2-氨基-6-[(4-羟基-4-氧代丁酰基)氨基]庚二酸 | 26605-36-7

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 2-氨基-6-[(4-羟基-4-氧代丁酰基)氨基]庚二酸
• 英文名称: N-succinyl-L,L-2,6-diaminopimelate
• 英文别名: N-succinyl-L,L-diaminopimelic acid；L_S-threo-2-amino-6-(3-carboxy-propionylamino)-heptanedioic acid；L_S-threo-2-Amino-6-(3-carboxy-propionylamino)-heptandisaeure；N-succinyl-LL-2,6-diaminopimelic acid；(2S,6S)-2-amino-6-(3-carboxypropanoylamino)heptanedioic acid
• CAS: 26605-36-7
• 化学式: C₁₁H₁₈N₂O₇
• 分子量: 290.273
• InChiKey: GLXUWZBUPATPBR-BQBZGAKWSA-N

物化性质

• 沸点：
  679.0±55.0 °C(Predicted)
• 密度：
  1.420±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -3.9
• 重原子数：
  20
• 可旋转键数：
  10
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  167
• 氢给体数：
  5
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2-氨基-6-[(4-羟基-4-氧代丁酰基)氨基]庚二酸 在 Haemophilus influenzae N-succinyl-L,L-diaminopimelic acid desuccinylase, recombinant, Mr: 41500 作用下， 生成 (6S,2S)-二氨基庚二酸
  参考文献：
  名称：

  Structural Basis for Catalysis by the Mono- and Dimetalated Forms of the dapE-Encoded N-succinyl-l,l-Diaminopimelic Acid Desuccinylase

  摘要：

  Biosynthesis of lysine and meso-diaminopimelic acid in bacteria provides essential components for protein synthesis and construction of the bacterial peptidoglycan cell wall. The dapE operon enzymes synthesize both mesodiaminopimelic acid and lysine and, therefore, represent potential targets for novel antibacterials. The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase functions in a late step of the pathway and converts N-succinyl-L,L-diaminopimelic acid to L,L-diaminopimelic acid and succinate. Deletion of the dapE gene is lethal to Helicobacter pylori and Mycobacterium smegmatis, indicating that DapE's are essential for cell growth and proliferation. Since there are no similar pathways in humans, inhibitors that target DapE may have selective toxicity against only bacteria. A major limitation in developing antimicrobial agents that target DapE has been the lack of structural information. Herein, we report the high-resolution X-ray crystal structures of the DapE from Haemophilus influenzae with one and two zinc ions bound in the active site, respectively. These two forms show different activity. Based on these newly determined structures, we propose a revised catalytic mechanism of peptide bond cleavage by DapE enzymes. These structures provide important insight into catalytic mechanism of DapE enzymes as well as a structural foundation that is critical for the rational design of DapE inhibitors. (c) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.jmb.2010.01.062
• 作为产物：
  描述：

  (S)-2-(3-Carboxy-propionylamino)-6-oxo-heptanedioic acid 在 LL-diaminopimelate aminotransferase 磷酸吡哆醛 、 2-氨基戊二酸酯 、 还原型辅酶II(NADPH)四钠盐 作用下， 以 various solvents 为溶剂， 生成 2-氨基-6-[(4-羟基-4-氧代丁酰基)氨基]庚二酸
  参考文献：
  名称：

  Synthesis and in vitro enzyme activity of peptide derivatives of bacterial cell wall biosynthesis inhibitors

  摘要：

  二氨基庚二酸转氨酶（DAP-AT）是一个良好的新型抗菌药物设计潜在靶点。我们基于DAP-AT天然底物的结构，合成了一系列肽酰肼化合物。这些化合物在体外对大肠杆菌来源的DAP-AT表现出不同的抑制性质，并具有中等程度的抗大肠杆菌活性。抑制动力学的研究表明，肽酰肼及其取代物表现出两阶段慢速结合抑制作用。文章还讨论了可能的抑制机制。

  DOI：

  10.1039/b002701o

文献信息

• Atomic-Resolution 1.3 Å Crystal Structure, Inhibition by Sulfate, and Molecular Dynamics of the Bacterial Enzyme DapE
  作者：Matthew Kochert、Boguslaw P. Nocek、Thahani S. Habeeb Mohammad、Elliot Gild、Kaitlyn Lovato、Tahirah K. Heath、Richard C. Holz、Kenneth W. Olsen、Daniel P. Becker

  DOI：10.1021/acs.biochem.0c00926

  日期：2021.3.30

  We report the atomic-resolution (1.3 Å) X-ray crystal structure of an open conformation of the dapE-encoded N-succinyl-l,l-diaminopimelic acid desuccinylase (DapE, EC 3.5.1.18) from Neisseria meningitidis. This structure [Protein Data Bank (PDB) entry 5UEJ] contains two bound sulfate ions in the active site that mimic the binding of the terminal carboxylates of the N-succinyl-l,l-diaminopimelic acid (l,l-SDAP) substrate. We demonstrated inhibition of DapE by sulfate (IC50 = 13.8 ± 2.8 mM). Comparison with other DapE structures in the PDB demonstrates the flexibility of the interdomain connections of this protein. This high-resolution structure was then utilized as the starting point for targeted molecular dynamics experiments revealing the conformational change from the open form to the closed form that occurs when DapE binds l,l-SDAP and cleaves the amide bond. These simulations demonstrated closure from the open to the closed conformation, the change in RMS throughout the closure, and the independence in the movement of the two DapE subunits. This conformational change occurred in two phases with the catalytic domains moving toward the dimerization domains first, followed by a rotation of catalytic domains relative to the dimerization domains. Although there were no targeting forces, the substrate moved closer to the active site and bound more tightly during the closure event.

  我们报告了脑膜炎奈瑟菌中由 dapE 编码的 N-琥珀酰-l,l-二氨基亚庚酸脱琥珀酰化酶（DapE，EC 3.5.1.18）的开放构象的原子分辨率（1.3 Å）X 射线晶体结构。该结构[蛋白质数据库（PDB）条目 5UEJ]的活性位点含有两个结合的硫酸根离子，模拟 N-琥珀酰-l,l-二氨基亚庚酸（l,l-SDAP）底物末端羧酸根的结合。我们证实了硫酸盐对 DapE 的抑制作用（IC50 = 13.8 ± 2.8 mM）。与 PDB 中其他 DapE 结构的比较显示了该蛋白结构域间连接的灵活性。随后，以这一高分辨率结构为起点，进行了有针对性的分子动力学实验，揭示了当 DapE 结合 l,l-SDAP 并裂解酰胺键时，从开放形态到封闭形态的构象变化。这些模拟展示了从开放构象到封闭构象的闭合、整个闭合过程中 RMS 的变化以及两个 DapE 亚基运动的独立性。这种构象变化分为两个阶段，首先是催化结构域向二聚结构域移动，然后是催化结构域相对于二聚结构域的旋转。虽然没有靶向力，但底物在闭合过程中更靠近活性位点，结合得更紧密。
• Gilvarg, Journal of Biological Chemistry, 1959, vol. 234, p. 2955,2958
  作者：Gilvarg

  DOI：——

  日期：——
• Synthesis and in vitro enzyme activity of peptide derivatives of bacterial cell wall biosynthesis inhibitors
  作者：Russell J. Cox、Helen Jenkins、James A. Schouten、Rosie A. Stentiford、Katrina J. Wareing

  DOI：10.1039/b002701o

  日期：——

  The enzyme diaminopimelate aminotransferase (DAP-AT) is a good potential target for the design of novel antibacterial agents. We have synthesised a series of peptide hydrazines based on the structure of the natural substrate of DAP-AT. These compounds show varied inhibition properties in vitrovs. DAP-AT from E. coli as well as moderate antimicrobial activity vs. E. coli. Examination of the kinetics of inhibition reveals that hydrazine, as well as the substituted hydrazino-peptides, shows two-phase slow-binding inhibition. Possible mechanisms for inhibition are discussed.

  二氨基庚二酸转氨酶（DAP-AT）是一个良好的新型抗菌药物设计潜在靶点。我们基于DAP-AT天然底物的结构，合成了一系列肽酰肼化合物。这些化合物在体外对大肠杆菌来源的DAP-AT表现出不同的抑制性质，并具有中等程度的抗大肠杆菌活性。抑制动力学的研究表明，肽酰肼及其取代物表现出两阶段慢速结合抑制作用。文章还讨论了可能的抑制机制。
• Structural Basis for Catalysis by the Mono- and Dimetalated Forms of the dapE-Encoded N-succinyl-l,l-Diaminopimelic Acid Desuccinylase
  作者：Boguslaw P. Nocek、Danuta M. Gillner、Yao Fan、Richard C. Holz、Andrzej Joachimiak

  DOI：10.1016/j.jmb.2010.01.062

  日期：2010.4

  Biosynthesis of lysine and meso-diaminopimelic acid in bacteria provides essential components for protein synthesis and construction of the bacterial peptidoglycan cell wall. The dapE operon enzymes synthesize both mesodiaminopimelic acid and lysine and, therefore, represent potential targets for novel antibacterials. The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase functions in a late step of the pathway and converts N-succinyl-L,L-diaminopimelic acid to L,L-diaminopimelic acid and succinate. Deletion of the dapE gene is lethal to Helicobacter pylori and Mycobacterium smegmatis, indicating that DapE's are essential for cell growth and proliferation. Since there are no similar pathways in humans, inhibitors that target DapE may have selective toxicity against only bacteria. A major limitation in developing antimicrobial agents that target DapE has been the lack of structural information. Herein, we report the high-resolution X-ray crystal structures of the DapE from Haemophilus influenzae with one and two zinc ions bound in the active site, respectively. These two forms show different activity. Based on these newly determined structures, we propose a revised catalytic mechanism of peptide bond cleavage by DapE enzymes. These structures provide important insight into catalytic mechanism of DapE enzymes as well as a structural foundation that is critical for the rational design of DapE inhibitors. (c) 2010 Elsevier Ltd. All rights reserved.