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
  • [21] MEISLER MH, 1969, J BIOL CHEM, V244, P4961
  • [22] MURATA M, 1982, B JPN SOC SCI FISH, V48, P549
  • [23] STRUCTURES OF 3 NEW HOMOTYROSINE-CONTAINING MICROCYSTINS AND A NEW HOMOPHENYLALANINE VARIANT FROM ANABAENA SP STRAIN 66
    NAMIKOSHI, M
    SIVONEN, K
    EVANS, WR
    CARMICHAEL, WW
    ROUHIAINEN, L
    LUUKKAINEN, R
    RINEHART, KL
    [J]. CHEMICAL RESEARCH IN TOXICOLOGY, 1992, 5 (05) : 661 - 666
  • [24] POLYOMA SMALL AND MIDDLE T-ANTIGENS AND SV40 SMALL T-ANTIGEN FORM STABLE COMPLEXES WITH PROTEIN PHOSPHATASE-2A
    PALLAS, DC
    SHAHRIK, LK
    MARTIN, BL
    JASPERS, S
    MILLER, TB
    BRAUTIGAN, DL
    ROBERTS, TM
    [J]. CELL, 1990, 60 (01) : 167 - 176
  • [25] MICROCYSTIN-LA FROM A BLUE-GREEN-ALGA BELONGING TO THE STIGONEMATALES
    PRINSEP, MR
    CAPLAN, FR
    MOORE, RE
    PATTERSON, GML
    HONKANEN, RE
    BOYNTON, AL
    [J]. PHYTOCHEMISTRY, 1992, 31 (04) : 1247 - 1248
  • [26] NODULARIN, MICROCYSTIN, AND THE CONFIGURATION OF ADDA
    RINEHART, KL
    HARADA, K
    NAMIKOSHI, M
    CHEN, C
    HARVIS, CA
    MUNRO, MHG
    BLUNT, JW
    MULLIGAN, PE
    BEASLEY, VR
    DAHLEM, AM
    CARMICHAEL, WW
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1988, 110 (25) : 8557 - 8558
  • [27] ACANTHIFOLICIN, A NEW EPISULFIDE-CONTAINING POLYETHER CARBOXYLIC-ACID FROM EXTRACTS OF THE MARINE SPONGE PANDAROS-ACANTHIFOLIUM
    SCHMITZ, FJ
    PRASAD, RS
    GOPICHAND, Y
    HOSSAIN, MB
    VANDERHELM, D
    SCHMIDT, P
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1981, 103 (09) : 2467 - 2469
  • [28] SHENOLIKAR S, 1991, ADV SEC MESS PHOSPH, V23, P1
  • [29] STRUCTURALLY DIFFERENT MEMBERS OF THE OKADAIC ACID CLASS SELECTIVELY INHIBIT PROTEIN SERINE THREONINE BUT NOT TYROSINE PHOSPHATASE-ACTIVITY
    SUGANUMA, M
    FUJIKI, H
    OKABE, S
    NISHIWAKI, S
    BRAUTIGAN, D
    INGEBRITSEN, TS
    ROSNER, MR
    [J]. TOXICON, 1992, 30 (08) : 873 - 878
  • [30] OKADAIC ACID, A CYTO-TOXIC POLYETHER FROM 2 MARINE SPONGES OF THE GENUS HALICHONDRIA
    TACHIBANA, K
    SCHEUER, PJ
    TSUKITANI, Y
    KIKUCHI, H
    VANENGEN, D
    CLARDY, J
    GOPICHAND, Y
    SCHMITZ, FJ
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1981, 103 (09) : 2469 - 2471