N-Substituted amino acid inhibitors of the phosphatase domain of the soluble epoxide hydrolase
N-Substituted amino acid inhibitors of the phosphatase domain of the soluble epoxide hydrolase
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可溶性环氧化物水解酶磷酸酶结构域的 N-取代氨基酸抑制剂
DOI：
10.1016/j.bbrc.2019.05.088
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Hasumi K.
中科院分区：
文献类型：
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作者：
Matsumoto N;Kataoka M;Hirosaki H;Morisseau C;Hammock B;Suzuki E;Hasumi K.
可溶性环氧化物水解酶（sEH）是一种参与炎症调节的双功能酶。n端结构域具有磷酸酶活性（N-phos），与脂质磷酸单酯具有亲和力，c端结构域具有水解抗炎脂质环氧化物（C-EH）的活性。虽然已经发现了许多有效的C-EH抑制剂，但对N-phos抑制剂知之甚少。在这里，我们确定了n -取代的氨基酸作为N-phos的选择性抑制剂。许多取代的氨基酸抑制小鼠和人类N-phos的方式不同；苯丙氨酸衍生物对小鼠N-phos具有相对的选择性，而酪氨酸衍生物对人类N-phos具有更高的选择性。最佳抑制剂Fmoc-l-Phe(4-CN)（67）和Boc-l-Tyr(Bzl)（23）在低微摩尔范围内竞争性地抑制小鼠和人的N-phos。这些化合物对N-phos活性的抑制作用比C-EH强37-(67)和137倍（23）。抑制剂结构活性的差异表明不同物种的活性位点结构不同，因此，小鼠和人类N-phos可能存在不同的底物偏好。
The soluble epoxide hydrolase (sEH) is a bifunctional enzyme implicated in the regulation of inflammation. The N-terminal domain harbors a phosphatase activity (N-phos) with an affinity to lipid phosphomonoesters, and the C-terminal domain has an activity to hydrolyze anti-inflammatory lipid epoxides (C-EH). Although many potent inhibitors of C-EH have been discovered, little is known about inhibitors of N-phos. Here, we identifyN-substituted amino acids as selective inhibitors of N-phos. Many of theN-substituted amino acids inhibited differently mouse and human N-phos; phenylalanine derivatives are relatively selective for mouse N-phos, whereas tyrosine derivatives are more selective for human N-phos. The best inhibitors, Fmoc-l-Phe(4-CN) (67) and Boc-l-Tyr(Bzl) (23), inhibited mouse and human N-phos competitively withKIin the low micromolar range. These compounds inhibit the N-phos activity 37- (67) and 137-folds (23) more potently than the C-EH. The differences in inhibitor structure activity suggest different active site structure between species, and thus, probably a divergent substrate preference between mouse and human N-phos.