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通过聚硫化物强烈激活氨酸二氧化酶

Micah T Nelp¹, Vincent Zheng¹, Katherine M Davis¹

¹Department of Chemistry , Princeton University , Princeton , New Jersey 08544 , United States.

Journal of the American Chemical Society

|August 23, 2019

概括

聚硫化物通过降低其非活性铁态来激活免疫调节酶氨酸二氧化酶 (IDO1). 这一发现揭示了反应性硫物种作为自身免疫性疾病的潜在治疗剂.

科学领域:

生物化学
免疫学
酵素学

背景情况:

印度氨酸二氧化酶 (IDO1) 是一种对免疫抑制,炎症和自身免疫反应至关重要的血酶.
IDO1的活性是由其血辅因子的氧化还原变化调节的,在循环过程中,该辅因子转变为不活跃的铁态,从而增加了辅因子的可变性.
IDO1活动的细胞调节涉及血红素和还原剂的供应.

研究的目的:

研究多硫化物在调节IDO1活动中的作用.
通过调节 IDO1 来探索反应性硫种和新型小分子作为自身免疫疾病治疗剂的潜力.

主要方法:

停止流量光谱测试以确定二硫化与铁IDO1的结合率.
用FeK边缘XANES和EPR光谱分析硫种与IDO1的氧化还原状态和结合.
作为IDO1的新型激活剂的3 - 墨英多尔 (3MI) 的研究.

主要成果:

聚硫化物结合并将非活性铁IDO1降低到其活性铁状态,从而在生理学上相关的度下实现最大的酶循环.
硫化与铁IDO1的结合速度很快 (> 10^6 M^-1 s^-1).
通过促进来自谷氨的电子转移,维持酶活性,3- 甲英 (3MI) 选择性地结合并激活铁基 IDO1.

结论:

多硫化物通过kynurenine路径作为免疫调节的重要信号因子,显示出对IDO1的μM亲和力.
反应性硫物种被确定为具有治疗潜力的免疫媒介.
3MI代表了一种提高先天性免疫抑制的新策略,

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