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• W2014621836 abstract "Glycosylphosphatidylinositol phospholipase C (GPI-PLC) from Trypanosoma brucei and phosphatidylinositol phospholipase C (PI-PLC) from Bacillus sp. both cleave glycosylphosphatidylinositols (GPIs). However, phosphatidylinositol, which is efficiently cleaved by PI-PLC, is a very poor substrate for GPI-PLC. We examined GPI-PLC substrate requirements using glycoinositol analogs of GPI components as potential inhibitors. Glucosaminyl(α1→6)-D-myo-inositol (GlcN(α1→6)Ins), GlcN(α1→6)Ins 1,2-cyclic phosphate, GlcN(α1→6)-2-deoxy-Ins, and GlcN(α1→6)Ins 1-dodecyl phosphonate inhibited GPI-PLC. GlcN(α1→6)Ins was as effective as Man(α1→4)GlcN(α1→6)Ins; we surmise that GlcN(α1→6)Ins is the crucial glycan motif for GPI-PLC recognition. Inhibition by GlcN(α1→6)Ins 1,2-cyclic phosphate suggests product inhibition since GPIs cleaved by GPI-PLC possess a GlcN(α1→6)Ins 1,2-cyclic phosphate at the terminus of the residual glycan. The effectiveness of GlcN(α1→6)-2-deoxy-Ins indicates that the D-myo-inositol (Ins) 2-hydroxyl is not required for substrate recognition, although it is probably essential for catalysis. GlcN(α1→6)-2-deoxy-L-myo-inositol, unlike GlcN(α1→6)-2-deoxy-Ins, had no effect on GPI-PLC; hence, GPI-PLC can distinguish between the two enantiomers of Ins. Surprisingly, GlcN(α1→6)Ins 1,2-cyclic phosphate was not a potent inhibitor of Bacillus cereus PI-PLC, and GlcN(α1→6)Ins had no effect on the enzyme. However, both GlcN(α1→6)Ins 1-phosphate and GlcN(α1→6)Ins 1-dodecyl phosphonate were competitive inhibitors of PI-PLC. These observations suggest an important role for a phosphoryl group at the Ins 1-position in PI-PLC recognition of GPIs. Other studies indicate that abstraction of a proton from the Ins 2-hydroxyl is not an early event in PI-PLC cleavage of GPIs. Furthermore, both GlcN(α1→6)-2-deoxy-Ins 1-phosphate and GlcN(α1→6)-2-deoxy-L-myo-inositol inhibited PI-PLC without affecting GPI-PLC. Last, the aminoglycoside G418 stimulated PI-PLC, but had no effect on GPI-PLC. Thus, these enzymes represent mechanistic subclasses of GPI phospholipases C, distinguishable by their sensitivity to GlcN(α1→6)Ins derivatives and aminoglycosides. Possible allosteric regulation of PI-PLC by GlcN(α1→6)Ins analogs is discussed. Glycosylphosphatidylinositol phospholipase C (GPI-PLC) from Trypanosoma brucei and phosphatidylinositol phospholipase C (PI-PLC) from Bacillus sp. both cleave glycosylphosphatidylinositols (GPIs). However, phosphatidylinositol, which is efficiently cleaved by PI-PLC, is a very poor substrate for GPI-PLC. We examined GPI-PLC substrate requirements using glycoinositol analogs of GPI components as potential inhibitors. Glucosaminyl(α1→6)-D-myo-inositol (GlcN(α1→6)Ins), GlcN(α1→6)Ins 1,2-cyclic phosphate, GlcN(α1→6)-2-deoxy-Ins, and GlcN(α1→6)Ins 1-dodecyl phosphonate inhibited GPI-PLC. GlcN(α1→6)Ins was as effective as Man(α1→4)GlcN(α1→6)Ins; we surmise that GlcN(α1→6)Ins is the crucial glycan motif for GPI-PLC recognition. Inhibition by GlcN(α1→6)Ins 1,2-cyclic phosphate suggests product inhibition since GPIs cleaved by GPI-PLC possess a GlcN(α1→6)Ins 1,2-cyclic phosphate at the terminus of the residual glycan. The effectiveness of GlcN(α1→6)-2-deoxy-Ins indicates that the D-myo-inositol (Ins) 2-hydroxyl is not required for substrate recognition, although it is probably essential for catalysis. GlcN(α1→6)-2-deoxy-L-myo-inositol, unlike GlcN(α1→6)-2-deoxy-Ins, had no effect on GPI-PLC; hence, GPI-PLC can distinguish between the two enantiomers of Ins. Surprisingly, GlcN(α1→6)Ins 1,2-cyclic phosphate was not a potent inhibitor of Bacillus cereus PI-PLC, and GlcN(α1→6)Ins had no effect on the enzyme. However, both GlcN(α1→6)Ins 1-phosphate and GlcN(α1→6)Ins 1-dodecyl phosphonate were competitive inhibitors of PI-PLC. These observations suggest an important role for a phosphoryl group at the Ins 1-position in PI-PLC recognition of GPIs. Other studies indicate that abstraction of a proton from the Ins 2-hydroxyl is not an early event in PI-PLC cleavage of GPIs. Furthermore, both GlcN(α1→6)-2-deoxy-Ins 1-phosphate and GlcN(α1→6)-2-deoxy-L-myo-inositol inhibited PI-PLC without affecting GPI-PLC. Last, the aminoglycoside G418 stimulated PI-PLC, but had no effect on GPI-PLC. Thus, these enzymes represent mechanistic subclasses of GPI phospholipases C, distinguishable by their sensitivity to GlcN(α1→6)Ins derivatives and aminoglycosides. Possible allosteric regulation of PI-PLC by GlcN(α1→6)Ins analogs is discussed." @default.
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• W2014621836 date "1995-02-01" @default.
• W2014621836 modified "2023-10-02" @default.
• W2014621836 title "Glycan Requirements of Glycosylphosphatidylinositol Phospholipase C from Trypanosoma brucei" @default.
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• W2014621836 doi "https://doi.org/10.1074/jbc.270.6.2517" @default.
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