5-bromo-L-kynurenine | 565159-62-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 5-bromo-L-kynurenine
• 英文别名: (2S)-2-amino-4-(2-amino-5-bromophenyl)-4-oxobutanoic acid
• CAS: 565159-62-8
• 化学式: C₁₀H₁₁BrN₂O₃
• 分子量: 287.113
• InChiKey: XVTAZJDWEOGSAW-QMMMGPOBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.5
• 重原子数：
  16
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  106
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-bromo-L-kynurenine 在 sodium tetrahydroborate 作用下， 生成 5-bromodihydrokynurenine
  参考文献：
  名称：

  The phosphate of pyridoxal-5′-phosphate is an acid/base catalyst in the mechanism ofPseudomonas fluorescenskynureninase

  摘要：

  Kynureninase (l‐kynurenine hydrolase, EC 3.7.1.3) catalyzes the hydrolytic cleavage of l‐kynurenine to l‐alanine and anthranilic acid. The proposed mechanism of the retro‐Claisen reaction requires extensive acid/base catalysis. Previous crystal structures showed that Tyr226 in the Pseudomonas fluorescens enzyme (Tyr275 in the human enzyme) hydrogen bonds to the phosphate of the pyridoxal‐5′‐phosphate (PLP) cofactor. This Tyr residue is strictly conserved in all sequences of kynureninase. The human enzyme complexed with a competitive inhibitor, 3‐hydroxyhippuric acid, showed that the ligand carbonyl O is located 3.7 Å from the phenol of Tyr275 (Lima, S., Kumar, S., Gawandi, V., Momany, C. & Phillips, R. S. (2009) J. Med. Chem. 52, 389–396). We prepared a Y226F mutant of P. fluorescens kynureninase to probe the role of this residue in catalysis. The Y226F mutant has approximately 3000‐fold lower activity than wild‐type, and does not show the pKa values of 6.8 on kcat and 6.5 and 8.8 on kcat/Km seen for the wild‐type enzyme (Koushik, S. V., Moore, J. A. III, Sundararaju, B. & Phillips, R. S. (1998) Biochemistry 37, 1376–1382). Wild‐type kynureninase shows a resonance at 4.5 ppm in 31P‐NMR, which is shifted to 5.0, 3.3 and 2.0 ppm when the potent inhibitor 5‐bromodihydrokynurenine is added. However, Y226F kynureninase shows resonances at 3.6 and 2.5 ppm, and no change in the peak position is seen when 5‐bromodihydrokynurenine is added. Taken together, these results suggest that Tyr226 mediates proton transfer between the substrate and the phosphate, which accelerates formation of external aldimine and gem‐diol intermediates. Thus, the phosphate of PLP acts as an acid/base catalyst in the mechanism of kynureninase.

  DOI：

  10.1111/febs.12671
• 作为产物：
  描述：

  N-乙酰-L-色氨酸甲酯 在 盐酸 、 溴 、 sodium acetate 、 臭氧 作用下， 以 甲醇 、 溶剂黄146 为溶剂， 反应 19.0h， 生成 5-bromo-L-kynurenine
  参考文献：
  名称：

  溴化对荧光假单胞菌（Pseudomonasfluorescens）犬尿尿苷酶的底物和抑制剂的不同作用。

  摘要：

  合成了一系列溴化化合物，并评估了它们作为荧光假单胞菌犬尿氨酸酶的底物和抑制剂。发现3-溴-L-犬尿氨酸和5-溴-L-犬尿氨酸都是具有与L-犬尿氨酸相似的k（cat）值的底物，但是3-溴-L-犬尿氨酸的K（m）值非常高与5-溴-L-犬尿氨酸（11 microM）和L-犬尿氨酸（25 microM）相比要高（大约2 mM）。溴尿肾上腺素的两个异构体在停止流仪器的死时间（约1毫秒）内与尿尿氨酸酶反应，形成最大波长为494 nm的醌型中间体，其降解速率常数为300-600 s-1，与L相似。 -犬尿氨酸。还制备了5-溴二氢-L-犬尿氨酸的两种非对映异构体，它们是比二氢-L-犬尿氨酸更有效的抑制剂。（4R）-5-溴二氢-L-犬尿氨酸是迄今发现的最有效的荧光假单胞菌犬尿氨酸酶抑制剂（Ki = 55 nM），也可作为慢速底物；另一方面，（4S）-受体没有显示可测量的底物活性，但是它是有效的竞争性抑制剂，Ki值为170

  DOI：

  10.1039/b208910f

文献信息

• Substituents effects on activity of kynureninase from Homo sapiens and Pseudomonas fluorescens
  作者：Chandan Maitrani、Robert S. Phillips

  DOI：10.1016/j.bmc.2013.05.039

  日期：2013.8

  5-chloro-l, 3,5-dibromo-l and 5-bromo-3-chloro-dl) have been synthesized and tested for their substrate activity with human and Pseudomonas fluorescens kynureninase. All of the substituted kynurenines examined have substrate activity with both human as well as P. fluorescens kynureninase. For the human enzyme, 3- and 5-substituted kynurenines have kcat and kcat/Km values higher than l-kynurenine, but less

  一系列取代的犬尿氨酸的（3-溴- DL，3-氯DL，3-氟- DL，3-甲基DL，5-溴升，5-氯升，3,5-二溴升和已经合成了5-溴-3-氯-dl），并用人和荧光假单胞菌kynureninase检测了它们的底物活性。检查的所有取代的犬尿氨酸都具有人和荧光假单胞菌犬尿氨酸酶的底物活性。对于人类酶，3-和5取代的犬尿氨酸具有k cat和k cat / K m值高于1- kynurenine，但低于生理底物3-hydroxykynurenine。然而，3，5-二溴-和5-溴-3-氯炔尿氨酸的k cat和k cat / K m值与人炔尿苷酶的3-羟基犬尿氨酸接近。3-卤代取代基对与人犬尿氨酸酶的反应性的影响可能归因于电子效应和/或卤素键。相比之下，对于细菌酶，3-甲基，3-卤代和3,5-二卤代尿嘧啶是较差的底物，而3-氟，5-溴和5-氯炔尿氨酸具有k cat和k cat / K m其生理底物1-
• Substrate and inhibitor specificity of kynurenine monooxygenase from Cytophaga hutchinsonii
  作者：Robert S. Phillips、Andrew D. Anderson、Harvey G. Gentry、Osman F. Güner、J. Phillip Bowen

  DOI：10.1016/j.bmcl.2017.02.080

  日期：2017.4

  Kynurenine monooxygenase (KMO) is a potential drug target for treatment of neurodegenerative disorders such as Huntington's and Alzheimer's diseases. We have evaluated substituted kynurenines as substrates or inhibitors of KMO from Cytophaga hutchinsonii. Kynurenines substituted with a halogen at the 5-position are excellent substrates, with values of k(cat) and k(cat)/Km comparable to or higher than kynurenine. However, kynurenines substituted in the 3-position are competitive inhibitors, with K-I values lower than the Km for kynurenine. Bromination also enhances inhibition, and 3,5-dibromokynurenine is a potent competitive inhibitor with a K-1 value of 1.5 mu M. A pharmacophore model of KMO was developed, and predicted that 3,4-dichlorohippuric acid would be an inhibitor. The K1 for this compound was found to be 34 mu M, thus validating the pharmacophore model. We are using these results and our model to design more potent inhibitors of KMO. (C) 2017 Elsevier Ltd. All rights reserved.
• 2-AMINOBENZOYL DERIVATIVES
  申请人：NEURIM PHARMACEUTICALS (1991) LIMITED

  公开号：EP1644316B1

  公开（公告）日：2010-03-10
• Differential effects of bromination on substrates and inhibitors of kynureninase from Pseudomonas fluorescens
  作者：Christian Heiss、Jay Anderson、Robert S. Phillips

  DOI：10.1039/b208910f

  日期：2003.1.13

  inhibitors of kynureninase from Pseudomonas fluorescens. Both 3-bromo-L-kynurenine and 5-bromo-L-kynurenine were found to be substrates with similar k(cat) values to L-kynurenine, but the K(m) value for 3-bromo-L-kynurenine is very high (ca. 2 mM) compared to that for 5-bromo-L-kynurenine (11 microM) and L-kynurenine (25 microM). Both isomers of bromokynurenine react with kynureninase within the dead

  合成了一系列溴化化合物，并评估了它们作为荧光假单胞菌犬尿氨酸酶的底物和抑制剂。发现3-溴-L-犬尿氨酸和5-溴-L-犬尿氨酸都是具有与L-犬尿氨酸相似的k（cat）值的底物，但是3-溴-L-犬尿氨酸的K（m）值非常高与5-溴-L-犬尿氨酸（11 microM）和L-犬尿氨酸（25 microM）相比要高（大约2 mM）。溴尿肾上腺素的两个异构体在停止流仪器的死时间（约1毫秒）内与尿尿氨酸酶反应，形成最大波长为494 nm的醌型中间体，其降解速率常数为300-600 s-1，与L相似。 -犬尿氨酸。还制备了5-溴二氢-L-犬尿氨酸的两种非对映异构体，它们是比二氢-L-犬尿氨酸更有效的抑制剂。（4R）-5-溴二氢-L-犬尿氨酸是迄今发现的最有效的荧光假单胞菌犬尿氨酸酶抑制剂（Ki = 55 nM），也可作为慢速底物；另一方面，（4S）-受体没有显示可测量的底物活性，但是它是有效的竞争性抑制剂，Ki值为170
• The phosphate of pyridoxal-5′-phosphate is an acid/base catalyst in the mechanism of<i>Pseudomonas fluorescens</i>kynureninase
  作者：Robert S. Phillips、Israel Scott、Riya Paulose、Akshay Patel、Taylor Colt Barron

  DOI：10.1111/febs.12671

  日期：2014.2

  Kynureninase (l‐kynurenine hydrolase, EC 3.7.1.3) catalyzes the hydrolytic cleavage of l‐kynurenine to l‐alanine and anthranilic acid. The proposed mechanism of the retro‐Claisen reaction requires extensive acid/base catalysis. Previous crystal structures showed that Tyr226 in the Pseudomonas fluorescens enzyme (Tyr275 in the human enzyme) hydrogen bonds to the phosphate of the pyridoxal‐5′‐phosphate (PLP) cofactor. This Tyr residue is strictly conserved in all sequences of kynureninase. The human enzyme complexed with a competitive inhibitor, 3‐hydroxyhippuric acid, showed that the ligand carbonyl O is located 3.7 Å from the phenol of Tyr275 (Lima, S., Kumar, S., Gawandi, V., Momany, C. & Phillips, R. S. (2009) J. Med. Chem. 52, 389–396). We prepared a Y226F mutant of P. fluorescens kynureninase to probe the role of this residue in catalysis. The Y226F mutant has approximately 3000‐fold lower activity than wild‐type, and does not show the pKa values of 6.8 on kcat and 6.5 and 8.8 on kcat/Km seen for the wild‐type enzyme (Koushik, S. V., Moore, J. A. III, Sundararaju, B. & Phillips, R. S. (1998) Biochemistry 37, 1376–1382). Wild‐type kynureninase shows a resonance at 4.5 ppm in 31P‐NMR, which is shifted to 5.0, 3.3 and 2.0 ppm when the potent inhibitor 5‐bromodihydrokynurenine is added. However, Y226F kynureninase shows resonances at 3.6 and 2.5 ppm, and no change in the peak position is seen when 5‐bromodihydrokynurenine is added. Taken together, these results suggest that Tyr226 mediates proton transfer between the substrate and the phosphate, which accelerates formation of external aldimine and gem‐diol intermediates. Thus, the phosphate of PLP acts as an acid/base catalyst in the mechanism of kynureninase.