Inhibition of GPI Phospholipase C fromTrypanosoma bruceiby Fluoro-Inositol Dodecylphosphonates

Glycosyl phosphatidylinositol phospholipase C (GPI-PLC) ofTrypanosoma bruceiis inhibited bymyo-inositol(Ins)-1-O-dodecylphosphonate (VP-602L). Several novel fluoro-substituted analogs of 2-deoxy-myo-Ins-1-O-dodecylphosphonate, among which 2-deoxy-2-fluoro-scyllo-Ins-1-O-dodecylphosphonate (VP-616L)...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Biochemical and biophysical research communications 1998-03, Vol.244 (3), p.873-876
Hauptverfasser: Morris, James C., Ping-Sheng, Lei, Zhai, Hai-Xiao, Shen, Tsung-Ying, Mensa-Wilmot, Kojo
Format: Artikel
Sprache:eng
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:Glycosyl phosphatidylinositol phospholipase C (GPI-PLC) ofTrypanosoma bruceiis inhibited bymyo-inositol(Ins)-1-O-dodecylphosphonate (VP-602L). Several novel fluoro-substituted analogs of 2-deoxy-myo-Ins-1-O-dodecylphosphonate, among which 2-deoxy-2-fluoro-scyllo-Ins-1-O-dodecylphosphonate (VP-616L) was the most powerful, were shown to be competitive inhibitors of GPI-PLC. VP-616L was 14-fold more active than VP-602L. 2-Deoxy-2-fluoro-myo-Ins-1-O-dodecylphosphonate and 2-deoxy-2,2-difluoro-myo-Ins-1-O-dodecylphosphonate were 1.55- and 4.67-fold, respectively, more potent than VP-602L. Methyl 2-deoxy-2,2-difluoro-myo-Ins-1-O-dodecylphosphonate did not inhibit GPI-PLC. These observations provide several insights into how GPI-PLC might interact with its substrate at the active site. We surmise that (i) the 2-OH of Ins is probably dispensable for substrate recognition; (ii) an equatorially oriented active site residue might interact with substituents at the 2-position of Ins, and (iii) the negative charge on the phosphoryl at the 1-OH position of Ins might be important for substrate recognition.
ISSN:0006-291X
1090-2104
DOI:10.1006/bbrc.1998.8355