Elsevier

Regulatory Peptides

Volume 85, Issue 1, 30 November 1999, Pages 9-24
Regulatory Peptides

Review
Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides

https://doi.org/10.1016/S0167-0115(99)00089-0Get rights and content

Abstract

Dipeptidyl-peptidase IV (DPP IV/CD26) has a dual function as a regulatory protease and as a binding protein. Its role in the inactivation of bioactive peptides was recognized 20 years ago due to its unique ability to liberate Xaa–Pro or Xaa–Ala dipeptides from the N-terminus of regulatory peptides, but further examples are now emerging from in vitro and vivo experiments. Despite the minimal N-terminal truncation by DPP IV, many mammalian regulatory peptides are inactivated — either totally or only differentially — for certain receptor subtypes. Important DPP IV substrates include neuropeptides like neuropeptide Y or endomorphin, circulating peptide hormones like peptide YY, growth hormone-releasing hormone, glucagon-like peptides(GLP)-1 and -2, gastric inhibitory polypeptide as well as paracrine chemokines like RANTES (regulated on activation normal T cell expressed and secreted), stromal cell-derived factor, eotaxin and macrophage-derived chemokine. Based on these findings the potential clinical uses of selective DPP IV inhibitors or DPP IV-resistant analogues, especially for the insulinotropic hormone GLP-1, have been tested to enhance insulin secretion and to improve glucose tolerance in diabetic animals. Thus, DPP IV appears to be a major physiological regulator for some regulatory peptides, neuropeptides, circulating hormones and chemokines.

Section snippets

Discovery and classification of DPP IV

The enzyme and binding protein dipeptidyl-peptidase IV (DPP IV, EC 3.4.14.5; CD26) was discovered by Hopsu-Havu and Glenner [40] in rat liver homogenates and commercial enzyme preparations as an activity liberating naphthylamine from Gly–Pro-2-naphthylamide, and initially termed glycylproline naphthylamidase. Since the amino acid sequence Gly–Pro is frequently found in collagens, a possible metabolic significance in collagen metabolism was proposed. However, the enzyme is unable to cleave

Distribution

A physiological role in the inactivation of bioactive peptides has been postulated for all membrane-bound proline-/alanine-specific exopeptidases [66], [104], but that of DPP IV has been investigated and documented best. In contrast to X–Pro aminopeptidase and Pro–X carboxypeptidase which showed a restricted distribution most vertebrate tissues contain DPP IV, but their activities vary widely (Fig. 1).

In the kidney, where the enzyme is exceptionally concentrated, it is located primarily in the

Molecular and catalytic properties

Human DPP IV solubilized from membranes by detergents is a glycoprotein with Mr of about 240 000 composed of two 120 000 subunits (e.g. the human placenta enzyme [87]). Due to the presence of sialic acids in the carbohydrate structure, DPP IV has an acidic isoelectric point. The cDNA codes for a polypeptide of 766 (rat 767) residues [70]. DPP IV is anchored in the plasma membrane by a 22 amino residues hydrophobic membrane-spanning domain (VLLG LLGAAALVTI ITVPVVLL) preceded by a short,

Cleavage of regulatory peptides by DPP IV

The unique substrate specificity of DPP IV together with its localization as an ectoenzyme at the plasma membrane led to the assumption that this protease should either take part in the final catabolism of proline-rich peptides or have a regulatory role in the inactivation of bioactive peptides. Whereas initially the potency of DPP IV to cleave potential neuropeptide-, peptide hormone- or cytokine-/chemokine- substrates was investigated, later studies elucidated the role of DPP IV in body

Action of DPP IV on neuropeptides

Substance P is a widespread neuropeptide that acts, e.g. as a transmitter of sensory information including noxious stimuli, as a potent contractor of smooth muscles, and as an immunoregulator. Three different G-protein-coupled receptor subtypes, NK1, NK2 and NK3, are known that are stimulated also by the neurokinins A and B which share a common C-terminal pentapeptide sequence (Phe–Xaa–Gly–Leu–Met–NH2) with substance P. Therefore, the sequential liberation of the dipeptides Arg–Pro and Lys–Pro

Action on circulating peptide hormones

In Section 5 the involvement of DPP IV in the post-secretory processing of a peptide hormone with N-terminal Xaa–Pro sequence, PYY, was reviewed. Action of DPP IV on other Xaa–Pro peptide hormones circulating in the blood (Table 2) do not appear to be of biological importance. However, DPP IV plays a pivotal role for the inactivation of several Xaa–Ala peptide hormones that all belong to the GRH-glucagon family of peptide hormones. Within this family of 29–44 residue peptides considerable

Action on chemokines

Chemokines constitute a large group of small (8000–10 000) secreted proteins that act as cell-type selective chemoattractants. They can be divided into four subfamilies, based on structural, functional and genetic criteria. The two most important subfamilies are the CXC and CC chemokines (α- and β-family), which differ in the spacing of the first two cysteine residues that form disulphide links with two other cysteines. In CXC chemokines these first cysteine residues are separated by one amino

Other enzymatic and binding functions of DPP IV

Apart from its function as a regulatory protease, important other roles for DPP IV have been reported. As mentioned above, intestinal and renal DDP IV is involved in the final digestion of proline-containing oligopeptides and in the absorption of their fragments ( [12] for review). DPP IV acts also as a binding and costimulatory protein. DPP IV binds to collagens, preferentially collagens I and III, via its cysteine rich domain, not by its catalytic site [56]. Binding to extracellular matrix

Conclusion and perspectives

DPP IV/CD26 has been discovered and investigated from two points of view: as a protease and as a binding/co-stimulatory protein. Its role as a regulatory protease and not merely a digestive enzyme for collagen or proline-rich peptide nutrients has been highlighted in recent years by in vitro and in vivo studies profiting from the development of specific inhibitors and DPP IV-deficient animals. Despite the only minimal truncation at the N-terminus of 30 to 80 residue peptides, DPP IV has a

Acknowledgements

My own experimental work in this field was supported by grants from the Deutsche Forschungsgemeinschaft. I thank the co-workers from my laboratory for their fruitful collaboration, especially my year long technicians Martina Burmester and Hella Rix-Matzen for their excellent, continuous work and their ever friendly help, and my teacher Eberhard Heymann for his steady encouragement and support. I am indebted Clemens Franke for drawing the figures, and to E. Brandt (Forschungsinstitut Borstel,

References (112)

  • D Grandt et al.

    Two molecular forms of peptide YY (PYY) are abundant in human blood: characterization of a radioimmunoassay recognizing PYY 1–36 and PYY 3–36

    Regul. Pept.

    (1994)
  • D Grandt et al.

    Neuropeptide Y 3–36 is an endogenous ligand selective for Y2 receptors

    Regul. Pept

    (1996)
  • E Heymann et al.

    Liver dipeptidyl aminopeptidase IV hydrolyzes substance P

    FEBS Lett.

    (1978)
  • T Hoffmann et al.

    Dipeptidyl peptidase IV (CD 26) and aminopeptidase N (CD 13) catalyzed hydrolysis of cytokines and peptides with N-terminal cytokine sequences

    FEBS Lett.

    (1993)
  • K Hupe-Sodmann et al.

    Characterisation of the processing by human neutral endopeptidase 24.11 of GLP-1(7–36)amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides

    Regul Pept

    (1995)
  • H Jörnvall et al.

    Amino acid sequence and heterogeneity of the gastric inhibitory polypeptide (GIP)

    FEBS Lett

    (1981)
  • T Kato et al.

    Successive cleavage of N-terminal Arg1–Pro2 and Lys3–Pro4 from substance P but no release of Arg1–Pro2 from bradykinin, by X–Pro dipeptidyl aminopeptidase

    Biochim. Biophys. Acta

    (1978)
  • U Kettmann et al.

    Ultrastructural localization of dipeptidyl peptidase-IV in the glomerulum of the rat kidney

    Acta Histochem

    (1992)
  • G Kreil

    Processing of precursors by dipeptidylaminopeptidases: a case of molecular ticketing

    Trends Biochem. Sci.

    (1990)
  • L de Lecea et al.

    Transcripts encoding a neural membrane CD26 peptidase-like protein are stimulated by synaptic activity

    Mol. Brain Res.

    (1994)
  • K Löster et al.

    The cysteine-rich region of dipeptidyl peptidase IV (CD26) is the collagen-binding site

    Biochem. Biophys. Res. Commun.

    (1995)
  • R Ludwig et al.

    Metabolism of neuropeptide Y and calcitonin gene-related peptide by cultivated neurons and glial cells

    Mol. Brain. Res.

    (1996)
  • R.A Martin et al.

    Dipeptidyl peptidase IV (DPP-IV) from pig kidney cleaves analogs of bovine growth hormone-releasing factor (bGRF) modified at position 2 with Ser, Thr or Val. Extended DPP-IV substrate specificity?

    Biochim Biophys Acta

    (1993)
  • R Mentlein

    Proline residues in the maturation and degradation of peptide hormones and neuropeptides

    FEBS Lett.

    (1988)
  • R Mentlein et al.

    Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV

    Regul Pept

    (1993)
  • R Mentlein et al.

    Dipeptidyl peptidase IV as a new surface marker for a subpopulation of human T-lymphocytes

    Cell Immunol

    (1984)
  • R Mentlein et al.

    Proline-specific proteases in cultivated neuronal and glial cells

    Brain. Res.

    (1990)
  • R Mentlein et al.

    Proteases involved in the metabolism of angiotensin II, bradykinin, calcitonin gene-related peptide, and neuropeptide Y by vascular smooth muscle cells

    Peptides

    (1996)
  • Y Misumi et al.

    Molecular cloning and sequence analysis of human dipeptidyl peptidase-IV, a serine proteinase on the cell surface

    Biochim. Biophys. Acta

    (1992)
  • C Nilsson et al.

    Processing of neuropeptide Y and somatostatin in human cerebrospinal fluid as monitored by radioimmunoassay and mass spectrometry

    Peptides

    (1998)
  • T Ohtsuki et al.

    Negative regulation of the anti-human immunodeficiency virus and chemotatic activity of human stromal cell-derived factor 1α by CD26/dipeptidyl peptidase IV

    FEBS Lett.

    (1998)
  • M.N Pangalos et al.

    Isolation and expression of novel human glutamate carboxypeptidases with N-acetylated alpha-linked acidic dipeptidase and dipeptidyl peptidase IV activity

    J. Biol. Chem.

    (1999)
  • R.P Pauly et al.

    Investigation of glucose-dependent insulinotropic polypeptide-(1–42) and glucagon-like peptide-1-(3–36) degradation in vitro by dipeptidyl peptidase IV using matrix-assisted Laser desorption/ionization-time of flight mass spectrometry

    J. Biol. Chem.

    (1996)
  • P Proost et al.

    Amino-terminal truncation of chemokines by CD26/dipeptidyl-peptidase IV. Conversion of RANTES into a potent inhibitor of monocyte chemotaxis and HIV-1 infection

    J. Biol. Chem.

    (1998)
  • P Proost et al.

    Processing by CD26/dipeptidyl-peptidase I.V. reduces the chemotactic and anti-HIV-1 activity of stromal-cell-derived factor-1alpha

    FEBS Lett.

    (1998)
  • P Proost et al.

    Truncation of macrophage-derived chemokine by CD26/dipeptidyl peptidase IV beyond its predicted cleavage site affects chemotactic activity and CC chemokine receptor 4 interaction

    J. Biol. Chem.

    (1999)
  • J Rahfeld et al.

    Are diprotin A (Ile–Pro–Ile) and diprotin B (Val–Pro–Leu) inhibitors or substrates of dipeptidyl peptidase IV?

    Biochim. Biophys. Acta

    (1991)
  • J.S Russell et al.

    Substance P and neurokinin metabolism by cultured human skeletal muscle myocytes and fibroblasts

    Peptides

    (1996)
  • D Schols et al.

    CD26-processed RANTES(3–36), but not intact RANTES, has potent anti-HIV-1 activity

    Antiviral Res

    (1998)
  • R Shane et al.

    Modulation of endomorphin-2-induced analgesia by dipeptidyl peptidase IV

    Brain Res.

    (1999)
  • C Shaw et al.

    Neuropeptide Y and neuropeptide Y 3–36: isolation from human pancreatic endocrine tumours

    Regul. Pept

    (1993)
  • E.G Siegel et al.

    Biological activity of GLP-1-analogues with N-terminal modifications

    Regul. Pept

    (1999)
  • C.A Abbott et al.

    Genomic organization, exact localization, and tissue expression of the human CD26 (dipeptidyl peptidase IV) gene

    Immunogenetics

    (1994)
  • S Ahmad et al.

    Dipeptidyl(amino)peptidase IV and aminopeptidase M metabolize circulating substance P in vivo

    J. Pharmacol. Exp. Therapeut.

    (1992)
  • A.J Atherton et al.

    Dipeptidyl peptidase-IV expression identifies a functional sub-population of breast fibroblasts

    Int. J. Cancer

    (1992)
  • J.M Bathon et al.

    Cultured human synovial fibroblasts rapidly metabolize kinins and neuropeptides

    J. Clin. Invest.

    (1992)
  • S.K Böhm et al.

    Human dipeptidyl peptidase IV gene promoter: tissue-specific regulation from a TATA-less GC-rich sequence characteristic of a housekeeping gene promoter

    Biochem. J.

    (1995)
  • M Brandsch et al.

    Role of dipeptidyl peptidase IV (DP IV) in intestinal and renal absorption of peptides

  • C.F Deacon et al.

    Dipeptidyl peptidase IV inhibition potentiates the insulinotropic effect of glucagon-like peptide 1 in the anesthetized pig

    Diabetes

    (1998)
  • Cited by (0)

    View full text