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X-Ray Crystallography to Study the Oligomeric State Transition of the Thermotoga maritima M42 Aminopeptidase TmPep1050
Published on: May 13, 2020
Structure and mechanism of metallocarboxypeptidases
1Molecular Biology Institute of Barcelona, CSIC, Barcelona, Spain. xgrcri@ibmb.csic.es
Critical Reviews in Biochemistry and Molecular Biology
|October 22, 2008
Summary
Metallocarboxypeptidases, crucial for physiological processes and pathology, are classified into cowrins and funnelins based on structural differences. Both enzyme groups utilize a conserved catalytic mechanism for cleaving C-terminal residues.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Metallocarboxypeptidases are enzymes that remove C-terminal amino acids from peptides, playing roles in biological functions and disease.
- Structural analysis reveals two distinct classes: cowrins and funnelins, differing in domain size, active-site cleft characteristics, and substrate specificity.
- Cowrins are larger enzymes (500-700 residues) with deep, narrow active sites, while funnelins (approx. 300 residues) possess shallow, funnel-like cavities.
Purpose of the Study:
- To structurally differentiate and characterize the two main groups of metallocarboxypeptidases: cowrins and funnelins.
- To elucidate the conserved structural features and catalytic mechanisms common to both enzyme classes.
Main Methods:
- Comparative structural analysis of metallocarboxypeptidase domains.
- Identification of conserved amino acid residues critical for catalysis in both cowrins and funnelins.
- Analysis of active-site cleft morphology and its implications for substrate accessibility.
Main Results:
- Cowrins exhibit a conserved core of 17 helices and a 3-stranded beta-sheet, with a catalytic motif HEXXH+EXXS/G+H+Y/R+Y.
- Funnelins feature a central 8-stranded beta-sheet flanked by 8 helices, with a catalytic motif HXXE+R+NR+H+Y+E.
- Both classes employ a common general base/acid mechanism involving a metal-bound solvent molecule and a conserved glutamate residue for peptide bond hydrolysis.
Conclusions:
- Metallocarboxypeptidases can be structurally and functionally classified into cowrins and funnelins.
- Despite structural variations, both groups share a conserved catalytic mechanism essential for their function.
- Understanding these structural and mechanistic differences aids in comprehending their diverse physiological roles and pathological contributions.
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