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Mechanism of Inactivation of Neuronal Nitric Oxide Synthase by (S)-2-Amino-5-(2-(methylthio)acetimidamido)pentanoic Acid
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2015-05-05 , DOI: 10.1021/jacs.5b01202 Wei Tang 1 , Huiying Li 2 , Emma H Doud 3 , Yunqiu Chen 3 , Stephanie Choing 1 , Carla Plaza 2 , Neil L Kelleher 3 , Thomas L Poulos 2 , Richard B Silverman 1
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2015-05-05 , DOI: 10.1021/jacs.5b01202 Wei Tang 1 , Huiying Li 2 , Emma H Doud 3 , Yunqiu Chen 3 , Stephanie Choing 1 , Carla Plaza 2 , Neil L Kelleher 3 , Thomas L Poulos 2 , Richard B Silverman 1
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Nitric oxide synthase (NOS) catalyzes the conversion of l-arginine to l-citrulline and the second messenger nitric oxide. Three mechanistic pathways are proposed for the inactivation of neuronal NOS (nNOS) by (S)-2-amino-5-(2-(methylthio)acetimidamido)pentanoic acid (1): sulfide oxidation, oxidative dethiolation, and oxidative demethylation. Four possible intermediates were synthesized. All compounds were assayed with nNOS, their IC50, KI, and kinact values were obtained, and their crystal structures were determined. The identification and characterization of the products formed during inactivation provide evidence for the details of the inactivation mechanism. On the basis of these studies, the most probable mechanism for the inactivation of nNOS involves oxidative demethylation with the resulting thiol coordinating to the cofactor heme iron. Although nNOS is a heme-containing enzyme, this is the first example of a NOS that catalyzes an S-demethylation reaction; the novel mechanism of inactivation described here could be applied to the design of inactivators of other heme-dependent enzymes.
中文翻译：
(S)-2-氨基-5-(2-(甲硫基)乙酰亚氨基)戊酸灭活神经元一氧化氮合酶的机制
一氧化氮合酶 (NOS) 催化 L-精氨酸转化为 L-瓜氨酸和第二信使一氧化氮。 (S)-2-氨基-5-(2-(甲硫基)乙酰亚氨基)戊酸 (1) 提出了三种使神经元 NOS (nNOS) 失活的机制途径：硫化物氧化、氧化脱硫基和氧化脱甲基化。合成了四种可能的中间体。所有化合物均用 nNOS 进行测定，获得其 IC50、KI 和 kinact 值，并确定其晶体结构。灭活过程中形成的产物的鉴定和表征为灭活机制的细节提供了证据。根据这些研究，nNOS 失活最可能的机制涉及氧化去甲基化，所产生的硫醇与辅因子血红素铁配位。虽然nNOS是一种含血红素的酶，但这是催化S-去甲基化反应的NOS的第一个例子；这里描述的新的失活机制可以应用于其他血红素依赖性酶的失活剂的设计。
更新日期：2015-05-05
中文翻译：
(S)-2-氨基-5-(2-(甲硫基)乙酰亚氨基)戊酸灭活神经元一氧化氮合酶的机制
一氧化氮合酶 (NOS) 催化 L-精氨酸转化为 L-瓜氨酸和第二信使一氧化氮。 (S)-2-氨基-5-(2-(甲硫基)乙酰亚氨基)戊酸 (1) 提出了三种使神经元 NOS (nNOS) 失活的机制途径：硫化物氧化、氧化脱硫基和氧化脱甲基化。合成了四种可能的中间体。所有化合物均用 nNOS 进行测定，获得其 IC50、KI 和 kinact 值，并确定其晶体结构。灭活过程中形成的产物的鉴定和表征为灭活机制的细节提供了证据。根据这些研究，nNOS 失活最可能的机制涉及氧化去甲基化，所产生的硫醇与辅因子血红素铁配位。虽然nNOS是一种含血红素的酶，但这是催化S-去甲基化反应的NOS的第一个例子；这里描述的新的失活机制可以应用于其他血红素依赖性酶的失活剂的设计。
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