@article {1489,
	title = {Crystal structures of protein phosphatase-1 bound to motuporin and dihydromicrocystin-LA: Elucidation of the mechanism of enzyme inhibition by cyanobacterial toxins},
	journal = {Journal of Molecular Biology},
	volume = {356},
	number = {1},
	year = {2006},
	note = {ISI Document Delivery No.: 007AFTimes Cited: 17Cited Reference Count: 42},
	month = {Feb},
	pages = {111-120},
	type = {Article},
	abstract = {The microcystins and nodularins are tumour promoting hepatotoxins that are responsible for global adverse human health effects and wildlife fatalities in countries where drinking water supplies contain cyanobacteria. The toxins function by inhibiting broad specificity Ser/Thr protein phosphatases in the host cells, thereby disrupting signal transduction pathways. A previous crystal structure of a microcystin bound to the catalytic subunit of protein phosphatase-1 (PP-1c) showed distinct changes in the active site region when compared with protein phosphatase-1 structures bound to other toxins. We have elucidated the crystal structures of the cyanotoxins, motuporin (nodularin-V) and dihydromicrocystin-LA bound to human protein phosphatase-1c (gamma isoform). The atomic structures of these complexes reveal the structural basis for inhibition of protein phosphatases by these toxins. Comparisons of the structures of the cyanobacterial toxin:phosphatase complexes explain the biochemical mechanism by which microcystins but not nodularins permanently modify their protein phosphatase targets by covalent addition to an active site cysteine residue. (c) 2005 Elsevier Ltd. All rights reserved.},
	keywords = {CATALYTIC SUBUNIT, COMPLEX, crystal structure, cyanobacteria, IN-VIVO, microcystin, MICROCYSTIN-LR, MOLECULAR-MECHANISMS, nodularin, POTENT, PROGRAM, TUMOR-PROMOTER, TYPE-1},
	isbn = {0022-2836},
	url = {<Go to ISI>://000234938600010},
	author = {Maynes, J. T. and Luu, H. A. and Cherney, M. M. and Andersen, R. J. and Williams, D. and Holmes, C. F. B. and James, M. N. G.}
}
@article {4879,
	title = {The adsorption of microcystin-LR by natural clay particles},
	journal = {Toxicon},
	volume = {38},
	number = {2},
	year = {2000},
	note = {ISI Document Delivery No.: 257VLTimes Cited: 40Cited Reference Count: 35},
	month = {Feb},
	pages = {303-308},
	type = {Article},
	abstract = {The microcystin cyanobacterial hepatotoxins represent an increasingly severe global health hazard. Sines microcystins are found world wide in drinking water reservoirs concern about the impact on human health has prompted investigations into remedial water treatment methods. This preliminary study investigates the scavenging from water of microcystin-LR by fine-grained particles known to have a high concentration of the clay minerals kaolinite and montmorillonite. The results show that more than 81\% of microcystin-LR can be removed from water by clay material. Thus, microcystin-LR is indeed scavenged from water bodies by fine-grained particles and that this property may offer an effective method of stripping these toxins from drinking water supplies. (C) 1999 Elsevier Science Ltd. All rights reserved.},
	keywords = {BLOOM, cyanobacteria, DECOMPOSITION, DIARRHETIC SHELLFISH TOXINS, ENVIRONMENT, IDENTIFICATION, OKADAIC ACID, OSCILLATORIA-AGARDHII, PROTEIN PHOSPHATASE INHIBITORS, TUMOR PROMOTION},
	isbn = {0041-0101},
	url = {<Go to ISI>://000083803000016},
	author = {Morris, R. J. and Williams, D. E. and Luu, H. A. and Holmes, C. F. B. and Andersen, R. J. and Calvert, S. E.}
}
@article {4158,
	title = {Bioaccumulation and clearance of microcystins from salt water, mussels, Mytilus edulis, and in vivo evidence for covalently bound microcystins in mussel tissues},
	journal = {Toxicon},
	volume = {35},
	number = {11},
	year = {1997},
	note = {ISI Document Delivery No.: YM145Times Cited: 73Cited Reference Count: 48},
	month = {Nov},
	pages = {1617-1625},
	type = {Article},
	abstract = {Over a period of 3 days saltwater mussels, Mytilus edulis, were fed a cyanobacteria, Microcystis aeruginosa, that contained a high concentration of microcystins, The mussels were killed on a periodic basis over the course of 2 months, Mussels were also collected at two sites were high levels of microcystins in tissues had been noted. A strategy based on the chemically unique nature of the C-20 beta-amino acid, (2S,3S,8S,9S)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoi c acid (Adda), portion of the microcystins was used in conjunction with a protein phosphatase (PPase) assay to analyse for both covalently bound microcystins and free microcystins in the mussel tissues, The mussel PPase assay results were compared with the Lemieux oxidation gas chromatography-mass spectrometry (GCMS) analysis. Less than 0.1\% of the total microcystin burden in the mussel tissue was found to be extractable with MeOH. Thus, direct evidence was provided for the existence of covalently bound microcystins in mussel tissues in vivo. The mussels rapidly cleared the covalently bound microcystins when transferred to untreated seawater. Within 4 days the total microcystin burden dropped from a high of 336.9 (+/- 45.8) mu g/g wet tissue to 11.3 (+/- 2.6) mu g/g. After 4 days postexposure until completion of the experiment the total levels remained below the detection limits of the GCMS method, The levels of free microcystins, extracted with MeOH and detected by the PPase assay, fell from 204 ng/g wet tissue to a residual 14 ng/g over a 53 day postexposure period. Presumably the bound microcystin present in the mussel tissue exists as a covalent complex with the PP-1 and PP-2A enzymes. We conclude that in any shellfish monitoring program it is the total tissue microcystin burden that needs to be considered. (C) 1997 Elsevier Science Ltd.},
	keywords = {AERUGINOSA, BLUE-GREEN-ALGAE, cyanobacteria, DIARRHETIC SHELLFISH TOXINS, IDENTIFICATION, LR, OKADAIC ACID, PEPTIDE TOXIN, PROTEIN PHOSPHATASE INHIBITORS, TUMOR PROMOTION},
	isbn = {0041-0101},
	url = {<Go to ISI>://000071033700005},
	author = {Williams, D. E. and Dawe, S. C. and Kent, M. L. and Andersen, R. J. and Craig, M. and Holmes, C. F. B.}
}
@article {3640,
	title = {Molecular mechanisms underlying the interaction of motuporin and microycystins with type-1 and type-2A protein phosphatases},
	journal = {Biochemistry and Cell Biology-Biochimie Et Biologie Cellulaire},
	volume = {74},
	number = {4},
	year = {1996},
	note = {ISI Document Delivery No.: VX367Times Cited: 61Cited Reference Count: 35},
	pages = {569-578},
	type = {Article},
	abstract = {Heptapeptide microcystin and pentapeptide motuporin (nodularin-V) are equipotent inhibitors of type-1 and type-2A protein phosphatase catalytic subunits (PP-1c and PP-2Ac). Herein we describe elucidation of the molecular mechanisms involved in the interaction of these structurally similar hepatotoxins with PP-1c/PP-2Ac and identification of an important functional difference between their mode of interaction with these enzymes. Microcystin-LR, microcystin-LA and microcystin-LL were found to interact with PP-2Ac and PP-1c by a two-step mechanism involving rapid binding and inactivation of the protein phosphatase (PPase) catalytic subunit, followed by a slower covalent interaction (within hours). Covalent adducts comprising PPase-toxin complexes were separated from free PPase by C-18 reverse-phase liquid chromatography, thus allowing the time course of covalent adduct formation to be quantitated. In contrast to microcystins, motuporin (nodularin-V) and nodularin-R were unable to form covalent complexes with either PP-1c or PP-2Ac even after 96 h incubation. Specific reduction of microcystin-LA to dihydromicrocystin-LA abolished the ability of the toxin to form a covalent adduct with PP-2Ac. Specific methyl esterification of the single Glu residue in microcystin-LR rendered this toxin inactive as a PPase inhibitor and abolished subsequent formation of a covalent adduct. Our data indicate that inactivation of PP-2Ac/PP-1c by microcystins precedes covalent modification of the PPases via a Michael addition reaction between a nucleophilic phosphatase residue and Mdha in the heptapeptide toxin. In contrast, following rapid inactivation of PP-2Ac/PP-1c by motuporin, the equivalent N-methyldehydrobutyrine residue in this toxin is unreactive and does not form a covalent bond with the PPases. These results are consistent with structural data for (i) the NMR solution structures of microcystin-LR and motuporin, which indicate a striking difference in the relative positions of their corresponding dehydroamino acids in the toxin peptide backbone, and (ii) X-ray crystallographic data on an inactive complex between PP-1c and microcystin-LR, which show a covalent bond between Cys-273 and the bound toxin.},
	keywords = {BLUE-GREEN-ALGAE, CATALYTIC SUBUNIT, cyanobacteria, IDENTIFICATION, MICROCYSTIN-LR, microcystins, motuporin, nodularin, OKADAIC ACID, PHOSPHORYLATION, POTENT INHIBITOR, PROTEIN, PROTEIN PHOSPHATASES, RAT-LIVER, TOXINS},
	isbn = {0829-8211},
	url = {<Go to ISI>://A1996VX36700017},
	author = {Craig, M. and Luu, H. A. and McCready, T. L. and Williams, D. and Andersen, R. J. and Holmes, C. F. B.}
}
