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Human prochymase activation. A novel role for heparin in zymogen processing
M Murakami1, S S Karnik, A Husain
1Department of Molecular Cardiology, Cleveland Clinic Foundation, Ohio 44195.
The Journal of Biological Chemistry
|February 3, 1995
Summary
Heparin acts as a crucial cofactor in activating human prochymase, an enzyme essential for mast cell function. This interaction facilitates specific propeptide cleavage by dipeptidylpeptidase I, enabling enzyme activation.
Area of Science:
- Biochemistry
- Enzymology
- Cell Biology
Background:
- Human prochymase is stored in mast cell granules alongside heparin.
- Prochymase activation is primarily mediated by dipeptidylpeptidase I.
Purpose of the Study:
- To elucidate the role of heparin in prochymase activation.
- To understand the mechanism by which dipeptidylpeptidase I specifically cleaves the prochymase propeptide.
Main Methods:
- Investigated the interaction between heparin and prochymase.
- Utilized conserved Glu mutations in the propeptide to assess heparin's effect.
- Employed surrogate peptide studies to analyze the enzyme's activation groove.
Main Results:
- A high-affinity interaction between heparin and prochymase is essential for propeptide cleavage by dipeptidylpeptidase I.
- A conserved glutamic acid residue in the propeptide is critical for the heparin-mediated activation.
- Prochymase activation involves the capture of the newly generated NH2 terminus by an activation groove, preventing degradation.
Conclusions:
- Heparin serves as a vital cofactor in the specific activation of human prochymase.
- The activation groove mechanism explains how a non-specific enzyme achieves specific substrate processing.