2-aminomuconic acid semialdehyde | 150994-59-5

• 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
• 英文名称: 2-aminomuconic acid semialdehyde
• 英文别名: 2-aminomuconate semialdehyde；2-amino-6-oxo-hexa-2,4-dienoic acid；2-Amino-6-oxohexa-2,4-dienoic acid
• CAS: 150994-59-5
• 化学式: C₆H₇NO₃
• 分子量: 141.126
• InChiKey: QCGTZPZKJPTAEP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  10
• 可旋转键数：
  3
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  80.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-aminomuconic acid semialdehyde 在 ALDH₈A₁ 、 β-烟酰胺腺嘌呤二核苷酸 作用下， 以 水 为溶剂， 生成 丁二酸,1,4-二(2-乙氧基乙基)酯
  参考文献：
  名称：

  Reassignment of the human aldehyde dehydrogenase ALDH8A1 (ALDH12) to the kynurenine pathway in tryptophan catabolism

  摘要：

  The kynurenine pathway is the primary route for l-tryptophan degradation in mammals. Intermediates and side products of this pathway are involved in immune response and neurodegenerative diseases. This makes the study of enzymes, especially those from mammalian sources, of the kynurenine pathway worthwhile. Recent studies on a bacterial version of an enzyme of this pathway, 2-aminomuconate semialdehyde (2-AMS) dehydrogenase (AMSDH), have provided a detailed understanding of the catalytic mechanism and identified residues conserved for muconate semialdehyde recognition and activation. Findings from the bacterial enzyme have prompted the reconsideration of the function of a previously identified human aldehyde dehydrogenase, ALDH8A1 (or ALDH12), which was annotated as a retinal dehydrogenase based on its ability to preferentially oxidize 9-cis-retinal over trans-retinal. Here, we provide compelling bioinformatics and experimental evidence that human ALDH8A1 should be reassigned to the missing 2-AMS dehydrogenase of the kynurenine metabolic pathway. For the first time, the product of the semialdehyde oxidation by AMSDH is also revealed by NMR and high-resolution MS. We found that ALDH8A1 catalyzes the NAD(+)-dependent oxidation of 2-AMS with a catalytic efficiency equivalent to that of AMSDH from the bacterium Pseudomonas fluorescens. Substitution of active-site residues required for substrate recognition, binding, and isomerization in the bacterial enzyme resulted in human ALDH8A1 variants with 160-fold increased K-m or no detectable activity. In conclusion, this molecular study establishes an additional enzymatic step in an important human pathway for tryptophan catabolism.

  DOI：

  10.1074/jbc.ra118.003320
• 作为产物：
  描述：

  (2Z)-2-氨基-3-[(1Z)-3-氧代-1-丙烯-1-基]-2-丁烯二酸 在 α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase 作用下， 以 aq. buffer 为溶剂， 生成 2-aminomuconic acid semialdehyde
  参考文献：
  名称：

  The Power of Two

  摘要：

  Although the crystal structure of alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase from Pseudomonas fluorescens was solved as a dimer, this enzyme is a mixture of monomer, dimer, and higher order structures in solution. In this work, we found that the dimeric state, not the monomeric state, is the functionally active form. Two conserved arginine residues are present in the active site: Arg-51 and an intruding Arg-239* from the neighboring subunit. In this study, they were each mutated to alanine and lysine, and all four mutants were catalytically inactive. The mutants were also incapable of accommodating pyridine-2,6-dicarboxylic acid, a competitive inhibitor of the native enzyme, suggesting that the two Arg residues are involved in substrate binding. It was also observed that the decarboxylase activity was partially recovered in a heterodimer hybridization experiment when inactive R51(A/K) and R239(A/K) mutants were mixed together. Of the 20 crystal structures obtained from mixing inactive R51A and R239A homodimers that diffracted to a resolution lower than 3.00 angstrom, two structures are clearly R51A/R239A heterodimers and belong to the C2 space group. They were refined to 1.80 and 2.00 angstrom resolutions, respectively. Four of the remaining crystals are apparently single mutants and belong to the P4(2)2(1)2 space group. In the heterodimer structures, one active site is shown to contain dual mutation of Ala-51 and Ala-239*, whereas the other contains the native Arg-51 and Arg-239* residues, identical to the wildtype structure. Thus, these observations provide the foundation for a molecular mechanism by which the oligomerization state of alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase could regulate the enzyme activity.

  DOI：

  10.1074/jbc.m113.496869