CHARACTERIZATION OF NATURAL TOXINS WITH INHIBITORY ACTIVITY AGAINST SERINE THREONINE PROTEIN PHOSPHATASES

被引:176
作者
HONKANAN, RE
CODISPOTI, BA
TSE, K
BOYNTON, AL
机构
[1] PACIFIC NW RES FDN, CELL & MOLEC BIOL PROGRAM, SEATTLE, WA 98122 USA
[2] UNIV HAWAII, CAN RES CTR HAWAII, HONOLULU, HI 96813 USA
关键词
D O I
10.1016/0041-0101(94)90086-8
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Recent studies suggest that the ability to inhibit the activity of certain serine/threonine protein phosphatases underlies the toxicity of several natural compounds including: okadaic acid, microcystin-LR, nodularin, calyculin A and tautomycin. To characterize further the actions of these toxins, this study compares the inhibitory effects of okadaic acid, chemical derivatives of okadaic acid, microcystin-LR, microcystin-LA, nodularin, calyculin A and tautomycin on the activity of serine/threonine protein phosphatases types 1 (PP1), 2A (PP2A) and a recently identified protein phosphatase purified from bovine brain (PP3). This study shows that, like PP1 and PP2A, the activity of PP3 is potently inhibited by okadaic acid, both microcystins, nodularin, calyculin A and tautomycin. Further characterization of the toxins employing the purified catalytic subunits of PP1, PP2A and PP3 under identical experimental conditions indicates that: (a) okadaic acid, microcystin-LR, and microcystin-LA inhibit PP2A and PP3 more potently than PP1 (order of potency PP2A > PP3 > PP1); (b) nodularin inhibits PP1 and PP3 at a similar concentration that is slightly higher than that which affects PP2A, and (c) both calyculin A and tautomycin show little selectivity among the phosphatases tested. This study also shows that the chemical modification of the (C1) carboxyl group of okadaic acid can have a profound influence on the inhibitory activity of this toxin. Esterification of okadaic acid, producing methyl okadaate, or reduction, producing okadaol, greatly decreases the inhibitory effects against all three enzymes tested. Further reduction, producing 1-nor-okadaone, or acetylation, producing okadaic acid tetraacetate, results in compounds with no inhibitory activity. In contrast, the substitution of alanine (-LA) for arginine (-LR) in microcystin has no apparent effect on the inhibitory activity against PP1, PP2A or PP3.
引用
收藏
页码:339 / 350
页数:12
相关论文
共 31 条
  • [1] INHIBITORY EFFECT OF A MARINE-SPONGE TOXIN, OKADAIC ACID, ON PROTEIN PHOSPHATASES - SPECIFICITY AND KINETICS
    BIALOJAN, C
    TAKAI, A
    [J]. BIOCHEMICAL JOURNAL, 1988, 256 (01) : 283 - 290
  • [2] Botes D.P., 1984, J CHEM SOC CHEM COMM, P2311
  • [3] BRAUTIGAN DL, 1988, METHOD ENZYMOL, V159, P339
  • [4] BRAUTIGAN DL, 1985, J BIOL CHEM, V260, P4295
  • [5] PPX, A NOVEL PROTEIN SERINE THREONINE PHOSPHATASE LOCALIZED TO CENTROSOMES
    BREWIS, ND
    STREET, AJ
    PRESCOTT, AR
    COHEN, PTW
    [J]. EMBO JOURNAL, 1993, 12 (03) : 987 - 996
  • [6] NAMING OF CYCLIC HEPTAPEPTIDE TOXINS OF CYANOBACTERIA (BLUE-GREEN-ALGAE)
    CARMICHAEL, WW
    BEASLEY, V
    BUNNER, DL
    ELOFF, JN
    FALCONER, I
    GORHAM, P
    HARADA, KI
    KRISHNAMURTHY, T
    YU, MJ
    MOORE, RE
    RINEHART, K
    RUNNEGAR, M
    SKULBERG, OM
    WATANABE, M
    [J]. TOXICON, 1988, 26 (11) : 971 - 973
  • [7] CHENG XC, 1990, J ANTIBIOT, V43, P809, DOI 10.7164/antibiotics.43.809
  • [8] COHEN P, 1991, METHOD ENZYMOL, V201, P389
  • [9] OKADAIC ACID - A NEW PROBE FOR THE STUDY OF CELLULAR-REGULATION
    COHEN, P
    HOLMES, CFB
    TSUKITANI, Y
    [J]. TRENDS IN BIOCHEMICAL SCIENCES, 1990, 15 (03) : 98 - 102
  • [10] AN IMPROVED PROCEDURE FOR IDENTIFYING AND QUANTITATING PROTEIN PHOSPHATASES IN MAMMALIAN-TISSUES
    COHEN, P
    KLUMPP, S
    SCHELLING, DL
    [J]. FEBS LETTERS, 1989, 250 (02) : 596 - 600