TY - JOUR
T1 - Human and mouse homo-oligomeric meprin A metalloendopeptidase
T2 - Substrate and inhibitor specificities
AU - Bylander, John E.
AU - Bertenshaw, Greg P.
AU - Matters, Gail L.
AU - Hubbard, Simon J.
AU - Bond, Judith S.
N1 - Funding Information:
The authors wish to acknowledge the excellent technical assistance of Xialoi Han, Penn State College of Medicine. The electron micrographs were prepared by Dr. Mona Norcum. This work was supported by National Institutes of Health Grant DK 19691 (to J.S.B.).
PY - 2007/11/1
Y1 - 2007/11/1
N2 - 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 950 000 to 1 500 000 Da vs. 900 000 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, α-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.
AB - 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 950 000 to 1 500 000 Da vs. 900 000 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, α-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.
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U2 - 10.1515/BC.2007.156
DO - 10.1515/BC.2007.156
M3 - Article
C2 - 17976009
AN - SCOPUS:35848939568
SN - 1431-6730
VL - 388
SP - 1163
EP - 1172
JO - Biological Chemistry
JF - Biological Chemistry
IS - 11
ER -
