions with Trp118 and Trp181 were also proven to stabilize the ribooxocarbenium ion-like transition state. Altogether we propose that, as an alternative to a covalent acylal reaction intermediate with Glu218, catalysis by bCD38 proceeds through the formation of a discrete and transient ribooxocarbenium intermediate which is stabilized within the active site mostly by electrostatic interactions. (C) 2014 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.bbapap.2014.03.014

文献信息

• Pyridine nucleotide chemistry. A new mechanism for the hydroxide-catalyzed hydrolysis of the nicotinamide-glycosyl bond
  作者：Randy W. Johnson、Thomas M. Marschner、Norman J. Oppenheimer

  DOI：10.1021/ja00215a041

  日期：1988.3
• Probing the catalytic mechanism of bovine CD38/NAD+glycohydrolase by site directed mutagenesis of key active site residues
  作者：Isabelle Kuhn、Esther Kellenberger、Céline Cakir-Kiefer、Hélène Muller-Steffner、Francis Schuber

  DOI：10.1016/j.bbapap.2014.03.014

  日期：2014.7

  Bovine CD38/NAD(+) glycohydrolase catalyzes the hydrolysis of NAD(+) to nicotinamide and ADP-ribose and the formation of cyclic ADP-ribose via a stepwise reaction mechanism. Our recent crystallographic study of its Michaelis complex and covalently-trapped intermediates provided insights into the modalities of substrate binding and the molecular mechanism of bCD38. The aim of the present work was to determine the precise role of key conserved active site residues (Trp118, Glu138, Asp147, Trp181 and Glu218) by focusing mainly on the cleavage of the nicotinamide-ribosyl bond. We analyzed the kinetic parameters of mutants of these residues which reside within the bCD38 subdomain in the vicinity of the scissile bond of bound NAD(+). To address the reaction mechanism we also performed chemical rescue experiments with neutral (methanol) and ionic (azide, formate) nucleophiles. The crucial role of Glu218, which orients the substrate for cleavage by interacting with the N-ribosyl 2'-OH group of NAD(+), was highlighted. This contribution to catalysis accounts for almost half of the reaction energy barrier. Other contributions can be ascribed notably to Glu138 and Asp147 via ground-state destabilization and desolvation in the vicinity of the scissile bond. Key interactions with Trp118 and Trp181 were also proven to stabilize the ribooxocarbenium ion-like transition state. Altogether we propose that, as an alternative to a covalent acylal reaction intermediate with Glu218, catalysis by bCD38 proceeds through the formation of a discrete and transient ribooxocarbenium intermediate which is stabilized within the active site mostly by electrostatic interactions. (C) 2014 Elsevier B.V. All rights reserved.