Human and mouse homo-oligomeric meprin A metalloendopeptidase: substrate and inhibitor specificities
Human and mouse homo-oligomeric meprin A metalloendopeptidase: substrate and inhibitor specificities
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DOI：
10.1515/bc.2007.156
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发表时间：
2007-11-01
影响因子：
3.7
通讯作者：
Bond, Judith S.
中科院分区：
文献类型：
--
作者：
Bylander, John E.;Bertenshaw, Greg P.;Bond, Judith S.
Meprin金属蛋白酶与糖尿病肾病和炎症性肠病的易感性和进展有关。我们对这些疾病的小鼠实验模型的研究与meprins调节炎症反应和组织损伤的结论一致。为了确定小鼠和人的酶是否不同，从两个物种的重组形式的meprin A的结构，底物和抑制剂进行了比较。人同源寡聚体meprin A形成的寡聚体范围为950000至1500000 Da，而小鼠meprin A为900000 Da。人和小鼠meprin A对偶氮酪蛋白、纤连蛋白、胶原IV和肽如甲状旁腺激素、胃饥饿素和胃泌素释放肽表现出相似的活性。人酶对明胶、缓激肽、α-黑素细胞刺激激素和神经降压素的活性较低，对促胰液素和orcokinin的活性较高。与小鼠meprin A不同，人meprin A在底物的P1'位置显示出对酸性残基的偏好。几种金属蛋白酶抑制剂的IC 50值在纳摩尔范围内，但效力范围从相似的值到来自两个物种的meprins的几个数量级的差异。这项工作提供了有价值的数据，以提高可预测性的人类系统的基础上meprin功能在小鼠模型。
Meprin metalloproteinases have been implicated in the susceptibility to and progression of diabetic nephropathy and inflammatory bowel diseases. Our studies with experimental models of these diseases in mice are congruent with the conclusion that meprins modulate the inflammatory responses and tissue damage. To determine whether the mouse and human enzymes differ, recombinant forms of meprin A from the two species were compared with respect to structure, substrates and inhibitors. Human homo-oligomeric meprin A formed oligomers ranging from 950000 to 1500000 Da vs. 900000 Da for mouse meprin A. Human and mouse meprin A exhibited similar activity against azocasein, fibronectin, collagen IV, and peptides such as parathyroid hormone, ghrelin, and gastrin-releasing peptide. The human enzyme had lower activity against gelatin, bradykinin, a-melanocyte-stimulating hormone and neurotensin, and higher activity against secretin and orcokinin. Human meprin A showed a preference for acidic residues in the P1' position of the substrate, unlike mouse meprin A. Several metalloproteinase inhibitors had IC50, values in the nanomolar range, but potency ranged from similar values to a difference of several orders of magnitude for meprins from the two species. This work provides valuable data to improve predictability for human systems based on meprin functions in mouse models.