scholarly journals The Biosynthesis and Metabolism of the N-Acylated Aromatic Amino Acids: N-Acylphenylalanine, N-Acyltyrosine, N-Acyltryptophan, and N-Acylhistidine

2022 ◽  
Vol 8 ◽  
Author(s):  
Suzeeta Bhandari ◽  
Kirpal S. Bisht ◽  
David J. Merkler
Keyword(s):  
Amino Acids ◽  
Fatty Acid ◽  
Acid Amide ◽  
Aromatic Amino Acids ◽  
Amide Bond ◽  
Future Research ◽  
Cellular Functions ◽  
Fatty Acid Amides ◽  
Biological Source ◽  
Fatty Acid Amide

The fatty acid amides are a family of lipids composed of two chemical moieties, a fatty acid and a biogenic amine linked together in an amide bond. This lipid family is structurally related to the endocannabinoid anandamide (N-arachidonoylethanolamine) and, thus, is frequently referred to as a family of endocannabinoid-related lipids. The fatty acid amide family is divided into different classes based on the conjugate amine; anandamide being a member of the N-acylethanolamine class (NAE). Another class within the fatty acid amide family is the N-acyl amino acids (NA-AAs). The focus of this review is a sub-class of the NA-AAs, the N-acyl aromatic amino acids (NA-ArAAs). The NA-ArAAs are not broadly recognized, even by those interested in the endocannabinoids and endocannabinoid-related lipids. Herein, the NA-ArAAs that have been identified from a biological source will be highlighted and pathways for their biosynthesis, degradation, enzymatic modification, and transport will be presented. Also, information about the cellular functions of the NA-ArAAs will be placed in context with the data regarding the identification and metabolism of these N-acylated amino acids. A review of the current state-of-knowledge about the NA-ArAAs is to stimulate future research about this underappreciated sub-class of the fatty acid amide family.

scholarly journals Synthesis, Quantification, and Characterization of Fatty Acid Amides from In Vitro and In Vivo Sources

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2543
Author(s):  
Ruidong Ni ◽  
Suzeeta Bhandari ◽  
Perry R. Mitchell ◽  
Gabriela Suarez ◽  
Neel B. Patel ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Fatty Acid ◽  
Apis Mellifera ◽  
Chemical Synthesis ◽  
Acid Amide ◽  
Fatty Acid Amides ◽  
Fatty Acid Amide

Fatty acid amides are a diverse family of underappreciated, biologically occurring lipids. Herein, the methods for the chemical synthesis and subsequent characterization of specific members of the fatty acid amide family are described. The synthetically prepared fatty acid amides and those obtained commercially are used as standards for the characterization and quantification of the fatty acid amides produced by biological systems, a fatty acid amidome. The fatty acid amidomes from mouse N18TG2 cells, sheep choroid plexus cells, Drosophila melanogaster, Bombyx mori, Apis mellifera, and Tribolium castaneum are presented.

scholarly journals Comparison of Candida Albicans Fatty Acid Amide Hydrolase Structure with Homologous Amidase Signature Family Enzymes

Crystals ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 472 ◽  
Author(s):  
Cho-Ah Min ◽  
Ji-Sook Yun ◽  
Eun Hwa Choi ◽  
Ui Wook Hwang ◽  
Dong-Hyung Cho ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Family Members ◽  
Fatty Acid Amides ◽  
Wide Range ◽  
Brown Rat ◽  
Amide Hydrolase ◽  
Fatty Acid Amide

Fatty acid amide hydrolase (FAAH) is a well-characterized member of the amidase signature (AS) family of serine hydrolases. The membrane-bound FAAH protein is responsible for the catabolism of neuromodulatory fatty acid amides, including anandamide and oleamide, that regulate a wide range of mammalian behaviors, including pain perception, inflammation, sleep, and cognitive/emotional state. To date, limited crystal structures of FAAH and non-mammalian AS family proteins have been determined and used for structure-based inhibitor design. In order to provide broader structural information, the crystal structure of FAAH from the pathogenic fungus Candida albicans was determined at a resolution of 2.2 Å. A structural comparison with a brown rat Rattus norvegicus FAAH as well as with other bacterial AS family members, MAE2 and PAM, showed overall similarities but there were several discriminative regions found: the transmembrane domain and the hydrophobic cap of the brown rat FAAH were completely absent in the fungal FAAH structure. Along with these results, a phylogenetic analysis of 19 species within the AS family showed that fungal FAAHs diverged from a common ancestor before the separation of eukarya and prokarya. Taken together, this study provides insights into developing more potent inhibitors of FAAH as well as expanding our knowledge of the relationships between AS family members.

scholarly journals Assessment of NSAIDS as Potential Inhibitors of the Fatty Acid Amide Hydrolase I (FAAH-1) using Three Different Primary Fatty Acid Amide Substrates In Vitro

2021 ◽  
Author(s):  
Julius T. Dongdem ◽  
Gideon K. Helegbe ◽  
Kwame Opare-Asamoah ◽  
Cletus A. Wezena ◽  
Augustine Ocloo
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Rank Order ◽  
Acid Amide ◽  
Substrate Affinity ◽  
Cox Inhibitors ◽  
Fatty Acid Amides ◽  
Hydrolysis Of ◽  
Fatty Acid Amide

Abstract Pain relief · remains a major subject of inadequately met need of patients. Therapeutic agents designed to treat pain and inflammation so far have low to moderate efficiencies with significant untoward side effects. FAAH-1 has been proposed as a promising target for the discovery of drugs to treat pain and inflammation without significant adverse effects. FAAH-1 is the primary enzyme accountable for the degradation of AEA and related fatty acid amides. Studies have revealed that the simultaneous inhibition of COX and FAAH-1 activities produce greater pharmacological efficiency with significantly lowered toxicity and ulcerogenic activity. Recently, the metabolism of endocannabinoids by COX-2 was suggested to be differentially regulated by NSAIDs. We analysed the affinity of ODA, ArDA and SyDA at the FAAH-1 in vitro and investigated the potency of selected NSAIDs on the hydrolysis of endocannabinoid-like molecules (ODA, ArDA and SyDA) by FAAH-1 from rat liver. NSAIDs were initially screened at 500 µM after which those that exhibited greater potency were further analysed over a range of inhibitor concentrations. The substrate affinity of FAAH-1 obtained, increased in a rank order of ODA < ArDA < SyDA with resultant Vmax values in a rank order of ArDA > ODA > SyDA. The selected NSAIDs caused a concentration-dependent inhibition of FAAH-1 activity with sulindac, carprofen and meclofenamate exhibiting the greatest potency. Michaelis-Menten analysis suggested the mode of inhibition of FAAH-1 hydrolysis of both ODA and ArDA by meclofenamate and indomethacin to be non-competitive in nature. Our data therefore suggest potential for study of these compounds as combined FAAH-1-COX inhibitors.

scholarly journals High-Throughput Screening for the Discovery of Inhibitors of Fatty Acid Amide Hydrolase Using a Microsome-Based Fluorescent Assay

2006 ◽  
Vol 11 (5) ◽  
pp. 519-527 ◽  
Author(s):  
Yuren Wang ◽  
Fernando Ramirez ◽  
Girija Krishnamurthy ◽  
Adam Gilbert ◽  
Nina Kadakia ◽  
...  
Keyword(s):  
Fatty Acid ◽  
High Throughput ◽  
Fatty Acid Amide Hydrolase ◽  
Acid Amide ◽  
Bioactive Lipids ◽  
Fluorescent Assay ◽  
Fatty Acid Amides ◽  
Amide Hydrolase ◽  
Faah Inhibitors ◽  
Fatty Acid Amide

Fatty acid amide hydrolase (FAAH) is a membrane-associated enzyme that catalyzes the hydrolysis of several endogenous bioactive lipids, including anandamide (AEA), N-palmitoylethanolamine (PEA), oleamide, and N-oleoylethanolamine (OEA). These fatty acid amides participate in many physiological activities such as analgesia, anxiety, sleep modulation, anti inflammatory responses, and appetite suppression. Because FAAH plays an essential role in controlling the tone and activity of these endogenous bioactive lipids, this enzyme has been implicated to be a drug target for the therapeutic management of pain, anxiety, and other disorders. In an effort to discover FAAH inhibitors, the authors have previously reported the development of a novel fluorescent assay using purified FAAH microsomes as an enzyme source and a fluorogenic substrate, arachidonyl 7-amino, 4-methyl coumarin amide (AAMCA). Herein, the authors have adapted this assay to a high-throughput format and have screened a large library of small organic compounds, identifying a number of novel FAAH inhibitors. These data further verify that this fluorescent assay is sufficiently robust, efficient, and low-cost for the identification of FAAH inhibitory molecules and open this class of enzymes for therapeutic exploration.

scholarly journals Assessment of NSAIDs as potential inhibitors of the fatty acid amide hydrolase I (FAAH-1) using three different primary fatty acid amide substrates in vitro

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Julius T. Dongdem ◽  
Gideon K. Helegbe ◽  
Kwame Opare-Asamoah ◽  
Cletus A. Wezena ◽  
Augustine Ocloo
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Amide Hydrolase ◽  
Rank Order ◽  
Acid Amide ◽  
Substrate Affinity ◽  
Cox Inhibitors ◽  
Fatty Acid Amides ◽  
Hydrolysis Of ◽  
Fatty Acid Amide

Abstract Background Pain relief remains a major subject of inadequately met need of patients. Therapeutic agents designed to treat pain and inflammation so far have low to moderate efficiencies with significant untoward side effects. FAAH-1 has been proposed as a promising target for the discovery of drugs to treat pain and inflammation without significant adverse effects. FAAH-1 is the primary enzyme accountable for the degradation of AEA and related fatty acid amides. Studies have revealed that the simultaneous inhibition of COX and FAAH-1 activities produce greater pharmacological efficiency with significantly lowered toxicity and ulcerogenic activity. Recently, the metabolism of endocannabinoids by COX-2 was suggested to be differentially regulated by NSAIDs. Methods We analysed the affinity of oleamide, arachidonamide and stearoylamide at the FAAH-1 in vitro and investigated the potency of selected NSAIDs on the hydrolysis of endocannabinoid-like molecules (oleamide, arachidonamide and stearoylamide) by FAAH-1 from rat liver. NSAIDs were initially screened at 500 μM after which those that exhibited greater potency were further analysed over a range of inhibitor concentrations. Results The substrate affinity of FAAH-1 obtained, increased in a rank order of oleamide < arachidonamide < stearoylamide with resultant Vmax values in a rank order of arachidonamide > oleamide > stearoylamide. The selected NSAIDs caused a concentration-dependent inhibition of FAAH-1 activity with sulindac, carprofen and meclofenamate exhibiting the greatest potency. Michaelis-Menten analysis suggested the mode of inhibition of FAAH-1 hydrolysis of both oleamide and arachidonamide by meclofenamate and indomethacin to be non-competitive in nature. Conclusion Our data therefore suggest potential for study of these compounds as combined FAAH-1-COX inhibitors.

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