Dipeptidyl-peptidase IV converts intact B-type natriuretic peptide into its des-SerPro form.
BACKGROUND
Analysis of plasma B-type natriuretic peptide (BNP) has suggested the in vivo formation of a truncated form, BNP (3-32), also called des-SerPro-BNP. The objectives of this study were to investigate (a) whether BNP and other natriuretic peptides are truncated by dipeptidyl-peptidase IV (DPP IV/CD26; EC 3.4.14.5) and (b) whether this truncation affects the susceptibility to cleavage by neutral endopeptidase (NEP; EC 3.4.24.11).


METHODS
Human BNP (1-32), A-type natriuretic peptide 1-28 (ANP 1-28), and related peptides were incubated with purified DPP IV and with human plasma. In addition, BNP (1-32), BNP (3-32), and ANP (1-28) were subjected to hydrolysis by NEP. Cleavage products were analyzed by mass spectrometry.


RESULTS
BNP (1-32) was cleaved by purified DPP IV with a specificity constant of 0.37 x 10(6) L.mol(-1).s(-1). The DPP IV activity in EDTA-plasma was able to truncate BNP (1-32) ex vivo. Addition of Vildagliptin, a specific DPP IV inhibitor, prevented this truncation in a concentration-dependent manner. Under in vitro circumstances in which ANP was hydrolyzed extensively, BNP (1-32) and BNP (3-32) were very resistant to NEP-mediated cleavage.


CONCLUSIONS
DPP IV cleaves BNP (1-32) with an efficiency higher than or comparable to several known in vivo substrates of the enzyme. Even after loss of the amino-terminal dipeptide, BNP remains highly resistant to cleavage by NEP.
Brandt
Inger
I
Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium.
Lambeir
Anne-Marie
AM
Ketelslegers
Jean-Marie
JM
Vanderheyden
Marc
M
Scharpé
Simon
S
De Meester
Ingrid
I
D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000097:blood; D004151:Dipeptides / Q000737:chemistry; D018819:Dipeptidyl Peptidase 4 / Q000097:blood*; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D020097:Natriuretic Peptide, Brain / Q000097:blood* / Q000737:chemistry; D015260:Neprilysin / Q000378:metabolism; D009570:Nitriles; D010446:Peptide Fragments / Q000097:blood*; D011480:Protease Inhibitors / Q000494:pharmacology; D011759:Pyrrolidines; D000077597:Vildagliptin
D004151:Dipeptides; D009570:Nitriles; D010446:Peptide Fragments; D011480:Protease Inhibitors; D011759:Pyrrolidines; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D018819:Dipeptidyl Peptidase 4; D015260:Neprilysin; D000077597:Vildagliptin; D000218:Adamantane