Inhibition of GPI phospholipase C from Trypanosoma brucei by fluoro-inositol dodecylphosphonates.
Glycosyl phosphatidylinositol phospholipase C (GPI-PLC) of Trypanosoma brucei is inhibited by myo-inositol(Ins)-1-O-dodecylphosphonate (VP-602L). Several novel fluoro-substituted analogs of 2-deoxy-myo-Ins-1-O-dedecylphosphonate, 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.
Morris
J C
JC
Department of Cellular Biology, University of Georgia, Athens 30602, USA.
Lei
P S
PS
Zhai
H X
HX
Shen
T Y
TY
Mensa-Wilmot
K
K
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005461:Fluorine; D054800:Glycosylphosphatidylinositol Diacylglycerol-Lyase; D007294:Inositol / Q000031:analogs & derivatives* / Q000494:pharmacology; D008956:Models, Chemical; D063065:Organophosphonates / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000201:enzymology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C100389:2-deoxy-2-fluoro-scyllo-inositol-1-O-dodecylphosphonate; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C111684:VP 602L; D005461:Fluorine; D007294:Inositol; D010738:Type C Phospholipases; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D054800:Glycosylphosphatidylinositol Diacylglycerol-Lyase