ReviewDipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides
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,
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