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Journal of Lipid Research, Vol. 50, 658-666, April 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Chemical synthesis, pharmacological characterization, and possible formation in unicellular fungi of 3-hydroxy-anandamide¹

L. De Petrocellis^*, R. Deva^3,, F. Mainieri, M. Schaefer^**, T. Bisogno, R. Ciccoli, A. Ligresti, K. Hill^**, S. Nigam^1,, G. Appendino and V. Di Marzo^2,

^* Endocannabinoid Research Group, Institutes of Cybernetics Consiglio Nazionale delle Ricerche, Pozzuoli (Napoli), Italy
Eicosanoid & Lipid Research Division & Experimental Gynecology and Breast Research, Department of Gynecology & Obstetrics, Charité Medical School Benjamin Franklin, Berlin, Germany
Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche e Farmacologiche, Università del Piemonte Orientale, Novara, Italy
^** Molekulare Pharmakologie und Zellbiologie, Neurowissenschaftliches Forschungszentrum, Charité-Universitätsmedizin Berlin, Germany
Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli (Napoli), Italy
Ente per le Nuove Tecnologie, l'Energia e l'Ambiente Centro Ricerche Casaccia, Rome, Italy
³ Present address of R. Deva: Dermatologie, HTCC-Haut Tumor Centrum Charité, Berlin

¹ This work is dedicated to the memory of Prof. Santosh Nigam, deceased on October 2, 2007, and of Prof. Michael J. Walker, deceased on January 5, 2008.

Published, JLR Papers in Press, November 17, 2008.

² To whom correspondence should be addressed. e-mail.: vdimarzo{at}icmib.na.cnr.it

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 a70–90-fold and 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.

Supplementary key words cannabinoid • vanilloid • TRPV1 • CB1 • CB2 • endocannabinoid • endovanilloid • yeasts • inflammation • pain

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