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The Determination of Protease Specificity in Mouse Tissue Extracts by MALDI-TOF Mass Spectrometry: Manipulating PH to Cause Specificity Changes
Published on: May 25, 2018
Human and mouse homo-oligomeric meprin A metalloendopeptidase: substrate and inhibitor specificities
John E Bylander1, Greg P Bertenshaw, Gail L Matters
1Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033-0850, USA.
Abstract:
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, alpha-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 IC(50) 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.
Insights
Comparing human and mouse meprin A reveals species-specific differences in structure, substrate preferences, and inhibitor responses. This research enhances the predictive value of mouse models for human diseases like diabetic nephropathy.
Area of Science:
- Biochemistry
- Enzymology
- Proteomics
Background:
- Meprin metalloproteinases are linked to diabetic nephropathy and inflammatory bowel diseases.
- Meprins influence inflammatory responses and tissue damage in experimental models.
Purpose of the Study:
- To compare human and mouse meprin A structure, substrates, and inhibitors.
- To assess species-specific differences in meprin A function.
Main Methods:
- Recombinant human and mouse meprin A were produced and characterized.
- Enzyme activity was tested against various substrates (azocasein, fibronectin, collagen IV, peptides).
- Inhibitor potencies (IC50) were determined for both species' meprin A.
Main Results:
- Human meprin A forms larger oligomers than mouse meprin A.
- Both enzymes show similar activity against many substrates, but differ in others (e.g., gelatin, secretin).
- Human meprin A exhibits distinct P1' substrate preferences and variable inhibitor responses compared to mouse meprin A.
Conclusions:
- Significant species-specific differences exist between human and mouse meprin A.
- These findings improve the translational relevance of mouse models for human diseases involving meprins.
- Understanding these differences is crucial for developing targeted therapies.
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