CHARACTERIZATION OF THE PROCESSING BY HUMAN NEUTRAL ENDOPEPTIDASE-24.11 OF GLP-1(7-36) AMIDE AND COMPARISON OF THE SUBSTRATE-SPECIFICITY OF THE ENZYME FOR OTHER GLUCAGON-LIKE PEPTIDES
CHARACTERIZATION OF THE PROCESSING BY HUMAN NEUTRAL ENDOPEPTIDASE-24.11 OF GLP-1(7-36) AMIDE AND COMPARISON OF THE SUBSTRATE-SPECIFICITY OF THE ENZYME FOR OTHER GLUCAGON-LIKE PEPTIDES
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DOI：
10.1016/0167-0115(95)00063-h
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发表时间：
1995-08-22
影响因子：
--
通讯作者：
VOIGT, K
中科院分区：
文献类型：
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作者：
HUPESODMANN, K;MCGREGOR, GP;VOIGT, K
强效促胰岛素肽激素GLP-1（7-36）酰胺的分泌后加工可能涉及一种或多种膜结合外肽酶。本文报告了重组人中性内肽酶（NEP）24.11对人GLP-1（7-36）酰胺的内蛋白水解的表征，NEP 24.11是最佳表征和广泛分布的外肽酶之一，参与其他肽激素的加工。使用高效液相色谱法分级分离后，通过质量和一级结构表征有限内蛋白水解的产物。估计NEP 24.11的这种内蛋白水解速率，并与GLP-1（7-36）酰胺相关肽的速率进行比较。GLP-1（7-36）酰胺似乎是NEP 24.11的良好底物，其中大部分但并非所有潜在靶键被裂解。此外，结构相关的肽，胰泌素和胰高血糖素似乎是良好的底物，而GIP和毒蜥外泌肽-4是非常差的底物。GLP-1（7-36）酰胺超激动剂毒蜥外泌肽-4是NEP 24.11的不良底物，这对于该肽可能用作开发临床有用的肽激动剂的原型是重要的。进一步的研究应揭示NEP 24.11是否对GLP-1（7-36）酰胺的代谢清除很重要，并将与实现GLP-1（7-36）酰胺的建议治疗价值的尝试高度相关。
The post-secretory processing of the potent insulinotropic peptide hormone, GLP-1(7-36)amide, probably involves one or more of a small group of membrane-bound ectopeptidases. Reported here, is the characterisation of the endoproteolysis of human GLP-1(7-36)amide by the recombinant human form of neutral endopeptidase (NEP) 24.11, which is one of the best characterised and widely-distributed of ectopeptidases and is involved in the processing of other peptide hormones. The products of the limited endoproteolysis were characterised by mass and primary structure following fractionation using high performance liquid chromatography. The rate of this endoproteolysis by NEP 24.11 was estimated and compared to that of GLP-1(7-36)amide-related peptides. GLP-1(7-36)amide appears to be good substrate for NEP 24.11 with most, but not all potential target bonds being cleaved. Also, the structurally-related peptides, secretin and glucagon appear to be good substrates whereas GIP and exendin-4 are very poor substrates. That the GLP-1(7-36)amide super-agonist, exendin-4 is a poor substrate for NEP 24.11 is significant for the possible use of this peptide as a prototype for the development of clinically-useful peptide agonists. Further studies should reveal whether NEP 24.11 is important for the metabolic clearance of GLP-1(7-36)amide and will be highly relevant for the attempts to realise the suggested therapeutic value of GLP-1(7-36)amide.