title: Different modes of dipeptidyl peptidase IV (CD26) inhibition by oligopeptides derived from the N-terminus of HIV-1 Tat indicate at least two inhibitor binding sites.
abstract: Dipeptidyl peptidase IV (DP IV, CD26) plays an essential role in the activation and proliferation of lymphocytes, which is shown by the immunosuppressive effects of synthetic DP IV inhibitors. Similarly, both human immunodeficiency virus-1 (HIV-1) Tat protein and the N-terminal peptide Tat(1-9) inhibit DP IV activity and T cell proliferation. Therefore, the N-terminal amino acid sequence of HIV-1 Tat is important for the inhibition of DP IV. Recently, we characterized the thromboxane A2 receptor peptide TXA2-R(1-9), bearing the N-terminal MWP sequence motif, as a potent DP IV inhibitor possibly playing a functional role during antigen presentation by inhibiting T cell-expressed DP IV [Wrenger, S., Faust, J., Mrestani-Klaus, C., Fengler, A., Stöckel-Maschek, A., Lorey, S., Kähne, T., Brandt, W., Neubert, K., Ansorge, S. & Reinhold, D. (2000) J. Biol. Chem.275, 22180-22186]. Here, we demonstrate that amino acid substitutions at different positions of Tat(1-9) can result in a change of the inhibition type. Certain Tat(1-9)-related peptides are found to be competitive, and others linear mixed-type or parabolic mixed-type inhibitors indicating different inhibitor binding sites on DP IV, at the active site and out of the active site. The parabolic mixed-type mechanism, attributed to both non-mutually exclusive inhibitor binding sites of the enzyme, is described in detail. From the kinetic investigations and molecular modeling experiments, possible interactions of the oligopeptides with specified amino acids of DP IV are suggested. These findings give new insights for the development of more potent and specific peptide-based DP IV inhibitors. Such inhibitors could be useful for the treatment of autoimmune and inflammatory diseases.
authors.affiliation: Department of Biochemistry/Biotechnology, Institute of Biochemistry, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Lorey
authors.forename: Angela
authors.initials: A
authors.lastname: Stöckel-Maschek
authors.forename: Jürgen
authors.initials: J
authors.lastname: Faust
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brandt
authors.forename: Beate
authors.initials: B
authors.lastname: Stiebitz
authors.forename: Mark D
authors.initials: MD
authors.lastname: Gorrell
authors.forename: Thilo
authors.initials: T
authors.lastname: Kähne
authors.forename: Carmen
authors.initials: C
authors.lastname: Mrestani-Klaus
authors.forename: Sabine
authors.initials: S
authors.lastname: Wrenger
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhold
authors.forename: Siegfried
authors.initials: S
authors.lastname: Ansorge
authors.forename: Klaus
authors.initials: K
authors.lastname: Neubert
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D002455:Cell Division; D006224:Cricetinae; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015696:Gene Products, tat / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D004791:Enzyme Inhibitors; D015696:Gene Products, tat; D008024:Ligands; D009842:Oligopeptides; D018819:Dipeptidyl Peptidase 4