title: Novel aspects of cellular action of dipeptidyl peptidase IV/CD26.
abstract: The cellular dipeptidyl peptidase IV (DPIV, E.C.3.4.14.5, CD26) is a type II membrane peptidase with various physio-logical functions. Our main knowledge on DPIV comes from studies of soluble DPIV which plays a role in regulation of glucose homeostasis by inactivation of the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic poly-peptide. It has been reported that membrane-bound DPIV plays a crucial role in the immune system and in other tissues and cells, but the knowledge on the action of cellular DPIV and its regulation is limited. In this study, we show particularly for immune cells that DPIV and not DP8 or DP9 is the most potent member of the DPIV family in regulating cellular immune functions. Moreover, we provide evidence that soluble and cellular DPIV differ in functions and hand-ling of substrates and inhibitors owing to the different accessibility of peptide substrates to the two access paths of DPIV. The different functions are based on the favored access path of the central pore of cellular DPIV and a special central pore binding site which assists substrate access to the active site of the enzyme. The newly discovered central pore binding site mediates an autosterical regulation of cellular DPIV and is its most crucial target site to regulate cellular functions such as growth and cytokine production. Neuropeptide Y (NPY) processing by cellular DPIV was found to be inhibited by ligands which interact with the central pore binding site. This finding suggests a crucial role of the immunosuppressive cytokine NPY in the function of DPIV in growth regulation.
authors.affiliation: IMTM GmbH, Department Immunopharm, Leipziger Str. 44, D-39120 Magdeburg, Germany. ansorge@imtm.de
authors.forename: Siegfried
authors.initials: S
authors.lastname: Ansorge
authors.forename: Karsten
authors.initials: K
authors.lastname: Nordhoff
authors.forename: Ute
authors.initials: U
authors.lastname: Bank
authors.forename: Anke
authors.initials: A
authors.lastname: Heimburg
authors.forename: Heiko
authors.initials: H
authors.lastname: Julius
authors.forename: Doreen
authors.initials: D
authors.lastname: Breyer
authors.forename: Anja
authors.initials: A
authors.lastname: Thielitz
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhold
authors.forename: Michael
authors.initials: M
authors.lastname: Täger
mesh_terms: D020134:Catalytic Domain; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry* / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology; D008958:Models, Molecular; D009478:Neuropeptide Y / Q000378:metabolism
chemical_list: D016207:Cytokines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009478:Neuropeptide Y; D004247:DNA; D018819:Dipeptidyl Peptidase 4