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Structure and function of prolyl peptidases
Author(s) -
Chiu Thang Kien,
Li Min,
Davies David R.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.504.11
Subject(s) - cleave , serine , proteases , chemistry , enzyme , proline , residue (chemistry) , biochemistry , stereochemistry , conformational change , prolyl endopeptidase , serine protease , protease , amino acid
Prolyl peptidases are serine proteases that are involved in a large variety of biological functions, including Type II diabetes, cancer, and neurological function, and have been implicated in Lou Gehrig's disease, Chagas' disease and Celiac Sprue. There are ten members in this enzyme family, which all recognize and cleave proteins and small peptides at proline residues, but differ from each other in the position of the proline residue that they recognize: aminoacyl‐, di‐, tri‐, and endo‐ prolylpeptidase (i.e., APP, DPP, TPP, and PEP) recognize and cleave the first, second, third, and internal proline residue from the N‐terminus, respectively. Previous studies have provided indirect evidence for an involvement of a conformational change in enzyme catalysis. We now directly demonstrate from the structures of prolyl endopeptidase that the apoenzyme exists in different conformational states, addition of substrate induces a conformational change from an opened to a closed state, and catalysis occurs through an induced‐fit mechanism. The significance of this finding for conformationally‐targeted drug design efforts against this family of enzyme with highly degenerate substrate recognition will be discussed.