N-terminal tetrapeptide of dermorphin and D-Arg-substituted tetrapeptides: inactivation process of the antinociceptive activity by peptidase.

N-terminal tetrapeptide of dermorphin and D-Arg-substituted tetrapeptides: inactivation process of the antinociceptive activity by peptidase.
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皮吗啡的 N 端四肽和 D-Arg 取代的四肽：肽酶的抗伤害活性失活过程。

DOI：
10.1016/0024-3205(90)90382-2
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发表时间：
1990
期刊：
Life sciences
影响因子：
6.1
通讯作者：
K. Suzuki
K. Suzuki
中科院分区：
医学2区
文献类型：
--
作者：
K. Chaki;S. Sakurada;T. Sakurada;K. Kisara;K. Suzuki

文献摘要

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用反相高效液相色谱法研究了脑啡肽降解酶对皮吗啡肽N端四肽H <$Tyr <$D <$Ala <$Phe <$Gly <$OH（ALPG）和D-Arg 2取代的皮吗啡肽四肽类似物H <$Tyr <$D <$Arg <$Phe <$Gly <$OH（ARPG）、H <$Tyr <$D <$Arg <$Phe <$Gly <$NH 2（TDAPG <$NH 2）和H <$Tyr <$D <$Arg <$Phe <$β <$Ala <$OH（TDAPA）的降解产物。5和25小时孵育的肽与溶解的酶的小鼠脑或脊髓，释放可观的Tyr 1残基观察到ALPG，但不是在ARPG，TDAPG NH 2和TDAPA。当ARPG和TDAPG-NH_2与酶一起孵育25小时时，主要降解产物是由Phe_3-Gly_4键水解产生的N-末端三肽。相反，TDAPA与酶孵育25小时后不产生N-末端三肽。在酶活性测定中，ARPG、TDAPG、TDAPA的Tyr 1-D-Arg 2键对氨肽酶M（AP-NH 2）的裂解比ALPG的稳定。羧肽酶Y（CP-Y）对ALPG、ARPG和TDAPA的Phe 3 β-Gly 4键在孵育3 h内易水解，而对TDAPA的Phe 3 β-Ala 4键则不水解。目前的结果和之前的行为数据表明，D-Arg取代的四肽具有强效且持久的抗伤害活性，主要归因于Tyr 1 D Arg 2键对肽酶的氨肽酶的稳定性。
Degradation products of the N-terminal tetrapeptide of dermorphin, HTyrDAlaPheGlyOH (ALPG) and D-Arg2-substituted tetrapeptide analogs of dermorphin, HTyrDArgPheGlyOH (ARPG), HTyrDArgPheGlyNH2(TDAPGNH2) and HTyrDArgPheβAlaOH (TDAPA) by enkephalin degrading enzymes were studied by using reversed-phase high-performance liquid chromatography. After 5 and 25 hr incubations of the peptides with solubilized enzymes of mouse brain or spinal cord, liberation of the appreciable Tyr1residue was observed in ALPG but not in ARPG, TDAPGNH2and TDAPA. When ARPG and TDAPGNH2were incubated with enzymes for 25 hr, a main degradation product was the N-terminal tripeptide produced from the hydrolysis of Phe3Gly4bond. Conversely, TDAPA did not produce the N-terminal tripeptide after 25 hr incubation with enzymes. In the enzyme assay, Tyr1-D-Arg2bond of ARPG, TDAPGNH2and TDAPA was more stable than that of ALPG to the cleavage by aminopeptidase M (APM). Phe3Gly4bond of ALPG, ARPG and TDAPGNH2were easily hydrolyzed by carboxypeptidase Y (CPY) within 3 hr incubation, whereas the hydrolysis of Phe3βAla4bond of TDAPA by CPY was not observed after 3 hr incubation. The present results and previous behavioural data suggest that a potent and prolonged antinociceptive activity of the D-Arg-substituted tetrapeptides is mainly attributed to the stability of Tyr1DArg2bond against aminopeptidase of peptidases.