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Methylation and acetylation of 15-hydroxyanandamide modulate its interaction with the endocannabinoid system.
Biochimie 2010; 92(4):378-87B

Abstract

The biological activity of endocannabinoids like anandamide (AEA) and 2-arachidonoylglycerol (2-AG) is subjected in vivo to a "metabolic control", exerted mainly by catabolic enzymes. AEA is inactivated by fatty acid amide hydrolase (FAAH), that is inhibited competitively by hydroxyanandamides (HAEAs) generated from AEA by lipoxygenase activity. Among these derivatives, 15-HAEA has been shown to be an effective (K(i) approximately 0.6 muM) FAAH inhibitor, that blocks also type-1 cannabinoid receptor (CB1R) but not other components of the "endocannabinoid system (ECS)", like the AEA transporter (AMT) or CB2R. Here, we extended the study of the effect of 15-HAEA on the AEA synthetase (NAPE-PLD) and the AEA-binding vanilloid receptor (TRPV1), showing that 15-HAEA activates the former (up to approximately 140% of controls) and inhibits the latter protein (down to approximately 70%). We also show that 15-HAEA halves the synthesis of 2-AG and almost doubles the transport of this compound across the membrane. In addition, we synthesized methyl and acetyl derivatives of 15-HAEA (15-MeOAEA and 15-AcOAEA, respectively), in order to check their ability to modulate FAAH and the other ECS elements. In fact, methylation and acetylation are common biochemical reactions in the cellular environment. We show that 15-MeOAEA, unlike 15-AcOAEA, is still a powerful competitive inhibitor of FAAH (K(i) approximately 0.7 muM), and that both derivatives have negligible interactions with the other proteins of ECS. Therefore, 15-MeOAEA is a FAAH inhibitor more selective than 15-HAEA. Further molecular dynamics analysis gave clues to the molecular requirements for the interaction of 15-HAEA and 15-MeOAEA with FAAH.

Authors+Show Affiliations

Department of Experimental Medicine and Biochemical Sciences, University of Rome, Tor Vergata, Rome, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20096328

Citation

Amadio, Daniele, et al. "Methylation and Acetylation of 15-hydroxyanandamide Modulate Its Interaction With the Endocannabinoid System." Biochimie, vol. 92, no. 4, 2010, pp. 378-87.
Amadio D, Fezza F, Catanzaro G, et al. Methylation and acetylation of 15-hydroxyanandamide modulate its interaction with the endocannabinoid system. Biochimie. 2010;92(4):378-87.
Amadio, D., Fezza, F., Catanzaro, G., Incani, O., van Zadelhoff, G., Finazzi Agrò, A., & Maccarrone, M. (2010). Methylation and acetylation of 15-hydroxyanandamide modulate its interaction with the endocannabinoid system. Biochimie, 92(4), pp. 378-87. doi:10.1016/j.biochi.2010.01.001.
Amadio D, et al. Methylation and Acetylation of 15-hydroxyanandamide Modulate Its Interaction With the Endocannabinoid System. Biochimie. 2010;92(4):378-87. PubMed PMID: 20096328.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Methylation and acetylation of 15-hydroxyanandamide modulate its interaction with the endocannabinoid system. AU - Amadio,Daniele, AU - Fezza,Filomena, AU - Catanzaro,Giuseppina, AU - Incani,Ottaviano, AU - van Zadelhoff,Guus, AU - Finazzi Agrò,Alessandro, AU - Maccarrone,Mauro, Y1 - 2010/01/21/ PY - 2009/05/26/received PY - 2010/01/03/accepted PY - 2010/1/26/entrez PY - 2010/1/26/pubmed PY - 2010/6/9/medline SP - 378 EP - 87 JF - Biochimie JO - Biochimie VL - 92 IS - 4 N2 - The biological activity of endocannabinoids like anandamide (AEA) and 2-arachidonoylglycerol (2-AG) is subjected in vivo to a "metabolic control", exerted mainly by catabolic enzymes. AEA is inactivated by fatty acid amide hydrolase (FAAH), that is inhibited competitively by hydroxyanandamides (HAEAs) generated from AEA by lipoxygenase activity. Among these derivatives, 15-HAEA has been shown to be an effective (K(i) approximately 0.6 muM) FAAH inhibitor, that blocks also type-1 cannabinoid receptor (CB1R) but not other components of the "endocannabinoid system (ECS)", like the AEA transporter (AMT) or CB2R. Here, we extended the study of the effect of 15-HAEA on the AEA synthetase (NAPE-PLD) and the AEA-binding vanilloid receptor (TRPV1), showing that 15-HAEA activates the former (up to approximately 140% of controls) and inhibits the latter protein (down to approximately 70%). We also show that 15-HAEA halves the synthesis of 2-AG and almost doubles the transport of this compound across the membrane. In addition, we synthesized methyl and acetyl derivatives of 15-HAEA (15-MeOAEA and 15-AcOAEA, respectively), in order to check their ability to modulate FAAH and the other ECS elements. In fact, methylation and acetylation are common biochemical reactions in the cellular environment. We show that 15-MeOAEA, unlike 15-AcOAEA, is still a powerful competitive inhibitor of FAAH (K(i) approximately 0.7 muM), and that both derivatives have negligible interactions with the other proteins of ECS. Therefore, 15-MeOAEA is a FAAH inhibitor more selective than 15-HAEA. Further molecular dynamics analysis gave clues to the molecular requirements for the interaction of 15-HAEA and 15-MeOAEA with FAAH. SN - 1638-6183 UR - https://www.unboundmedicine.com/medline/citation/20096328/Methylation_and_acetylation_of_15_hydroxyanandamide_modulate_its_interaction_with_the_endocannabinoid_system_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0300-9084(10)00002-7 DB - PRIME DP - Unbound Medicine ER -