The role of dipeptidyl peptidase IV in the cleavage of glucagon family peptides: in vivo metabolism of pituitary adenylate cyclase activating polypeptide-(1-38)

Dipeptidyl peptidase IV (DP-IV) is a cell surface serine dipeptidase that is involved in the regulation of the incretin hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). There is accumulating evidence that other members of the glucagon family of peptides...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-06, Vol.278 (25), p.22418-22423
Main Authors: Zhu, Lan, Tamvakopoulos, Constantin, Xie, Dan, Dragovic, Jasminka, Shen, Xiaolan, Fenyk-Melody, Judith E, Schmidt, Keith, Bagchi, Ansuman, Griffin, Patrick R, Thornberry, Nancy A, Sinha Roy, Ranabir
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Calibration
Dipeptidyl Peptidase 4 - metabolism
Glucagon - chemistry
Glucagon - metabolism
Hormones - chemistry
Hormones - metabolism
Kinetics
Mass Spectrometry
Mice
Neuropeptides - chemistry
Neuropeptides - metabolism
Pituitary Adenylate Cyclase-Activating Polypeptide
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
Substrate Specificity
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Summary:Dipeptidyl peptidase IV (DP-IV) is a cell surface serine dipeptidase that is involved in the regulation of the incretin hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). There is accumulating evidence that other members of the glucagon family of peptides are also endogenous substrates for this enzyme. To identify candidate substrates for DP-IV, a mass spectrometry-based protease assay was developed that measures cleavage efficiencies (kcat/Km) of polypeptides in a mixture, using only a few picomoles of each substrate and physiological amounts of enzyme in a single kinetic experiment. Oxyntomodulin and the growth hormone-(1-43) fragment were identified as new candidate in vivo substrates. Pituitary adenylate cyclase-activating polypeptide-(1-38) (PACAP38), a critical mediator of lipid and carbohydrate metabolism, was also determined to be efficiently processed by DP-IV in vitro. The catabolism of exogenously administered PACAP38 in wild type and DP-IV-deficient C57Bl/6 mice was monitored by tandem mass spectrometry. Animals lacking DP-IV exhibited a significantly slower clearance of the circulating peptide with virtually complete suppression of the inactive DP-IV metabolite, PACAP-(3-38). These in vivo results suggest that DP-IV plays a major role in the degradation of circulating PACAP38.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M212355200