What are Microcystins?

Aquatic environments around the globe have been facing an escalating crisis in recent years—the proliferation of harmful cyanobacterial blooms, and the accompanying release of potent toxins known as microcystins. These secondary metabolites produced by certain species of cyanobacteria, also referred to as blue-green algae, pose a grave threat to the health and stability of freshwater and marine ecosystems.

Microcystins are cyclic heptapeptides, composed of seven amino acids arranged in a unique cyclic structure. This molecular architecture endows them with remarkable stability and resistance to degradation, allowing them to persist in the environment long after the cyanobacterial blooms have subsided. The World Health Organization (WHO) has classified microcystins as potential carcinogens, with demonstrated hepatotoxicity and nephrotoxicity in both human and animal studies.

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Chemistry of Microcystin

Microcystins are the most abundant class of cyanotoxins, with over 80 different structural analogs. They share a common cyclic heptapeptide structure of D-Ala¹-X²-D-Masp³-Z⁴-Adda⁵-D-γ-Glu⁶-Mdha⁷, where X and Z are variable amino acids. The systematic name for a microcystin is based on the one-letter codes of the amino acids at the variable X and Z positions, such as:

• LR: Leucine (L) in the X position, Arginine (R) in the Z position
• LA: Leucine (L) in the X position, Alanine (A) in the Z position
• RR: Arginine (R) in both the X and Z positions
• YR: Tyrosine (Y) in the X position, Arginine (R) in the Z position

Surrounding the variable X and Z positions are five conserved amino acids, including the unique and highly hydrophobic amino acid known as Adda (3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-dienoic acid). This Adda moiety is crucial for the toxicity of microcystins, as it facilitates their binding to cellular protein phosphatases.

The combination of the cyclic structure and the presence of the Adda group confers remarkable stability to microcystins, making them resistant to hydrolysis, oxidation, and even high temperatures. This chemical resilience contributes to their persistence in the environment, posing significant challenges for their detection, quantification, and remediation.

Figure 1. General structure of microcystins.
(Source: Butler, N. et al., 2009)

Toxicology of Microcystins

• Human Mortality and Morbidity
  While no human deaths from ingesting microcystins have been reported, exposure to cyanotoxins, including microcystins, can lead to various health effects. Liver damage is the most common sign of microcystin poisoning. A notable event has been reported in Caruaru, Brazil, where patients experienced visual disturbances, nausea, vomiting, muscle weakness, acute liver failure, and even death due to the use of cyanotoxin-contaminated water during dialysis.
• Liver Toxicity
  Microcystins are highly toxic to the liver. Studies conducted on mice and rats through direct injections of microcystin LR into the abdominal cavity have shown rapid onset of liver damage and cell death, leading to death within hours. Microcystins inhibit protein phosphatases, which disrupts normal biochemical pathways and causes an accumulation of phosphorylated proteins. This disruption is believed to be the primary mechanism by which microcystins destroy liver cells. The affected cells undergo programmed cell death, known as apoptosis, and exhibit characteristic changes. Other variants of microcystins, such as LA, RR, and YR, have similar toxicity and effects on the liver. Therefore, the toxicity criteria established for microcystin LR are also applied to these variants.
• Liver Tumor Promotion
  The inhibition of protein phosphatases, particularly PP1 and PP2A, is considered the main mechanism behind the toxicity of microcystins and their association with tumor development. Mutations in PP2A subunit genes have been linked to the risk of primary liver cancer. LR, a specific variant of microcystin, initiates liver tumor development by inhibiting PP2A activity, leading to excessive protein phosphorylation and damage to liver cells. However, the complete understanding of the signaling network and downstream targets of PP2A in relation to LR is still lacking.
  Zebrafish, specifically the krasV12 transgenic zebrafish model, is commonly used to study liver-related diseases. This model allows for the observation of the cancer-promoting effects of LR on zebrafish liver, especially when induced by doxycycline (DOX). DOX is an effective inducer in the Tet-on system, and krasV12 zebrafish treated with DOX have shown the development of histological hepatocellular carcinoma (HCC). While recent studies have improved our understanding of the toxic effects of LR, the detailed mechanisms underlying its tumor-promoting effects remain unclear.

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