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(Received for publication, April 1, 1996)
From the The incretins glucose-dependent
insulinotropic polypeptide (GIP1-42) and glucagon-like
peptide-1-(7-36)-amide (GLP-17-36), hormones that
potentiate glucose-induced insulin secretion from the endocrine
pancreas, are substrates of the circulating exopeptidase dipeptidyl
peptidase IV and are rendered biologically inactive upon cleavage of
their N-terminal dipeptides. This study was designed to determine if
matrix-assisted laser desorption/ionization-time of flight mass
spectrometry is a useful analytical tool to study the hydrolysis of
these hormones by dipeptidyl peptidase IV, including kinetic analysis.
Spectra indicated that serum-incubated peptides were cleaved by this
enzyme with only minor secondary degradation due to other serum
protease activity. Quantification of the mass spectrometric signals
allowed kinetic constants for both porcine kidney- and human serum
dipeptidyl peptidase IV-catalyzed incretin hydrolysis to be calculated.
The binding constants (Km) of these incretins to
purified porcine kidney-derived enzyme were 1.8 ± 0.3 and
3.8 ± 0.3 µ, whereas the binding constants
observed in human serum were 39 ± 29 and 13 ± 9 µ for glucose-dependent-insulinotropic
polypeptide and glucagon-like peptide-1-(7-36)-amide respectively. The
large range of Km values found in human serum
suggests a heterogeneous pool of enzyme. The close correlation between
the reported kinetic constants and those previously described validates
this novel approach to kinetic analysis.
Volume 271, Number 38,
Issue of September 20, 1996
pp. 23222-23229
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
A NOVEL KINETIC APPROACH
,
,
and
Department of Physiology, University of
British Columbia, Vancouver, British Columbia V6T 1Z3, Canada and
§ Hans-Knöll-Institute of Natural Product Research
Jena, Weinbergweg 23, D-06120 Halle (Saale), Federal Republic of
Germany
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