Exploring the binding mode of semicarbazide-sensitive amine oxidase/VAP-1:: Identification of novel substrates with insulin-like activity
Exploring the binding mode of semicarbazide-sensitive amine oxidase/VAP-1:: Identification of novel substrates with insulin-like activity
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DOI：
10.1021/jm0499211
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发表时间：
2004-09-23
影响因子：
7.3
通讯作者：
Zorzano, A
中科院分区：
文献类型：
--
作者：
Marti, L;Abella, A;Zorzano, A
我们以前报道，底物氨基脲敏感胺氧化酶与低浓度的钒酸盐的组合发挥有效的胰岛素样作用。在这里，我们进行同源建模的小鼠SSAO/VAP-1的催化结构域，并通过化学数据库搜索，以确定新的SSAO底物。催化结构域的建模显示，芳香族残基Tyr 384，Phe 389和Tyr 394定义了一个口袋的稳定大小，可能参与非极性底物的结合。我们确定了一些胺作为人类，大鼠和小鼠SSAO的底物。化合物PD 0119035、2，3-二甲氧基苄胺和C-萘-1-基-甲胺作为大鼠SSAO的底物显示出高亲和力。C-萘-1-基-甲胺是唯一对人SSAO表现出高亲和力的底物。C-萘-1-基-甲胺和4-氨甲基-苯磺酰胺表现出最高的能力，刺激葡萄糖转运在分离的大鼠脂肪细胞。这些发现对糖尿病新疗法的发展的影响进行了讨论。
We previously reported that substrates of semicarbazide-sensitive amine oxidase in combination with low concentrations of vanadate exert potent insulin-like effects. Here we performed homology modeling of the catalytic domain of mouse SSAO/VAP-1 and searched through chemical databases to identify novel SSAO substrates. The modeling of the catalytic domain revealed that aromatic residues Tyr384, Phe389, and Tyr394 define a pocket of stable size that may participate in the binding of apolar substrates. We identified a number of amines as substrates of human, rat, and mouse SSAO. The compounds PD0119035, 2,3-dimethoxybenzylamine, and C-naphthalen-1-yl-methylamine showed high affinity as substrates of rat SSAO. C-Naphthalen-1-yl-methylamine was the only substrate that showed high affinity for human SSAO. C-Naphthalen-1-yl-methylamine and 4-aminomethyl-benzenesulfonamide showed the highest capacity to stimulate glucose transport in isolated rat adipocytes. The impact of these findings on the development of new treatments for diabetes is discussed.