Different roles for the acyl chain and the amine leaving group in the substrate selectivity of <i>N</i>-Acylethanolamine acid amidase

Ghidini, Andrea; Scalvini, Laura; Palese, Francesca; Lodola, Alessio; Mor, Marco; Piomelli, Daniele

doi:10.1080/14756366.2021.1912035

Cited by 7 publications

(4 citation statements)

References 45 publications

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“…In rabbit ( Oryctolagus cuniculus ), a cysteine hydrolase, designated N -acylethanolamine acid amidase (NAAA) was shown to have a marked preference towards NAE16:0, and this seems to be dependent on the nature of its SBP. Indeed, it appears that through evolution, NAAA acquired a restrictively shaped SBP that is optimal for NAE16:0, and less efficient towards other acyl amides of longer or shorter acyl chain 40 . Thus, similar to mammals, the legume M. truncatula may have elaborated FAAH isoforms that selectively process a range of acylamide substrates.…”

Section: Discussionmentioning

confidence: 99%

Two legume fatty acid amide hydrolase isoforms with distinct preferences for microbial- and plant-derived acylamides

Arias-Gaguancela,

Herrell,

Aziz

et al. 2023

Sci Rep

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Fatty acid amide hydrolase (FAAH) is a widely conserved amidase in eukaryotes, perhaps best known for inactivating N-acylethanolamine lipid mediators. However, FAAH enzymes hydrolyze a wide range of acylamide substrates. Analysis of FAAHs from multiple angiosperm species revealed two conserved phylogenetic groups that differed in key conserved residues in the substrate binding pocket. While the foundation group of plant FAAHs, designated FAAH1, has been studied at the structural and functional level in Arabidopsis thaliana, nothing is known about FAAH2 members. Here, we combined computational and biochemical approaches to compare the structural and enzymatic properties of two FAAH isoforms in the legume Medicago truncatula designated MtFAAH1 and MtFAAH2a. Differences in structural and physicochemical properties of the substrate binding pockets, predicted from homology modeling, molecular docking, and molecular dynamic simulation experiments, suggested that these two FAAH isoforms would exhibit differences in their amidohydrolase activity profiles. Indeed, kinetic studies of purified, recombinant MtFAAHs indicated a reciprocal preference for acylamide substrates with MtFAAH1 more efficiently utilizing long-chain acylamides, and MtFAAH2a more efficiently hydrolyzing short-chain and aromatic acylamides. This first report of the enzymatic behavior of two phylogenetically distinct plant FAAHs will provide a foundation for further investigations regarding FAAH isoforms in legumes and other plant species.

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Section: Discussionmentioning

confidence: 99%

Two legume fatty acid amide hydrolase isoforms with distinct preferences for microbial- and plant-derived acylamides

Arias-Gaguancela,

Herrell,

Aziz

et al. 2023

Sci Rep

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“…Parallel lipid analyses showed that the early surge in NAAA expression was accompanied by a ≈30% decrease in nigral PEA content (Fig. 3G), whereas levels of the less-preferred NAAA substrate, oleoylethanolamide (OEA) (Ueda et al, 2013;Ghidini et al, 2021) were only marginally affected (Fig. 3H).…”

Section: -Ohda Enhances Naaa Expression In Mouse Nigrostriatal Dopami...mentioning

confidence: 99%

Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of Parkinson’s disease

Palese

Pontis

Realini

et al. 2022

Preprint

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The lysosomal cysteine hydrolase N-acylethanolamine acid amidase (NAAA) deactivates the lipid-derived mediator palmitoylethanolamide (PEA), an endogenous PPAR-alpha agonist that is critically involved in the control of inflammation and nociception. In this study, we asked whether NAAA-regulated PEA signaling might contribute to the pathogenesis of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive loss of nigrostriatal dopamine neurons. Analyses of postmortem brain cortex and premortem blood-derived exosomes found elevated levels of NAAA expression in persons with PD compared to age-matched controls. Furthermore, in vitro experiments showed that the dopaminergic neurotoxins, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), enhanced NAAA expression and lowered PEA content in human SH-SY5Y cells. A similar effect was observed in dopamine neurons and, subsequently, in microglia following 6-OHDA injection in mice. Importantly, deletion of the Naaa gene or pharmacological inhibition of NAAA activity markedly attenuated both dopamine neuron death and parkinsonian symptoms in mice treated with 6-OHDA or MPTP. The results identify NAAA-regulated PEA signaling as a control node for dopaminergic neuron survival and a potential target for therapeutic intervention in PD.

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“…Different from FAAH-1, which is found in the endoplasmic reticulum and the nucleus, FAAH-2 may be localized to lipid droplets (Kaczocha et al, 2010). NAAA and acid ceramidase also hydrolyze AEA, albeit with low activity (Ghidini et al, 2021;Tsuboi et al, 2021). In addition to hydrolytic degradation, AEA can be oxygenated by lipoxygenases (5-, 12-, 15-LOX), COX-2 or CYP450 (Fig.…”

Section: B Enzymes Of Aea Degradationmentioning

confidence: 99%

“…The crystal structures of NAAA elucidated that autoproteolysis exposes the buried active site to enable catalysis (Gorelik et al, 2018). NAAA hydrolyzes various fatty acid ethanolamides in vitro but its highest reactivity is for N-palmitoylethanolamine (Ghidini et al, 2021). The fact that NAAA is highly expressed in macrophages (Tsuboi et al, 2007b) and other immune cells (Ribeiro et al, 2015), suggests that this enzyme may regulate fatty acid ethanolamide levels at the site of inflammation.…”

Section: B Enzymes Of Aea Degradationmentioning

confidence: 99%

Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years

et al. 2023

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The cannabis derivative marijuana is the most widely used recreational drug in the Western world, that is consumed by an estimated 83 million individuals (~3% of the world population). In recent years, there has been a marked transformation in society regarding the risk perception of cannabis, driven by its legalization and medical use in many states in the USA and worldwide. Compelling research evidence and the FDA cannabis-derived cannabidiol approval for severe childhood epilepsy have confirmed the large therapeutic potential of cannabidiol itself, Δ 9tetrahydrocannabinol (THC) and other plant-derived cannabinoids (phytocannabinoids). Of note, our body has a complex endocannabinoid system (ECS) -made of receptors, metabolic enzymes and transporters -that is also regulated by phytocannabinoids. The first endocannabinoid to be discovered 30 years ago was anandamide (N-arachidonoyl-ethanolamine); since then, distinct elements of ECS have been the target of drug design programs aimed at curing (or at least slowing down) a number of human diseases, both in the central nervous system and at the periphery. Here, a critical review of our knowledge of the goods and bads of ECS as a therapeutic target are presented, in order to define the benefits of ECS-active phytocannabinoids and ECS-oriented synthetic drugs for human health. Significance Statement -The endocannabinoid system plays important roles virtually everywhere in our body and is either involved in mediating key processes of central and peripheral diseases or represents a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of the components of this complex system, and in particular of key receptors (like CB 1 R and CB 2 R) and metabolic enzymes (like FAAH and MAGL), will advance our understanding of endocannabinoid signaling and activity at molecular, cellular, and system levels providing new opportunities to treat patients.

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Different roles for the acyl chain and the amine leaving group in the substrate selectivity of N-Acylethanolamine acid amidase

Cited by 7 publications

References 45 publications

Two legume fatty acid amide hydrolase isoforms with distinct preferences for microbial- and plant-derived acylamides

Two legume fatty acid amide hydrolase isoforms with distinct preferences for microbial- and plant-derived acylamides

Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of Parkinson’s disease

Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years

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