Background
Cyanotoxins are a variety of secondary metabolites produced by cyanobacteria of different genera that are toxic to eukaryotes, including algae, plants, animals, and even humans. Based on their chemical composition, cyanotoxins can be divided into three categories, namely cyclic peptides, alkaloids and lipopolysaccharides. Microcystins (MCs) are cyclic peptides, the largest and most diverse group of cyanobacterial toxins with a molecular weight of about 1000 Da. More than 100 structural variants have been identified, among which MC-LR, MC-RR and MC-YR contain different leucine (L), arginine (R) or tyrosine (Y). It is the most widely studied because of its widespread presence, abundant content, and toxicity. MCs contain seven peptide chain amino acids, with the two terminal amino acids of the linear peptide joining to form a cyclic bond, i.e. cyclic-D-Ala1-L-X2-D-isoMeAsp3-L-Z4-Adda5-D-isoGlu6-Mdha7. The second and fourth positions, X and Z, are highly variable L-amino acids that determine the suffixes in the MC nomenclature, e.g., MC-LR contains leucine (L) and arginine (R).
Figure 1. Chemical structure of microcystin-LR (MC-LR)
(Source: Chen L, et al. 2016)
Due to the hydrophilic nature of MCs, they require the assistance of specific transporters to enter the cell through an active transport mechanism. In hepatocytes, cellular uptake of MC-LR is mediated by the bile acid multi-specific transporter system. The effects of MCs on cellular metabolism and physiology vary with species/genetic background, cell type, MC congeners, level, and duration of exposure. MCs function as tumor promoters by inhibiting the proteins serine/threonine phosphatases 1 and 2A, which leads to hyperphosphorylation of cytoskeletal proteins and disruption of a variety of cellular processes, including disturbed cellular homeostasis, cytoskeletal alterations and rearrangements, and disruption of liver structure. MC has cytotoxic and tumor-promoting activity, and chronic exposure to low levels of MCLR increases the risk of cancer. MC is also genotoxic and induces DNA damage. Exposure to MC also induces overproduction of reactive oxygen species (ROS) and oxidative stress, leading to cytoskeletal disruption, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and DNA damage.
Figure 2. A schematic review of the mechanisms of microcystin-induced toxicity and cell death
(Source: Chen L, et al. 2016)
Alternative Names
anti-MC LR monoclonal antibody
MCLR mAb
MC-LR mAb
References
- 1. Chen L, et al. Mechanisms of Microcystin-induced Cytotoxicity and Apoptosis. Mini Rev Med Chem. 2016;16(13):1018-31.
- 2. Zegura B. An Overview of the Mechanisms of Microcystin-LR Genotoxicity and Potential Carcinogenicity. Mini Rev Med Chem. 2016;16(13):1042-62.
References
MC-LR Aggravates Liver Lipid Metabolism Disorders in Obese Mice Fed a High-Fat Diet via PI3K/AKT/mTOR/SREBP1 Signaling Pathway
Toxins (Basel)
Authors: Chu H, Du C, Yang Y, Feng X, Zhu L, Chen J, Yang F.
Abstract
Obesity, a metabolic disease caused by excessive fat accumulation in the body, has attracted worldwide attention. Microcystin-LR (MC-LR) is a hepatotoxic cyanotoxin which has been reportedly to cause lipid metabolism disorder. In this study, C57BL/6J mice were fed a high-fat diet (HFD) for eight weeks to build obese an animal model, and subsequently, the obese mice were fed MC-LR for another eight weeks, and we aimed to determine how MC-LR exposure affects the liver lipid metabolism in high-fat-diet-induced obese mice. The results show that MC-LR increased the obese mice serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), indicating damaged liver function. The lipid parameters include serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and liver TG, which were all increased, whilst the high-density lipoprotein cholesterol (HDL-c) was decreased. Furthermore, after MC-LR treatment, histopathological observation revealed that the number of red lipid droplets increased, and that steatosis was more severe in the obese mice. In addition, the lipid synthesis-related genes were increased and the fatty acid β-oxidation-related genes were decreased in the obese mice after MC-LR exposure. Meanwhile, the protein expression levels of phosphorylation phosphatidylinositol 3-kinase (p-PI3K), phosphorylation protein kinase B (p-AKT), phosphorylation mammalian target of rapamycin (p-mTOR), and sterol regulatory element binding protein 1c (SREBP1-c) were increased; similarly, the p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, and SREBP1/β-actin were significantly up-regulated in obese mice after being exposed to MC-LR, and the activated PI3K/AKT/mTOR/SREBP1 signaling pathway. In addition, MC-LR exposure reduced the activity of superoxide dismutase (SOD) and increased the level of malondialdehyde (MDA) in the obese mice's serum. In summary, the MC-LR could aggravate the HFD-induced obese mice liver lipid metabolism disorder by activating the PI3K/AKT/mTOR/SREBP1 signaling pathway to hepatocytes, increasing the SREBP1-c-regulated key enzymes for lipid synthesis, and blocking fatty acid β-oxidation.
The detoxification activities and mechanisms of microcystinase towards MC-LR
Ecotoxicol Environ Saf
Authors: Cai D, Wei J, Huang F, Feng H, Peng T, Luo J, Yang F.
Abstract
Microcystins (MCs) are the most common and toxic cyanotoxins that are hazardous to human health and ecosystems. Microcystinase is the enzyme in charge of the initial step in the biodegradation of MCs. The characterization, application conditions, and detoxification mechanisms of microcystinase from an indigenous bacterium Sphingopyxis sp. YF1 towards MC-LR were investigated in the current study. The microcystinase gene of strain YF1 was most similar to Sphingomonas sp. USTB-05 and contained a CAAX-family conversed abortive Infection (ABI) domain. The microcystinase was successful obtained and purified by overexpression in Escherichia coli. The highest degradation rate of MC-LR was 1.0 μg/mL/min under the optimal condition of 30 °C, pH 7, 20 μg/mL MC-LR, and 400 μg/mL microcystinase. The MC-degrading product was identified as linearized MC-LR, which possessed a much lower inhibitory activity against protein phosphatase 2A than MC-LR. Microcystinase interacted with MC-LR via amino acid residues involved in through the formation of conventional Hydrogen Bond, Pi-Pi T-shapes, Van der Waals force, and so on. The optimal MC-degrading condition of pure microcystinase and its detoxification mechanisms against MC-LR were revealed. The toxicity of purified linearized MC-LR was explored for the first time. These findings suggest that pure microcystinase may efficiently detoxify MCs and it is promising in the bioremediation of MC-polluted environments.
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