Chemical synthesis, pharmacological characterization, and possible formation in unicellular fungi of 3-hydroxy-anandamide

The fungal pathogen Candida albicans transforms arachidonic acid (AA) into 3-hydroxyarachidonic acid [3(R)HETE], and we investigated if its nonpathogenic and 3(R)HETE-producing close relative, Dipodascopsis uninucleata, could similarly transform the endocannabinoid/endovanilloid anandamide into 3-hydroxyanandamide (3-HAEA). We found that D. uninucleata converts anandamide into 3-HAEA, and we therefore developed an enantiodivergent synthesis for this compound to study its pharmacological activity. Both enantiomers of 3-HAEA were as active as anandamide at elevating intracellular Ca2+ via TRPV1 receptors overexpressed in HEK-293 cells, while a similar to 70-90-fold and similar to 45-60-fold lower affinity at cannabinoid CB1 and CB2 receptors was instead observed. Patch clamp recordings showed that 3(R)-HAEA activates a TRPV1-like current in TRPV1-expressing HEK-293 cells. Thus, 3(R)-HETE-producing yeasts might convert anandamide released by host cells at the site of infection into 3(R)-HAEA, and this event might contribute to the inflammatory and algogenous responses associated to fungal diseases.-De Petrocellis, L., R. Deva, F. Mainieri, M. Schaefer, T. Bisogno, R. Ciccoli, A. Ligresti, K. Hill, S. Nigam, G. Appendino, and V. Di Marzo. Chemical synthesis, pharmacological characterization, and possible formation in unicellular fungi of 3-hydroxyanandamide. J. Lipid Res. 2009. 50: 658-666.