Prolyl endopeptidase inhibitory activity of unsaturated fatty acids.
Prolyl endopeptidase (PEP, EC 3.4.21.26) is widely distributed in various organs, particularly in the brains of amnestic patients. Evaluation of PEP levels in postmortem brains of Alzheimer's disease patients revealed significant increases in PEP activity, suggesting that a specific PEP inhibitor can be a good candidate for an antiamnestic drug. In this study, mono- and polyunsaturated fatty acids were investigated to determine their role as PEP inhibitors. Oleic, linoleic, and arachidonic acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) showed PEP inhibitory activities (IC50 values of 23.6 +/- 0.4, 43.8 +/- 1.8, 53.4 +/- 1.2, 99.4 +/- 1.2, and 46.2 +/- 1.0 microM, respectively), indicating that they were effective PEP inhibitors, with inhibition constant (Ki) values of 26.7 +/- 0.3, 51.0 +/- 0.7, 91.3 +/- 3.1, 247.5 +/- 2.6, and 89.0 +/- 2.3 microM, respectively. Oleic acid showed the highest PEP inhibitory activity. Dixon plots of PEP inhibition showed oleic, linoleic, and arachidonic acids, EPA, and DHA are noncompetitive inhibitors; despite higher IC50 values of these unsaturated fatty acids than strong natural inhibitors, they may have potential use in preventing memory loss.
College of Environment and Applied Chemistry and Plant Metabolism Research Center, Kyung Hee University, Suwon 449-701, Korea.
Yoon-Seok
YS
Park
Hyun-Jung
HJ
Jang
Kyung-Ho
KH
Lee
Tae-Ryong
TR
Hahn
Young-Sook
YS
Paik
D000544:Alzheimer Disease / Q000201:enzymology; D016718:Arachidonic Acid / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D019787:Linoleic Acid / Q000494:pharmacology; D019301:Oleic Acid / Q000494:pharmacology; D000085822:Prolyl Oligopeptidases; D011480:Protease Inhibitors / Q000494:pharmacology*; D012697:Serine Endopeptidases
D005231:Fatty Acids, Unsaturated; D011480:Protease Inhibitors; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D019301:Oleic Acid; D019787:Linoleic Acid; D015118:Eicosapentaenoic Acid; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases