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 [3R-HETE], and we investigated if its nonpathogenic and 3R-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 approximately 70-90-fold and approximately 45-60-fold lower affinity at cannabinoid CB1 and CB2 receptors was instead observed. Patch clamp recordings showed that 3R-HAEA activates a TRPV1-like current in TRPV1-expressing HEK-293 cells. Thus, 3R-HETE-producing yeasts might convert anandamide released by host cells at the site of infection into 3R-HAEA, and this event might contribute to the inflammatory and algogenous responses associated to fungal diseases.
De Petrocellis
L
L
Endocannabinoid Research Group, Institutes of Cybernetics Consiglio Nazionale delle Ricerche, Pozzuoli (Napoli), Italy.
Deva
R
R
Mainieri
F
F
Schaefer
M
M
Bisogno
T
T
Ciccoli
R
R
Ligresti
A
A
Hill
K
K
Nigam
S
S
Appendino
G
G
Di Marzo
V
V
D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000096:biosynthesis* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D063388:Endocannabinoids; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D009181:Mycoses / Q000209:etiology / Q000378:metabolism / Q000382:microbiology; D018408:Patch-Clamp Techniques; D053284:Polyunsaturated Alkamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D004718:Saccharomycetales / Q000378:metabolism* / Q000472:pathogenicity; D013237:Stereoisomerism; D050916:TRPV Cation Channels / Q000378:metabolism
D001095:Arachidonic Acids; D063388:Endocannabinoids; D006893:Hydroxyeicosatetraenoic Acids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C069265:3-hydroxy-5,8,11,14-eicosatetraenoic acid; D016718:Arachidonic Acid; C078814:anandamide