The effect of structural variation in 21 microcystins on their inhibition of PP2A and the effect of replacing cys269 with glycine

Ikehara, Tsuyoshi; Imamura, Shihoko; Sano, Tomoharu; Nakashima, Junichi; Kuniyoshi, Kyoko; Oshiro, Naomasa; Yoshimoto, Masahiro; Yasumoto, Takeshi

doi:10.1016/j.toxicon.2009.05.028

Cited by 32 publications

(31 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, nodularin-R exhibits an IC 50 (1.8 nM), like that of MC-LR (2.2 nM) for human red blood cells PP2A [250] and nodularins do not form a covalent linkage to thiol group of Cys-273 in PP1 [120,258]. Similarly, MC congeners containing Dha 7 (e.g., [D-Asp 3 ,Dha 7 ]MC-LR) and its analogue containing Dhb 7 ([D-Asp 3 ,Dhb 7 ]MC-LR) have similar IC 50 values for PP2A of 0.254 ± 0.004 and 0.201 ± 0.003 nM, respectively [239].…”

Section: In Vitro Toxicity: Inhibition Of Serine/threonine Ppsmentioning

confidence: 97%

Structural Diversity, Characterization and Toxicology of Microcystins

Bouaı̈cha

Miles

Beach

et al. 2019

Toxins

319

192

View full text Add to dashboard Cite

Hepatotoxic microcystins (MCs) are the most widespread class of cyanotoxins and the one that has most often been implicated in cyanobacterial toxicosis. One of the main challenges in studying and monitoring MCs is the great structural diversity within the class. The full chemical structure of the first MC was elucidated in the early 1980s and since then, the number of reported structural analogues has grown steadily and continues to do so, thanks largely to advances in analytical methodology. The structures of some of these analogues have been definitively elucidated after chemical isolation using a combination of techniques including nuclear magnetic resonance, amino acid analysis, and tandem mass spectrometry (MS/MS). Others have only been tentatively identified using liquid chromatography-MS/MS without chemical isolation. An understanding of the structural diversity of MCs, the genetic and environmental controls for this diversity and the impact of structure on toxicity are all essential to the ongoing study of MCs across several scientific disciplines. However, because of the diversity of MCs and the range of approaches that have been taken for characterizing them, comprehensive information on the state of knowledge in each of these areas can be challenging to gather. We have conducted an in-depth review of the literature surrounding the identification and toxicity of known MCs and present here a concise review of these topics. At present, at least 279 MCs have been reported and are tabulated here. Among these, about 20% (55 of 279) appear to be the result of chemical or biochemical transformations of MCs that can occur in the environment or during sample handling and extraction of cyanobacteria, including oxidation products, methyl esters, or post-biosynthetic metabolites. The toxicity of many MCs has also been studied using a range of different approaches and a great deal of variability can be observed between reported toxicities, even for the same congener. This review will help clarify the current state of knowledge on the structural diversity of MCs as a class and the impacts of structure on toxicity, as well as to identify gaps in knowledge that should be addressed in future research.

show abstract

Section: In Vitro Toxicity: Inhibition Of Serine/threonine Ppsmentioning

confidence: 97%

Structural Diversity, Characterization and Toxicology of Microcystins

Bouaı̈cha

Miles

Beach

et al. 2019

Toxins

319

192

View full text Add to dashboard Cite

show abstract

“…Accordingly, a World Health Organization (WHO) guideline recommends imposing a maximum allowable level of 1 mg/L of MC-LR or its equivalent in water. Mammalian cell lines including hepatocytes have been widely used to quantify the toxicity of natural toxins, including MCs (Aune and Berg, 1986;Codd et al, 1989;Heinze, 1996;Ikehara et al, 2009). We also studied the cytotoxicity of 21 pure MCs in normal human hepatocytes and observed an inverse correlation between cellular viability and PP2A inhibition potency (Ikehara et al, 2009).…”

Section: Introductionmentioning

confidence: 96%

Different responses of primary normal human hepatocytes and human hepatoma cells toward cyanobacterial hepatotoxin microcystin-LR

Ikehara

Nakashima

et al. 2015

Toxicon

Self Cite

View full text Add to dashboard Cite

“…Similarly, Park et al [6] independently found that 2 and 3 both had the same IC 50 value of 0.3 nM in their PP1 assay. Ikehara et al [21] found that the IC 50 of MC-LF(9), which differs from MC-LY (5) only by the absence of a phenolic hydroxyl group on residue-2, was 3-fold higher than that of MC-LR (2) (0.096 vs. 0.032 nM) in their PP2A assay. Taken together with the data presented here, these results suggest that the replacement of D-Ala with D-Leu at position 1 in the MC structure has only a minor effect on the toxicity of MCs or on their inhibitory effects on PP1 and PP2A.…”

Section: Resultsmentioning

confidence: 97%

Isolation and Characterization of [D-Leu1]microcystin-LY from Microcystis aeruginosa CPCC-464

LeBlanc

Merkley

Thomas

et al. 2020

Toxins

View full text Add to dashboard Cite

[D-Leu1]MC-LY (1) ([M + H]+ m/z 1044.5673, Δ 2.0 ppm), a new microcystin, was isolated from Microcystis aeruginosa strain CPCC-464. The compound was characterized by 1H and 13C NMR spectroscopy, liquid chromatography–high resolution tandem mass spectrometry (LC–HRMS/MS) and UV spectroscopy. A calibration reference material was produced after quantitation by 1H NMR spectroscopy and LC with chemiluminescence nitrogen detection. The potency of 1 in a protein phosphatase 2A inhibition assay was essentially the same as for MC-LR (2). Related microcystins, [D-Leu1]MC-LR (3) ([M + H]+ m/z 1037.6041, Δ 1.0 ppm), [D-Leu1]MC-M(O)R (6) ([M + H]+ m/z 1071.5565, Δ 2.0 ppm) and [D-Leu1]MC-MR (7) ([M + H]+ m/z 1055.5617, Δ 2.2 ppm), were also identified in culture extracts, along with traces of [D-Leu1]MC-M(O2)R (8) ([M + H]+ m/z 1087.5510, Δ 1.6 ppm), by a combination of chemical derivatization and LC–HRMS/MS experiments. The relative abundances of 1, 3, 6, 7 and 8 in a freshly extracted culture in the positive ionization mode LC–HRMS were ca. 84, 100, 3.0, 11 and 0.05, respectively. These and other results indicate that [D-Leu1]-containing MCs may be more common in cyanobacterial blooms than is generally appreciated but are easily overlooked with standard targeted LC–MS/MS screening methods.

show abstract

The effect of structural variation in 21 microcystins on their inhibition of PP2A and the effect of replacing cys269 with glycine

Cited by 32 publications

References 19 publications

Structural Diversity, Characterization and Toxicology of Microcystins

Structural Diversity, Characterization and Toxicology of Microcystins

Different responses of primary normal human hepatocytes and human hepatoma cells toward cyanobacterial hepatotoxin microcystin-LR

Isolation and Characterization of [D-Leu1]microcystin-LY from Microcystis aeruginosa CPCC-464

Contact Info

Product

Resources

About