Substrate specificity of prostate-specific membrane antigen
Substrate specificity of prostate-specific membrane antigen
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DOI：
10.1016/j.bmc.2007.08.006
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发表时间：
2007-11-01
影响因子：
3.5
通讯作者：
Berkman, Clifford E.
中科院分区：
文献类型：
--
作者：
Anderson, Marc O.;Wu, Lisa Y.;Berkman, Clifford E.
制备了一系列前列腺特异性膜抗原（PSMA）的推定二肽底物，其探索了P1位置处的α-和β/γ-连接的酸性残基以及P2位置处的各种发色团，同时保持P1'残基恒定为L-Glu。检测了4种发色团，包括4-苯基偶氮苯甲酰基、1-芘丁酰基、9-蒽基羧基-γ-氨基丁酰基和4-硝基苯丁酰基。当评价这些发色团时，发现在P2位含有4-苯基偶氮苯甲酰基的底物被最有效地消耗。用酸性残基取代P1位置表明，只有γ-连接的L-Glu和D-Glu被酶识别，前者更容易蛋白水解。最后，内源性底物和我们最好的合成底物（4-phenylazobenzoyl-Glu-gamma-Glu）的结合模式提出了通过计算对接研究到PSMA胞外结构域的X射线晶体结构。(C)2007爱思唯尔有限公司保留所有权利。
A series of putative dipeptide substrates of prostate-specific membrane antigen (PSMA) was prepared that explored alpha- and beta/gamma-linked acidic residues at the P1 position and various chromophores at the P2 position, while keeping the P1' residue constant as L-Glu. Four chromophores were examined, including 4-phenylazobenzoyl, 1-pyrenebutyryl, 9-anthracenylcarboxyl-gamma-aminobutyryl, and 4-nitrophenylbutyryl. When evaluating these chromophores, it was found that a substrate containing 4-phenylazobenzoyl at the P2 position was consumed most efficiently. Substitution at the P1 position with acidic residues showed that only gamma-finked L-Glu and D-Glu were recognized by the enzyme, with the former being more readily proteolyzed. Lastly, binding modes of endogenous substrates and our best synthetic substrate (4-phenylazobenzoyl-Glu-gamma-Glu) were proposed by computational docking studies into an X-ray crystal structure of the PSMA extracellular domain. (C) 2007 Elsevier Ltd. All rights reserved.