肌醇多磷酸代谢新型抑制剂的动力学分析

Kinetic analysis of novel inhibitors of inositol polyphosphate metabolism.

作者信息

Hansbro P M, Foster P S, Liu C, Potter B V, Denborough M A

机构信息

Division of Biochemistry and Molecular Biology, John Curtin School of Medical Research, Australian National University, Canberra.

出版信息

Biochem Biophys Res Commun. 1994 Apr 15;200(1):8-15. doi: 10.1006/bbrc.1994.1407.

DOI:10.1006/bbrc.1994.1407

PMID:8166746

Abstract

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.

摘要

新型D-肌醇1,4,5-三磷酸[Ins(1,4,5)P₃]类似物L-手性肌醇1,4,6-三磷酸[L-chr Ins(1,4,6)P₃]以及相应的三硫代磷酸酯化合物[L-chr Ins(1,4,6)PS₃]对可溶性肌醇(1,4,5)P₃/(1,3,4,5)P₄-多磷酸5-磷酸酶的强效和选择性抑制能力已得到研究。L-chr Ins(1,4,6)P₃竞争性抑制Ins(1,4,5)P₃和肌醇1,3,4,5-四磷酸[Ins(1,3,4,5)P₄]的5-磷酸特异性去磷酸化，其表观Ki值分别为6.35和1.76微摩尔。L-chr Ins(1,4,6)PS₃竞争性抑制Ins(1,4,5)P₃的水解，并非竞争性抑制Ins(1,3,4,5)P₄的去磷酸化，其表观Ki值分别为0.67和0.44微摩尔。L-chr Ins(1,4,6)PS₃不影响Ins(1,4,5)P₃ 3-激酶活性。在本研究中，L-chr Ins(1,4,6)P₃和L-chr Ins(1,4,6)PS₃已被证明是迄今所描述的最有效和最具选择性的肌醇多磷酸代谢抑制剂。