Potent Activation of Indoleamine 2,3-Dioxygenase by Polysulfides.
Potent Activation of Indoleamine 2,3-Dioxygenase by Polysulfides.
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DOI：
10.1021/jacs.9b07338
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发表时间：
2019-09
影响因子：
15
通讯作者：
Micah T. Nelp;Vincent Zheng;K. Davis;K. Stiefel;J. Groves
中科院分区：
文献类型：
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作者：
Micah T. Nelp;Vincent Zheng;K. Davis;K. Stiefel;J. Groves
吲哚胺2，3-双加氧酶（IDO 1）是一种血红素酶，可催化色氨酸的吲哚环氧化生成N-甲酰犬尿氨酸。这种活性显著抑制免疫反应，介导炎症和自身免疫反应。这些间接的影响是通过IDO 1的血红素辅因子的氧化还原变化来调节的，IDO 1在周转过程中自动氧化成无活性的铁状态。这种氧化还原状态的变化增加了血红素辅因子的不稳定性，导致活性的进一步抑制。因此，细胞可以通过血红素和还原剂的供应来调节IDO 1活性。我们在这里表明，多硫化物结合到非活性铁IDO 1，并将其还原为氧结合亚铁态，从而激活IDO 1，即使在低的，生理上显著的浓度，以最大的营业额。使用停止流动光谱法，发现在pH 7下二硫化氢与铁IDO 1结合的结合速率>106 M-1 s-1。K-边XANES和EPR光谱表明，最初形成的低自旋铁硫结合的物种，然后减少到亚铁态。多硫化物对IDO 1的μM亲和力表明这些多硫化物是通过犬尿氨酸途径进行免疫调节的重要信号传导因子。色氨酸显著增强了硫化氢与IDO 1相对较低的亲和力结合，激发了小分子3-巯基吲哚（3 MI）的使用，其选择性结合并激活铁IDO 1。3 MI通过将还原当量从谷胱甘肽催化转移到IDO 1来维持周转，代表了上调先天性免疫抑制用于治疗自身免疫性疾病的新策略。因此，活性硫物质可能是未被识别的免疫介质，通过与IDO 1的这些相互作用具有作为治疗剂的潜力。
Indoleamine 2,3-dioxygenase (IDO1) is a heme enzyme that catalyzes the oxygenation of the indole ring of tryptophan to afford N-formylkynurenine. This activity significantly suppresses the immune response, mediating inflammation and auto-immune reactions. These consequential effects are regulated through redox changes in the heme cofactor of IDO1, which autoxidizes to the inactive ferric state dur-ing turnover. This change in redox status increases the lability of the heme cofactor leading to further suppression of activity. The cell can thus regulate IDO1 activity through the supply of heme and reducing agents. We show here that polysulfides bind to inactive ferric IDO1 and reduce it to the oxygen-binding ferrous state, thus activating IDO1 to maximal turnover even at low, physiologically significant concentrations. The on-rate for hydrogen disulfide binding to ferric IDO1 was found to be >106 M-1 s-1 at pH 7 using stopped flow-spectrometry. K-edge XANES and EPR spectroscopy indicated initial formation of a low-spin ferric sulfur-bound species followed by reduction to the ferrous state. The µM affinity of polysulfides for IDO1 implicates these polysulfides as important signaling factors in immune regulation through the kynurenine pathway. Tryptophan significantly enhanced the relatively lower-affinity binding of hydrogen sulfide to IDO1, inspiring the use of the small molecule 3-mercaptoindole (3MI), which selectively binds to and activates ferric IDO1. 3MI sustains turnover by catalytically transferring reducing equivalents from glutathione to IDO1, representing a novel strategy of upregulating innate immunosuppression for treatment of autoimmune disorders. Reactive sulfur species are thus likely unrecognized immune-mediators with potential as therapeutic agents through these interactions with IDO1.