Carbon monoxide releasing molecule-2 inhibition of snake venom thrombin-like activity: novel biochemical "brake"?
Carbon monoxide releasing molecule-2 inhibition of snake venom thrombin-like activity: novel biochemical "brake"?
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DOI：
10.1007/s11239-016-1442-4
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发表时间：
2017-02-01
影响因子：
4
通讯作者：
Bazzell, Charles M.
中科院分区：
文献类型：
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作者：
Nielsen, Vance G.;Bazzell, Charles M.
使用蛇毒酶（如anrod）进行去纤维蛋白原化治疗的一个并发症是，由于没有人类来源的抑制剂来灭活或降低这些酶的活性，导致低纤维蛋白原血症相关出血。有趣的是，鳕鱼含有一种关键的组氨酸残基，没有它，酶活性就会受到抑制，而一氧化碳已被证明通过与离子通道中的组氨酸部分相互作用来抑制生物分子功能。我们测试了一种假设，即将三种不同的蛇毒暴露于一氧化碳释放分子-2产生的一氧化碳中，通过血栓造影评估，可以降低它们对血浆凝固的影响。在马来亚蝮蛇和东方菱形响尾蛇的毒液中，一氧化碳降低了类似凝血酶的活性。相比之下，木响尾蛇毒液在一氧化碳暴露下表现出“凝血酶生成”活性的增强，同时凝血酶样活性的丧失。这些发现不仅可以作为继续研究蛇毒酶作为临床去纤维蛋白生成剂的潜力的理性基础，而且还可以评估通过明智地应用生化“刹车”（如一氧化碳）来阻止这些药物成为催化“失控的火车”的潜力。
A complication of defibrinogenation therapy with snake venom enzymes such as ancrod is hypofibrinogenemia associated bleeding secondary to no human-derived inhibitor being available to inactivate or diminish the activity of such enzymes. Of interest, ancrod contains a critical histidine residue without which enzymatic activity is inhibited, and carbon monoxide has been demonstrated to inhibit biomolecular function by interacting with histidine moieties in ion channels. We tested the hypothesis that exposure of three different snake venoms containing serine proteases with thrombin-like activity (which included ancrod) to carbon monoxide derived from carbon monoxide releasing molecule-2 would diminish their effects on plasmatic coagulation as assessed by thrombelastography. In the case of the Malayan pit viper and Eastern diamondback rattlesnake venoms, carbon monoxide diminished the effects of thrombin-like activity. In contrast, timber rattlesnake venom demonstrated enhancement of "thrombin-generating" activity with simultaneous loss of thrombin-like activity in response to carbon monoxide exposure. These findings may serve as the rational basis for not just continuing to investigate the potential of snake venom enzymes as clinical defibrinogenating agents, but to also to assess the potential to stop such agents from becoming a catalytic "runaway train" by judicious application of a biochemical "brake" such as carbon monoxide.