In:
PLOS ONE, Public Library of Science (PLoS), Vol. 19, No. 4 ( 2024-4-16), p. e0289239-
Abstract:
Dipeptidyl peptidase 4 (DP4)/CD26 regulates the biological function of various peptide hormones by releasing dipeptides from their N-terminus. The enzyme is a prominent target for the treatment of type-2 diabetes and various DP4 inhibitors have been developed in recent years, but their efficacy and side effects are still an issue. Many available crystal structures of the enzyme give a static picture about enzyme-ligand interactions, but the influence of amino acids in the active centre on binding and single catalysis steps can only be judged by mutagenesis studies. In order to elucidate their contribution to inhibitor binding and substrate catalysis, especially in discriminating the P 1 amino acid of substrates, the amino acids R125, N710, E205 and E206 were investigated by mutagenesis studies. Our studies demonstrated, that N710 is essential for the catalysis of dipeptide substrates. We found that R125 is not important for dipeptide binding but interacts in the P 1 `position of the peptide backbone. In contrast to dipeptide substrates both amino acids play an essential role in the binding and arrangement of long natural substrates, particularly if lacking proline in the P 1 position. Thus, it can be assumed that the amino acids R125 and N710 are important in the DP4 catalysed substrate hydrolysis by interacting with the peptide backbone of substrates up- and downstream of the cleavage site. Furthermore, we confirmed the important role of the amino acids E205 and E206. However, NP Y, displaying proline in P 1 position, is still processed without the participation of E205 or E206.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0289239
DOI:
10.1371/journal.pone.0289239.g001
DOI:
10.1371/journal.pone.0289239.g002
DOI:
10.1371/journal.pone.0289239.g003
DOI:
10.1371/journal.pone.0289239.t001
DOI:
10.1371/journal.pone.0289239.t002
DOI:
10.1371/journal.pone.0289239.t003
DOI:
10.1371/journal.pone.0289239.t004
DOI:
10.1371/journal.pone.0289239.t005
DOI:
10.1371/journal.pone.0289239.s001
DOI:
10.1371/journal.pone.0289239.s002
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2024
detail.hit.zdb_id:
2267670-3
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