Natural phosphatase inhibitors: the danger around us

If you’ve ever had diarrheic shellfish poisoning (DSP), it’s possible you’ve encountered the most common phosphatase inhibitor used in research studies. In the 1970s, 164 documented cases of food poisoning were reported in Japan from the consumption of cooked mussels and scallops. Research into the cause of the outbreak demonstrated that the food poisoning, which was further classified as DSP, was due to the toxin okadaic acid (Valdiglesias et al. 2013; Yasumoto et al. 1978). Okadaic acid, which is now known to accumulate in both marine sponges and shellfish, was shown to be a potent inhibitor of various serine/threonine phosphatases (PSTPs) (Yasumoto et al. 1978). This commonly used lab reagent continues to haunt us, as evidenced by a recent outbreak of DSP reported in South East England in July 2013, in which at least 70 people were affected. 

Phosphatase families

There are more than 130 protein phosphatases encoded in the human genome. These proteins function as critical modulators of cellular phosphorylation events by counteracting the addition of phosphate molecules on serine, threonine or tyrosine residues by protein kinases. Protein phosphatases are grouped according to their substrate specificity and are divided into either PSTPs (further divided into Mg2+-dependent PPM and PPP subtypes) or protein tyrosine phosphatases (PTP). Misregulated phosphatase activity results in human diseases such as cancer, diabetes, neurological and autoimmune disorders. As such, several phosphatases have been identified as key therapeutic targets, however the development of clinical phosphatase inhibitors is complicated by the fact that all known inhibitors act broadly on entire families rather than a single specific enzyme.  

Phosphatase inhibitors

Phosphatase inhibitors are ubiquitous and pose threats to our everyday life. For instance, a recurring problem worldwide is the rise of cyanobacteria that produce toxic microcystins in the drinking supply channels of humans. Over 50 different microcystins have been discovered so far, of which microcystin-LR is the most common and most toxic, known to inhibit 6 PSTPs (Swingle et al. 2007). In August 2014, the city of Toledo, Ohio issued a water advisory after detecting higher than normal levels of microcystins in Lake Erie, which provides the city’s drinking water. Microcystins threaten human health as they can cause liver failure, or death when consumed at high doses. In July 2015, the concentration of cyanobacteria in Toledo’s water system was estimated at 1.0 part per billion, which is in line with World Health Organization recommendations. However, while Toledo’s water supply might be fine for now, it is indicated that this number will continue to rise, as studies show that the prevalence of cyanobacteria will increase with warmer climate conditions. 

These natural phosphatase inhibitors are not just poisoning the water; they also contaminate blood. The sand fly Phlebotomus papatasi is a vector of Leishmania major, which is the causative agent of cutaneous Leishmaniasis. This is manifested as sores and skin ulcers that develop several weeks or months after initial exposure. The female sand fly is a known bloodsucker that carries poison in her saliva, causing delayed hypersensitivity, an inflammatory reaction initiated by mononuclear leukocytes, upon injection of salivary proteins. It has been shown that the saliva contains pharmacological concentrations of adenosine and 5′ adenosine monophosphate, which impede blood clotting and prolong the parasite’s feeding time (Ribeiro et al. 1999). P. papatasi saliva also contains PP-1/2A inhibitors that interfere with the regulation of nitric oxide production (Ribeiro et al. 1999). 

Phosphatase inhibitors seem to be all around us, lingering in various places ready to elicit harm. Perhaps the most alarming scenario is the rise of microcystins in the drinking water supply. Since global warming continues to be an issue, this raises questions of our future such as; will there be many more Lake Erie’s all over the world?