Aspartate aminotransferase generates proagonists of the aryl hydrocarbon receptor
Aspartate aminotransferase generates proagonists of the aryl hydrocarbon receptor
复制标题
DOI：
10.1124/mol.64.3.550
复制
发表时间：
2003-09-01
影响因子：
3.6
通讯作者：
Bradfield, CA
中科院分区：
文献类型：
--
作者：
Bittinger, MA;Nguyen, LP;Bradfield, CA
芳烃受体（aryl hydrocarbon receptor， AHR）结合平面芳香族化合物并上调一系列异种代谢酶的转录。为了鉴定参与内源性AHR配体生物合成的蛋白质，我们筛选了各种小鼠组织中AHR信号活性的提取物。我们发现心脏提取物可以激活AHR，并确定其活性成分为天冬氨酸转氨酶（EC 2.6.1.1）。我们证明这种转氨酶可以通过将l -色氨酸转化为吲哚-3-丙酮酸来激活AHR信号。反过来，吲哚-3-丙酮酸在水溶液中自发反应，形成大量的化合物，作为AHR的激动剂。酪氨酸和5-羟色胺前体5-羟色氨酸也可与天冬氨酸转氨酶联合激活AHR信号，提示4-羟基苯基丙酮酸和5-羟基吲哚丙酮酸也可作为AHR的先导剂。本研究表明，已知的色氨酸代谢中间体吲哚-3-丙酮酸是AHR的先导剂，在水溶液中反应形成多种AHR激动剂。
The aryl hydrocarbon receptor (AHR) binds planar aromatic compounds and up-regulates the transcription of a battery of xenobiotic-metabolizing enzymes. To identify proteins involved in the biosynthesis of endogenous AHR ligands, we screened extracts of various mouse tissues for AHR signaling activity. We found heart extract to activate AHR and identified the active component to be the enzyme aspartate aminotransferase (EC 2.6.1.1). We demonstrate that this transaminase can activate AHR signaling by converting L-tryptophan to indole-3-pyruvate. In turn, indole-3-pyruvate spontaneously reacts in aqueous solution to form a large number of compounds that act as agonists of AHR. Tyrosine and the serotonin-precursor 5-hydroxytryptophan also activate AHR signaling in combination with aspartate aminotransferase, suggesting that 4-hydroxyphenylpyruvate and 5-hydroxyindolepyruvate also act as proagonists of AHR. This study demonstrates that the known tryptophan metabolic-intermediate indole-3-pyruvate is a proagonist of AHR that reacts in aqueous solution to form a variety of AHR agonists.