Substrate properties of analogs of myo-inositol.
The hydrolysis of the minor cell membrane lipid phosphatidylinositol-4,5-bisphosphate mediates the action of many growth factors and hormones. As an approach to the development of specific inhibitors of this process, we have synthesized a series of analogs of myo-inositol and have evaluated their ability to serve as substrates for phosphatidylinositol synthetase. Modification at the 2-, 3-, or 4-positions produced compounds unable to serve as substrates, but several 5-modified analogs retained activity as substrates of phosphatidylinositol synthetase. The product formed from 5-deoxy-5-fluoro-myo-[3H]inositol by phatidylinositol synthetase was hydrolyzed by phospholipase D and gave 5-deoxy-5-fluoro-myo-inositol as the radiolabeled product. Two analogs, 5-deoxy-myo-inositol and 5-deoxy-5-fluoro-myo-inositol, were shown to permeate L1210 leukemia cells and be incorporated into cellular phospholipid. Analysis of the radiolabeled lipids formed on incubation of L1210 cells with 5-deoxy-5-fluoro-myo-[3H]inositol indicated that the fradulent lipid formed was further phosphorylated to the monophosphate but not to the diphosphate form.
Moyer
J D
JD
Laboratory of Biological Chemistry, National Cancer Institute, Bethesda, MD 20892.
Reizes
O
O
Ahir
S
S
Jiang
C
C
Malinowski
N
N
Baker
D C
DC
D051607:CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase; D007294:Inositol / Q000031:analogs & derivatives* / Q000378:metabolism; D008958:Models, Molecular; D010743:Phospholipids / Q000378:metabolism; D010770:Phosphotransferases; D013329:Structure-Activity Relationship; D017855:Transferases (Other Substituted Phosphate Groups)
D010743:Phospholipids; D007294:Inositol; D010770:Phosphotransferases; D017855:Transferases (Other Substituted Phosphate Groups); D051607:CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase