MODULATION OF THE GENERAL ANESTHETIC SENSITIVITY OF A PROTEIN - A TRANSITION BETWEEN 2 FORMS OF FIREFLY LUCIFERASE
MODULATION OF THE GENERAL ANESTHETIC SENSITIVITY OF A PROTEIN - A TRANSITION BETWEEN 2 FORMS OF FIREFLY LUCIFERASE
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DOI：
10.1073/pnas.88.1.134
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发表时间：
1991-01-01
影响因子：
11.1
通讯作者：
LIEB, WR
中科院分区：
文献类型：
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作者：
MOSS, GWJ;FRANKS, NP;LIEB, WR
大多数蛋白质的活性对全身麻醉药相对不敏感。 一个值得注意的例外是萤火虫荧光素酶，它对各种麻醉剂的敏感性与整个动物的敏感性非常相似。 我们现在已经发现这种敏感性可以由ATP控制。该酶在低浓度（μ M）ATP下不敏感，在高浓度（mM）下非常敏感。不同麻醉剂的敏感性差异不同，对于具有大非极性片段的分子差异最大（约100倍差异）。 这表明麻醉剂的敏感性是由麻醉剂结合口袋的疏水性的变化来调节的。麻醉剂竞争的底物萤火虫荧光素结合的平行变化表明，麻醉剂与萤火虫荧光素底物结合在同一位点。 结合口袋性质的这些变化不仅改变了对麻醉剂的敏感性，而且改变了伯醇类麻醉剂同源系列中“截止”的位置;截止位置可以从辛醇到十五醇不等，这取决于ATP的浓度。 我们的研究结果表明，在中枢神经系统中，特别敏感的麻醉靶点可能具有麻醉剂结合口袋，其极性由神经调节剂调节。
The activities of most proteins are relatively insensitive to general anesthetics. A notable exception is firefly luciferase, whose sensitivity to a wide range of anesthetic agents closely parallels that of whole animals. We have now found that this sensitivity can be controlled by ATP. The enzyme is insensitive at low (mu-M) concentrations of ATP and very sensitive at high (mM) concentrations. The differential sensitivity varies from anesthetic to anesthetic, being greatest (about a 100-fold difference) for molecules with large apolar segments. This suggests that anesthetic sensitivity is modulated by changes in the hydrophobicity of the anesthetic-binding pocket. Parallel changes in the binding of the substrate firefly luciferin, for which anesthetics compete, indicate that anesthetics bind at the same site as the luciferin substrate. These changes in the nature of the binding pocket modify not only the sensitivity to anesthetics but also the position of the "cutoff" in the homologous series of primary alcohol anesthetics; the cutoff position can vary from octanol to pentadecanol, depending upon the concentration of ATP. Our results suggest that particularly sensitive anesthetic target sites in the central nervous system may possess anesthetic-binding pockets whose polarities are regulated by neuromodulatory agents.