Use of a dehydroalanine-containing peptide as an efficient inhibitor of tripeptidyl peptidase II.
Tripeptidyl peptidase II is an intracellular exopeptidase, which has been purified from rat liver and human erythrocytes. An efficient specific inhibitor was obtained through beta-elimination of phosphate from the phosphopeptide Arg-Ala-Ser(P)-Val-Ala. The dehydroalanine-containing peptide formed was a competitive inhibitor with a Ki of 0.02 +/- 0.01 microM. This study demonstrated that replacing a serine residue in a good inhibitor with a dehydroalanine residue reduced the Ki 45 times. It is proposed that dehydroalanine-containing peptides could be of interest in the development of inhibitors for other peptidases as well.
Tomkinson
B
B
Department of Veterinary Medical Chemistry, Swedish University of Agricultural Sciences, Uppsala.
Grehn
L
L
Fransson
B
B
Zetterqvist
O
O
D000409:Alanine / Q000031:analogs & derivatives*; D000595:Amino Acid Sequence; D000626:Aminopeptidases; D000818:Animals; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D004912:Erythrocytes / Q000201:enzymology; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010748:Phosphopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D012697:Serine Endopeptidases / Q000097:blood / Q000378:metabolism*
D009842:Oligopeptides; D010748:Phosphopeptides; D011480:Protease Inhibitors; C015102:dehydroalanine; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C048001:tripeptidyl-peptidase 2; D012697:Serine Endopeptidases; D000409:Alanine