Reactivity of Biliatresone, a Natural Biliary Toxin, with Glutathione, Histamine, and Amino Acids.
Reactivity of Biliatresone, a Natural Biliary Toxin, with Glutathione, Histamine, and Amino Acids.
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DOI：
10.1021/acs.chemrestox.5b00308
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发表时间：
2016-02-15
影响因子：
4.1
通讯作者：
Porter JR
中科院分区：
文献类型：
--
作者：
Koo KA;Waisbourd-Zinman O;Wells RG;Pack M;Porter JR
在我们之前的工作中，我们发现了一种天然毒素，胆管松，来自于肾结石和海苔属植物，这两种特有植物与澳大利亚新生牲畜胆道闭锁的爆发有关。胆甾醇酮是一种非常罕见的类黄酮，其α-亚甲基酮位于两个苯基之间，1,2-二芳基-2-丙烯酮，以及亚甲基二氧基，二甲氧基和羟基官能团，可引起斑马鱼肝外胆道毒性。胆甾酮的毒性核心是相对于1,2-二芳基-2-丙烯酮的α-位置的亚甲基，作为亲电的迈克尔受体。通过反相高效液相色谱法（RP-HPLC）分析，双乙酰胆甾醇α-亚甲基分别与水和甲醇（MeOH）自发结合。我们在此报道了胆汁松对谷胱甘肽（GSH）、几种氨基酸和其他含硫醇或咪唑的生物分子的反应性。结合反应的LC-MS和HPLC分析表明，胆甾醇的反应活性依次为组氨酸> n -乙酰-d-半胱氨酸(D-NAC) = n -乙酰-l-半胱氨酸(L-NAC) >组胺>谷胱甘肽≥半胱氨酸>甘氨酸>谷氨酸>苯丙氨酸，而丝氨酸和腺嘌呤由于在质子溶剂中存在分子内氢键而无反应活性。乙基乙烯酮（EVK， 1-戊烯-3- 1）是高活性α，ß-不饱和酮的一个例子，其对谷胱甘肽的反应速率常数比胆曲内松低6.7倍。合成的毒性分子核心结构1,2-二芳基-2-丙烯-1- 1 （DP）的反应速率常数比胆汁松和EVK的反应速率常数分别弱10倍和1.5倍。这些结果表明，与DP和EVK相比，胆甾酮的亚二氧基、二甲氧基和羟基官能团有助于Michael受体α-亚甲基酮对亲核试剂的反应性更强。
In our previous work, we identified a natural toxin, biliatresone, from Dysphania glomulifera and D. littoralis, endemic plants associated with outbreaks of biliary atresia in Australian neonatal livestock. Biliatresone is a very rare isoflavonoid with an α-methylene ketone between two phenyls, 1,2-diaryl-2-propenone, along with methylenedioxy, dimethoxyl, and hydroxyl functional groups, that causes extrahepatic biliary toxicity in zebrafish. The toxic core of biliatresone is a methylene in the α-position relative to the ketone of 1,2-diaryl-2-propenone that serves as an electrophilic Michael acceptor. The α-methylene of biliatresone spontaneously conjugated with water and methanol (MeOH), respectively, via Michael addition in a reverse phase high-performance liquid chromatography (RP-HPLC) analysis. We here report the reactivity of biliatresone toward glutathione (GSH), several amino acids, and other thiol- or imidazole-containing biomolecules. LC-MS and HPLC analysis of the conjugation reaction showed the reactivity of biliatresone to be in the order histidine > N-acetyl-d-cysteine (D-NAC) = N-acetyl-l-cysteine (L-NAC) > histamine > glutathione ≥ cysteine ≫ glycine > glutamate > phenylalanine, while serine and adenine had no reactivity due to intramolecular hydrogen bonding in the protic solvents. The reactivity of ethyl vinyl ketone (EVK, 1-penten-3-one), an example of a highly reactive α,ß-unsaturated ketone, toward GSH gave a 6.7-fold lower reaction rate constant than that of biliatresone. The reaction rate constant of synthetic 1,2-diaryl-2-propen-1-one (DP), a core structure of the toxic molecule, was 10-fold and 1.5-fold weaker in potency compared to the reaction rate constants of biliatresone and EVK, respectively. These results demostrated that the methylenedioxy, dimethoxyl, and hydroxyl functional groups of biliatresone contribute to the stronger reactivity of the Michael acceptor α-methylene ketone toward nucleophiles compared to that of DP and EVK.