3-dehydroquinate

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-dehydroquinate
• 英文别名: (1R,3R,4S)-1,3,4-trihydroxy-5-oxocyclohexane-1-carboxylate
• 化学式: C₇H₉O₆
• 分子量: 189.145
• InChiKey: WVMWZWGZRAXUBK-SYTVJDICSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -1.7
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  118
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-dehydroquinate 在 zinc(II) sulfate 3-dehydroquinate dehydratase 、 HEPES buffer 、 oxidized β-nicotinamide-adenine dinucleotide 作用下， 以 sodium hydroxide 、 甘油 为溶剂， 生成 3-dehydroshikimate
  参考文献：
  名称：

  反应的热力学研究：{2-dehydro-3-deoxy-d-arabino-heptanoate 7-phosphate(aq)=3-dehydroquinate(aq) + 磷酸盐(aq)}和{3-dehydroquinate(aq)=3 -脱氢莽草酸盐(aq)+H2O(l)}

  摘要：

  摘要 微量热法和高效液相色谱 (hplc) 已被用于对 3-脱氢奎尼酸合酶和 3-脱氢奎尼酸脱水酶催化的反应进行热力学研究。这些是导致分支酸形成的代谢途径中的第二和第三反应。这两个反应是：{DAHP(aq)=3-脱氢奎宁酸(aq)+磷酸盐(aq)}和{3-脱氢奎宁酸(aq)=3-脱氢莽草酸(aq)+H 2 O(l)}。hplc 测量表明，第一个反应进行到完成，第二个反应的表观平衡常数值为 K ' =（4.6±1.5）（Hepes 缓冲液，温度 T = 298.15 K，pH = 7.50，离子强度I m =0.065 mol·kg -1 )。量热测量导致反应摩尔焓 Δ r H m ( cal )=-(50.9±1.1) kJ · mol -1（Hepes 缓冲液，T =298.15 K, pH=7.46, I m =0.070 mol · kg -1 ) 对于第一反应和 Δ r H m (

  DOI：

  10.1016/s0021-9614(02)00226-4
• 作为产物：
  描述：

  3,7-dideoxy-D-threo-hepto-2,6-diuolosonate 生成 3-dehydroquinate
  参考文献：
  名称：

  l-Aspartate Semialdehyde and a 6-Deoxy-5-ketohexose 1-Phosphate Are the Precursors to the Aromatic Amino Acids in Methanocaldococcus jannaschii

  摘要：

  No orthologs are present in the genomes of the archaea encoding genes for the first two steps in the biosynthesis of the aromatic amino acids leading to 3-dehydroquinate (DHQ). The absence of these genes prompted me to examine the nature of the reactions involved in the archaeal pathway leading to DHQ in Methanocaldococcus jannaschii. Here I report that 6-deoxy-5-ketofructose 1-phosphate and L-aspartate semialdehyde are precursors to DHQ. The sugar, which is derived from glucose 6-P, supplies a "hydroxyacetone" fragment, which, via a transaldolase reaction, undergoes an aldol condensation with the L-aspartate semialdehyde to form 2-amino-3,7-dideoxy-D-threo-hept-6-ulosonic acid. Despite the fact that both hydroxyacetone and hydroxyacetone-P were measured in the cell extracts and confirmed to arise from glucose 6-P, neither compound was found to serve as a precursor to DHQ. This amino sugar then undergoes a NAD dependent oxidative deamination to produce 3,7-dideoxy-D-threo-hept-2,6-diulosonic acid which cyclizes to 3-dehydroquinate. The protein product of the M. jannaschii MJ0400 gene catalyzes the transaldolase reaction and the protein product of the MJ1249 gene catalyzes the oxidative deamination and the cyclization reactions. The DHQ is readily converted into dehydroshikimate and shikimate in M. jannaschii cell extracts, consistent with the remaining steps and genes in the pathway being the same as in the established shikimate pathway.

  DOI：

  10.1021/bi0495127

文献信息

• 3-Dehydroquinate Production by Oxidative Fermentation and Further Conversion of 3-Dehydroquinate to the Intermediates in the Shikimate Pathway
  作者：Osao ADACHI、Somboon TANASUPAWAT、Nozomi YOSHIHARA、Hirohide TOYAMA、Kazunobu MATSUSHITA

  DOI：10.1271/bbb.67.2124

  日期：2003.1

  3-Dehydroquinate production from quinate by oxidative fermentation with Gluconobacter strains of acetic acid bacteria was analyzed for the first time. In the bacterial membrane, quinate dehydrogenase, a typical quinoprotein containing pyrroloquinoline quinone (PQQ) as the coenzyme, functions as the primary enzyme in quinate oxidation. Quinate was oxidized to 3-dehydroquinate with the final yield of almost 100% in earlier growth phase. Resting cells, dried cells, and immobilized cells or an immobilized membrane fraction of Gluconobacter strains were found to be useful biocatalysts for quinate oxidation. 3-Dehydroquinate was further converted to 3-dehydroshikimate with a reasonable yield by growing cells and also immobilized cells. Strong enzyme activities of 3-dehydroquinate dehydratase and NADP-dependent shikimate dehydrogenase were detected in the soluble fraction of the same organism and partially fractionated from each other. Since the shikimate pathway is remote from glucose in the metabolic pathway, the entrance into the shikimate pathway from quinate to 3-dehydroquinate looks advantageous to produce metabolic intermediates in the shikimate pathway.

  研究人员首次分析了醋酸细菌中的葡萄糖菌株通过氧化发酵从醌酸产生3-脱氢醌酸的过程。在细菌膜中，醌脱氢酶是一种典型的醌蛋白，含有吡咯喹啉醌（PQQ）作为辅酶，是醌氧化的主要酶。在早期生长阶段，奎宁酸被氧化成 3-脱氢奎宁酸，最终产量几乎达到 100%。研究发现，葡萄糖杆菌菌株的静止细胞、干燥细胞、固定化细胞或固定化膜部分是奎宁酸氧化的有效生物催化剂。生长细胞和固定化细胞可将 3-脱氢醌进一步转化为 3-脱氢ikimate，且产量合理。在同一生物体的可溶性馏分中检测到了3-脱氢醌脱水酶和依赖于NADP的莽草酸脱氢酶的强酶活性，并且它们之间有部分分离。由于莽草酸途径在新陈代谢途径中远离葡萄糖，因此从醌到3-脱氢醌进入莽草酸途径看起来有利于产生莽草酸途径的新陈代谢中间产物。
• Dehydroquinate synthase: the role of divalent metal cations and of nicotinamide adenine dinucleotide in catalysis
  作者：Steven L. Bender、Shujaath Mehdi、Jeremy R. Knowles

  DOI：10.1021/bi00445a009

  日期：1989.9.19

  The cofactor requirements of dehydroquinate synthase from Escherichia coli have been characterized. The homogeneous enzyme, purified from the overproducing strain RB791 (pJB14), is a monomeric metalloenzyme of Mr = 39,000 that contains 1 mol of tightly bound Co(II) according to atomic absorption analysis. The holoenzyme rapidly loses activity upon incubation with EDTA, giving rise to a stable but catalytically

  已经表征了来自大肠杆菌的脱氢奎宁酸合酶的辅因子需求。从过量生产的菌株RB791（pJB14）中纯化的同质酶是Mr = 39,000的单体金属酶，根据原子吸收分析，该酶含有1 mol紧密结合的Co（II）。与EDTA孵育后，全酶迅速丧失活性，从而产生稳定但催化失活的脱辅酶。通过用Co（II）重构可以完全恢复活性，而通过其他二价阳离子可以部分恢复活性。用Zn（II）（可能是体内起作用的金属）重建脱辅基酶可以将活性恢复到Co（II）-全酶水平的53％。底物3-脱氧-D-阿拉伯糖-庚酸7-磷酸酯（1）的存在阻止了EDTA的失活。脱氢奎宁合酶也结合1 mol NAD +，其存在对于催化活性至关重要。发现NAD +从Co（II）-全酶解离的速率常数为0.024 min-1。在具有饱和底物水平的周转条件下，NAD +的解离速率增加40倍，达到1 min-1。在这些条件下（pH 7.5，20摄氏度），NAD
• Mechanism and Stereochemistry of 5-Dehydroquinate Synthetase
  作者：S. L. Rotenberg、D. B. Sprinson

  DOI：10.1073/pnas.67.4.1669

  日期：1970.12

  3-Deoxy-D- arabino -heptulosonic acid 7-phosphate (DAHP) labeled at C-7 randomly or stereospecifically with tritium and at C-1 with ¹⁴ C was converted enzymically to 5-dehydroquinate. Tritium of all three substrates was completely retained in 5-dehydroquinate, in accord with formation of a non-ketonizing 6,7-enol intermediate. The 5-dehydroquinates were dehydrated to 5-dehydroshikimate by 5-dehydroquinate dehydratase, which is known to catalyze a cis -elimination. Only 5-dehydroquinate derived from [7- ³ H](7 R )-DAHP lost its tritium in this dehydration, indicating that the configuration at C-7 was inverted in the conversion of DAHP to 5-dehydroquinate.

  以氚标记的3-去氧-D-阿拉伯糖酮-7-磷酸（DAHP）在C-7处随机或立体特异性地标记，并在C-1处标记了14C，经酶催化转化为5-去氢槲皮酸。三种底物的氚完全保留在5-去氢槲皮酸中，符合形成非酮化的6,7-烯醇中间体的形成。5-去氢槲皮酸脱水为5-去氢香草酸，该过程已知由5-去氢槲皮酸脱水酶催化进行顺式消除。只有来自[7-3H]（7R）-DAHP的5-去氢槲皮酸在脱水过程中失去了其氚，表明在DAHP转化为5-去氢槲皮酸的过程中，C-7处的构型发生了反转。
• Structure of dehydroquinate synthase reveals an active site capable of multistep catalysis
  作者：Elisabeth P. Carpenter、Alastair R. Hawkins、John W. Frost、Katherine A. Brown

  DOI：10.1038/28431

  日期：1998.7

  Dehydroquinate synthase (DHQS) has long been regarded as a catalytic marvel because of its ability to perform several consecutive chemical reactions in one active site. There has been considerable debate as to whether DHQS is actively involved in all these steps,, or whether several steps occur spontaneously, making DHQS a spectator in its own mechanism. DHQS performs the second step in the shikimate

  脱氢奎宁酸合酶 (DHQS) 长期以来被认为是一种催化奇迹，因为它能够在一个活性位点进行多个连续的化学反应。关于 DHQS 是否积极参与所有这些步骤，或者几个步骤是否自发发生，使 DHQS 成为其自身机制的旁观者，一直存在相当大的争议。DHQS 执行莽草酸途径的第二步，这是细菌、微生物真核生物和植物中合成芳香族化合物所必需的。这种酶是新型抗真菌和抗菌药物的潜在靶标，因为哺乳动物不存在莽草酸途径，而病原体毒力需要 DHQS。在这里我们报告了 DHQS 的晶体结构，它有几个意想不到的特征，在新的蛋白质折叠中，包括以前未观察到的 NAD+ 结合模式和与乙醇脱氢酶惊人相似的活性位点组织。该结构揭示了活性位点和底物类似物抑制剂之间的相互作用，这表明 DHQS 如何在不形成不需要的副产物的情况下进行多步催化。
• Kinetic mechanism determination and analysis of metal requirement of dehydroquinate synthase from Mycobacterium tuberculosisH37Rv: an essential step in the function-based rational design of anti-TB drugs
  作者：Jordana Dutra de Mendonça、Osao Adachi、Leonardo Astolfi Rosado、Rodrigo Gay Ducati、Diogenes Santiago Santos、Luiz Augusto Basso

  DOI：10.1039/c0mb00085j

  日期：——

  The number of new cases of tuberculosis (TB) arising each year is increasing globally. Migration, socio-economic deprivation, HIV co-infection and the emergence of drug-resistant strains of Mycobacterium tuberculosis, the main causative agent of TB in humans, have all contributed to the increasing number of TB cases worldwide. Proteins that are essential to the pathogen survival and absent in the host, such as enzymes of the shikimate pathway, are attractive targets to the development of new anti-TB drugs. Here we describe the metal requirement and kinetic mechanism determination of M. tuberculosisdehydroquinate synthase (MtDHQS). True steady-state kinetic parameters determination and ligand binding data suggested that the MtDHQS-catalyzed chemical reaction follows a rapid-equilibrium random mechanism. Treatment with EDTA abolished completely the activity of MtDHQS, and addition of Co2+ and Zn2+ led to, respectively, full and partial recovery of the enzyme activity. Excess Zn2+ inhibited the MtDHQS activity, and isotitration microcalorimetry data revealed two sequential binding sites, which is consistent with the existence of a secondary inhibitory site. We also report measurements of metal concentrations by inductively coupled plasma atomic emission spectrometry. The constants of the cyclic reduction and oxidation of NAD+ and NADH, respectively, during the reaction of MtDHQS was monitored by a stopped-flow instrument, under single-turnover experimental conditions. These results provide a better understanding of the mode of action of MtDHQS that should be useful to guide the rational (function-based) design of inhibitors of this enzyme that can be further evaluated as anti-TB drugs.

  全球每年新增的结核病（TB）病例数量正在增加。移民、社会经济贫困、艾滋病合并感染以及结核分枝杆菌耐药菌株的出现（结核病的主要致病因素）都是导致全球结核病病例数量增加的原因。对病原体生存至关重要的蛋白质在宿主中缺失，例如，对羟基苯丙酸途径的酶，是开发新型抗结核药物的有吸引力的靶标。在这里，我们描述了结核分枝杆菌脱氢奎宁酸合成酶（MtDHQS）的金属需求和动力学机制测定。真正的稳态动力学参数测定和配体结合数据表明，MtDHQS催化的化学反应遵循快速平衡随机机制。用EDTA处理可完全消除MtDHQS的活性，而添加Co2+和Zn2+分别导致酶活性的完全和部分恢复。过量的Zn2+抑制了MtDHQS的活性，同位素滴定微量热法数据揭示了两个连续的结合位点，这与二级抑制位点的存在是一致的。我们还报告了通过电感耦合等离子体原子发射光谱法测量金属浓度。在单周转实验条件下，通过停止流动仪器监测MtDHQS反应过程中NAD+和NADH的循环还原和氧化常数。这些结果有助于更好地理解MtDHQS的作用方式，从而指导该酶抑制剂的合理（基于功能）设计，并进一步评估其作为抗结核药物的潜力。