Selectivity among dipeptidyl peptidases of the S9b family.
Dipeptidyl peptidase IV is a serine protease with an indirect role in antihyperglycaemia via degradation of the incretin hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide. Inhibition of the DPP-IV is thus a potential therapeutic strategy for type 2 diabetes. In this study, we have investigated upon selectivity of dipeptidyl peptidase IV compared to two other members of the S9b family, dipeptidyl peptidase 8 and 9, based on kinetic analyses of the pancreatic peptide hormones neuropeptide Y and peptide YY. We report a striking 250-fold preference for cleavage of neuropeptide Y compared to peptide YY observed for DPP-8/-9, but not for DPP-IV. This difference appears to be linked to differences in the S1' pocket within the active site, particularly via flexibility of the oxyanion stabilizing residue Y547. These aspects are discussed in relation to available protein structures of DPP-IV and data on DPP-IV selective inhibitors.
Bjelke
J R
JR
Protein Structure and Biophysics, Novo Nordisk A/S, Novo Allé, 2880 Bagsvaerd, Denmark.
Kanstrup
A B
AB
Rasmussen
H B
HB
D000818:Animals; D001665:Binding Sites; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009478:Neuropeptide Y / Q000378:metabolism; D019894:Peptide YY / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
D054873:Dipeptidyl-Peptidase IV Inhibitors; D007527:Isoenzymes; D009478:Neuropeptide Y; D019894:Peptide YY; D018819:Dipeptidyl Peptidase 4