Kinetic analysis of novel inhibitors of inositol polyphosphate metabolism.
The ability of the novel D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3] analogues, L-chiro-inositol 1,4,6-trisphosphate [L-chr Ins(1,4,6)P3] and the corresponding trisphosphorothioate compound [L-chr Ins(1,4,6)PS3] to inhibit soluble inositol (1,4,5)P3/(1,3,4,5)P4-polyphosphate 5-phosphatase, potently and selectively, has been investigated. L-chr Ins(1,4,6)P3 competitively inhibited 5-phosphate specific dephosphorylation of Ins(1,4,5)P3 and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] with apparent Ki values of 6.35 and 1.76 microM, respectively. L-chr Ins(1,4,6)PS3 competitively inhibited hydrolysis of Ins(1,4,5)P3 and noncompetitively inhibited dephosphorylation of Ins(1,3,4,5)P4 with apparent Ki values of 0.67 and 0.44 microM, respectively. L-chr Ins(1,4,6)PS3 did not affect Ins(1,4,5)P3 3-kinase activity. In the present investigation L-chr Ins(1,4,6)P3 and L-chr Ins(1,4,6)PS3 have been shown to be the most potent and selective inhibitors of inositol polyphosphate metabolism yet described.
Hansbro
P M
PM
Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra.
Foster
P S
PS
Liu
C
C
Potter
B V
BV
Denborough
M A
MA
D000818:Animals; D015544:Inositol 1,4,5-Trisphosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism*; D000072181:Inositol Polyphosphate 5-Phosphatases; D007700:Kinetics; D009132:Muscles / Q000201:enzymology; D009946:Organothiophosphorus Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D013552:Swine
D007295:Inositol Phosphates; D009946:Organothiophosphorus Compounds; C086879:inositol 1,4,6-trisphosphorothioate; C086878:inositol 1,4,6-trisphosphate; D015544:Inositol 1,4,5-Trisphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases