Characterization of microcystin-LR, a potent inhibitor of type 1 and type 2A protein phosphatases.

Honkanen, Richard E.; Zwiller, Jean; Moore, Richard E.; Daily, Shannon; Khatra, Balwant S.; Dukelow, M; Boynton, Alton L.

doi:10.1016/s0021-9258(17)45384-1

Cited by 532 publications

(100 citation statements)

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“…In vitro, apoptotic changes can be induced in cell types other than hepatocytes through exposure of the cells for long periods of time at concentrations approximately 1-2 orders of magnitude higher than those that affect hepatocytes (21,26). Once inside the cell, MCLR binds to protein phosphatases 1 and 2A with very high affinity (5,25,11). The subsequent inhibition of these protein phosphatases results in increased phosphorylation of proteins throughout the cell (5).…”

Section: Discussionmentioning

confidence: 99%

“…When treated with MCLR in vitro, hepatic nonparenchymal cells (primarily sinusoidal endothelial and Kupffer cells) were not morphologically affected at doses up to 10 jig MCLR/ml [hepatocyte plasma membrane blebbing due to MCLR occurred at 0.1-10.0 f.Lg MCLR/ ml (14)]. Inside the hepatocytes, MCLR selectively binds to protein phosphatases 1 and 2A with high affinity (5,11,25). In vitro, inhibition of phosphatases 1 and 2A by MCLR and related protein phosphatase inhibitors such as okadaic acid have been used as models of apoptosis (2).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fulminant Hepatocyte Apoptosis In Vivo Following Microcystin-LR Administration to Rats

Hooser

2000

Toxicol Pathol

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fulminant Hepatocyte Apoptosis In Vivo Following Microcystin-LR Administration to Rats

Hooser

2000

Toxicol Pathol

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“…Nodularin inhibits serine/threonine protein phosphatases 1 and 2A in rat liver epithelial cells. 11 This inhibition leads to hyperphosphorylation of cytoskeletal proteins in hepatocytes. A rapid loss of hepatic architecture and accumulation of blood in the sinusoids follows.…”

Section: Discussionmentioning

confidence: 99%

Pathologic Findings and Toxin Identification in Cyanobacterial (Nodularia spumigena) Intoxication in a Dog

et al. 2011

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A 3-year-old Cairn Terrier dog that had been in contact with sea water containing cyanobacteria (blue-green algae) was euthanized because of acute hepatic failure and anuria after a 5-day illness. Histologic findings included lytic and hemorrhagic centrilobular hepatocellular necrosis and renal tubular necrosis. The cyanotoxin nodularin was detected in liver and kidney by highperformance liquid chromatography-mass spectrometry. Nodularin is a potent hepatotoxin produced by the algal species Nodularia spumigena. The intensity of algal blooms has increased during the past decades in the Baltic Sea region, thus increasing the risk for intoxications in domestic and wild animals. The authors describe the pathologic findings of cyanobacterial toxicosis in a dog with direct identification of the toxin from organ samples.Keywords cyanobacterium, dog, hepatic necrosis, kidney, liquid chromatography-mass spectrometry, liver, nodularin, renal tubular necrosis Hepatic necrosis due to toxins produced by blue-green algae (cyanobacteria) is a well-known cause for acute hepatic failure and death in wild and domestic animals. Although at least 40 species of cyanobacteria, with worldwide distribution, can synthesize a range of hepatotoxins, neurotoxins, and dermatotoxins, the threat of cyanotoxin-contaminated water is often ignored. 3,24Blooming of blue-green algae, especially the toxigenic species Nodularia spumigena, occurs annually in the Baltic Sea region, presenting a threat for animals exposed to contaminated water. Previously, the identification of blue-green algal toxin was laborious, requiring water samples and the use of experimental animals; 5,6,10,16,25,26 algal toxins have not been analyzed routinely from animal tissues in diagnostic cases. In this report, blue-green algal toxicosis was confirmed by direct toxin analysis from organ samples. Case HistoryA 3-year-old female Cairn Terrier weighing 9.6 kg was exposed to sea water containing blue-green algae in the Finnish southwest coastal region of the Baltic Sea. The exact route of exposure is uncertain; the dog was not seen swimming in the sea but may have consumed algal scum or drunk contaminated water. Subsequently, the dog became acutely lethargic with vomiting and inappetence. Initially, it was treated supportively with antiemetics and fluid therapy. Three days after the onset of clinical signs, the dog was admitted to the university hospital because of further clinical deterioration.Upon physical examination, the dog was lethargic, dehydrated, and icteric. Abnormal hematologic findings included mild nonregenerative anemia (packed cell volume, 32%; reference range, 38%-57%; mean corpuscular volume and hemoglobin within reference ranges) with normal leukocyte count (14.0 Â 10 9 /liter; reference range, 5.4-17.4 Â 10 9 /liter). Serum biochemistry profile abnormalities included elevated alanine aminotransferase (6211 U/liter; reference range, 18-77 U/liter), alkaline phosphatase (392 U/liter; reference range, 33-215 U/liter), total bilirubin (272.5 mmol/liter...

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“…The highly conserved active site as well as the nonselective substrate specificity make PPs particularly prone to naturally derived inhibitors. Indeed, a range of PP inhibitors such as cantharidin, [23] okadaic acid, [24,25] calyculin A, [26,27] microcystin LR, [28,29] tautomycin (TTM), [10,30,31] tautomycetin (TTN), [32,33] and spirastrellolide A [34][35][36] (Figure 1) have been isolated from various natural sources and possess various degrees of potency, with IC 50 values ranging from 1 700 to 0.1 nM for PP1 and PP2A ( Figure 1). Most of the known PP inhibitors either exhibit nonselective or PP2A selective inhibition when comparing PP1 and PP2A.…”

Section: Introductionmentioning

confidence: 99%

Tautomycetin Synthetic Analogues: Selective Inhibitors of Protein Phosphatase I

2020

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Ser/Thr protein phosphatases (PPs) regulate a substantial range of cellular processes with protein phosphatases 1 (PP1) and 2 A (PP2A) accounting for over 90 % of the activity within cells. Nevertheless, tools to study PPs are limited as PPs inhibitors, particularly those selective for PP1 inhibition, are relatively scarce. Two examples of PP1‐selective inhibitors, which share structural similarities, are tautomycin (TTM) and tautomycetin (TTN). This work describes the development of PP1/PP2A inhibitors that incorporate key structural features of TTM and TTN and are designed to conserve regions known to bind the active site of PP1/PP2A but vary regions that differentially contact the hydrophobic groove of PP1/PP2A. In all 28 TTN analogues were synthetically generated that inhibit PP1/PP2A activity at <250 mM; seven possessed inhibition activity at 100 nM. The IC50 values were determined for the seven most active analogues, which ranged from 34 to 1500 nM (PP1) and 70 to 6800 nM (PP2A). Four of the seven analogues possessed PP1 selectivity, and one demonstrated eightfold selectivity in the nanomolar range (PP1 IC50=34 nM, PP2A IC50=270 nM). A rationale is given for the observed differences in selectivity.

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Characterization of microcystin-LR, a potent inhibitor of type 1 and type 2A protein phosphatases.

Cited by 532 publications

References 19 publications

Fulminant Hepatocyte Apoptosis In Vivo Following Microcystin-LR Administration to Rats

Fulminant Hepatocyte Apoptosis In Vivo Following Microcystin-LR Administration to Rats

Pathologic Findings and Toxin Identification in Cyanobacterial (Nodularia spumigena) Intoxication in a Dog

Tautomycetin Synthetic Analogues: Selective Inhibitors of Protein Phosphatase I

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