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  • Title: Short-chain phosphatidylinositol conformation and its relevance to phosphatidylinositol-specific phospholipase C.
    Author: Zhou C, Garigapati V, Roberts MF.
    Journal: Biochemistry; 1997 Dec 16; 36(50):15925-31. PubMed ID: 9398326.
    Abstract:
    The solution conformation of chiral diheptanoylphosphatidylinositol (D- and L-inositol isomers) has been characterized by NMR spectroscopy. A positive NOE between the inositol C2 proton and an sn-3 glycerol CH2 proton has been observed in the D- but not in the L-inositol isomer of diheptanoylphosphatidylinositol (PI). Computer modeling using QUANTA constrained by this NOE and ring coupling constants suggests that the inositol ring is nearly parallel to the chain packing direction, leaving the phosphate ester accessible to attack by phosphatidylinositol-specific phospholipase C enzymes. In this model, the hydroxyl groups in the 2- and 6-positions of inositol form hydrogen bonds with the pro-R and ester oxygens, respectively. Chemical shifts and 13C spin-lattice relaxation times were also used to assess conformation and lipid dynamics in monomer and micelle states. The 13C T1's of inositol C2 and C6 in monomeric phosphatidylinositol were markedly less than for other inositol ring carbons. These results are consistent with the hydrogen bonds to the phosphate constraining the motions of C2 and C6. Diheptanoylphosphatidyl-2-O-methylinositol is a good inhibitor of PI-specific phospholipase C because it blocks the initial phosphotransferase step in PI hydrolysis. Introduction of the methyl group on the C-2 hydroxyl group lowers the CMC of the derivative compared to diheptanoylphosphatidylinositol. However, an NOE between an sn-3 glycerol proton and the inositol C2 proton constrains the orientation of the inositol ring with respect to the glycerol backbone in a conformation similar to diheptanoylphosphatidylinositol. Modeling of the 2-O-methylinositol derivative suggests that the methyl group blocks one side of the phosphate, consistent with the observation that nonspecific phospholipase C enzymes which are able to hydrolyze PI, albeit poorly, are unable to hydrolyze diheptanoylphosphatidyl-2-O-methylinositol.
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