Natural Substrates of Dipeptidyl Peptidase IV
During the last decade it has become clear that DPP IV may have various substrates in vivo and that the preferred peptide will depend on the localization and physiological circumstances. It is at present impossible to depict a certain chain length as the maximal acceptable substrate size as it turns out that the immediate surrounding and surface accessibility of the NH2-terminal dipeptide are determining the susceptibility for cleavage of a peptide.
From the above, it is clear that the result of dipeptide removal by DPP IV may vary from no effect over activation or change in receptor selectivity to inactivation of the substrate. Therefore, biological interpretation of assays that do not distinguish intact and modified peptides, should be interpreted with caution. Furthermore, collection and conservation of samples for peptide analysis should occur in the cold and if possible in the presence of appropriate protease inhibitors.
Clinical implications of peptide processing by DPP IV include that the therapeutic potential of peptides that are degraded by DPP IV may largely be enhanced by creating DPP IV-resistant, active analogues, and that the most suitable NH2-terminal modification may vary from one peptide to another.
Most exciting are the observations that the in vivo introduction of DPP IV specific inhibitors can enhance the levels of intact endogeneous peptides creating therapeutical perspectives (Hoist et al 1998). Extensive in vivo experiments to reveal whether DPP IV is a powerful and safe pharmaceutical target, are awaited with interest.
KeywordsPancreatic Polypeptide Gastric Inhibitory Polypeptide Dipeptidyl Peptidase Islet Amyloid Polypeptide Growth Hormone Release Factor
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