TAILIEUCHUNG - Báo cáo khoa học: Hydrogen bond residue positioning in the 599–611 loop of thimet oligopeptidase is required for substrate selection

Thimet oligopeptidase (EC ) is a zinc(II) endopeptidase implicated in the processing of numerous physiological peptides. Although its role in selecting and processing peptides is not fully understood, it is believed that flexible loop regions lining the substrate-binding site allow the enzyme to conform to substrates of varying structure. | ỊFEBS Journal Hydrogen bond residue positioning in the 599-611 loop of thimet oligopeptidase is required for substrate selection Lisa A. Bruce1 Jeffrey A. Sigman2 Danica Randall2 Scott Rodriguez2 Michelle M. Song1 Yi Dai1 Donald E. Elmore1 Amanda Pabon3 Marc J. Glucksman3 and Adele J. Wolfson1 1 Chemistry Department Wellesley College MA USA 2 Chemistry Department Saint Mary s College of California Moraga CA USA 3 Midwest Proteome Center and Department of Biochemistry and Molecular Biology Rosalind Franklin University of Medicine and Science Chicago IL USA Keywords enzyme flexibility hydrogen bonding metallopeptidase substrate selectivity thimet oligopeptidase Correspondence A. J. Wolfson Wellesley College Office of the Dean of the College 106 CentralStreet Wellesley MA 02481-8203 USA Fax 1 781 283 3695 Tel 1 781 283 3583 E-mail awolfson@ Received 28 July 2008 revised 15 September 2008 accepted 17 September 2008 doi Thimet oligopeptidase EC is a zinc II endopeptidase implicated in the processing of numerous physiological peptides. Although its role in selecting and processing peptides is not fully understood it is believed that flexible loop regions lining the substrate-binding site allow the enzyme to conform to substrates of varying structure. This study describes mutant forms of thimet oligopeptidase in which Gly or Tyr residues in the 599-611 loop region were replaced individually and in combination to elucidate the mechanism of substrate selection by this enzyme. Decreases in kcat observed on mutation of Tyr605 and Tyr612 demonstrate that these residues contribute to the efficient cleavage of most substrates. Modeling studies showing that a hinge-bend movement brings both Tyr612 and Tyr605 within hydrogen bond distance of the cleaved peptide bond supports this role. Thus molecular modeling studies support a key role in transition state stabilization of this enzyme by Tyr605. Interestingly kinetic .

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