FAAH

Official Full Name

fatty acid amide hydrolase

Organism

Homo sapiens

GeneID

2166

Background

This gene encodes a protein that is responsible for the hydrolysis of a number of primary and secondary fatty acid amides, including the neuromodulatory compounds anandamide and oleamide. [provided by RefSeq, Jul 2008]

Synonyms

PSAB; FAAH1; FAAH-1;

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Detailed Information

Fatty acid amide hydrolase (Faah) is a kind of membrane amide signal family protease. It is the main catalyzed hydrolytic metabolic enzyme of many biologically active fatty acid amide (FAAs) messenger molecules in organisms. This hydrolase can hydrolyze N-acylethanolamine (NAE) into fatty acids and ethanolamine. Fatty amide hydrolase in the human body is composed of 597 amino acids with a molecular weight of 63KDa. Faah is distributed in a variety of tissues, including cast, intestine, liver, testis, uterus, kidney, eyes, spleen and lungs. In the brain, the degree of expression of Faah is different in different regions. The activity of Faah is the strongest in the globus pallidus and hippocampus, while the activity is the worst in the encephalon. In the immune system, Faah activity is expressed by lymphocytes and macrophages. As a member of the endocannabinoid system, Faah plays an important role in the termination of cannabinoid signaling and is a potential target for the treatment of neurological diseases, inflammation, metabolic diseases and cardiovascular diseases.

The Structure of Faah

As a family of enzymes that hydrolyze fatty acid bonds, Faah consists of 579 amino acids, which contains a highly conserved region rich in glycine, serine and alanine residues. This region is called the signature sequence and corresponds to the amino acid sequence at positions 215-257 in the mammalian Faah protein. Through sequence comparison, the Faah amino acid sequence of human, rat, mouse and porcine showed that their similarity reached 73%, and the similarity reached 90% in the characteristic amino acid sequence of 215-257. There is a transmembrane domain at the amino terminus of Faah. This domain affects the self-association of Faah. The 492-512 amino acid residues form an important structural domain that binds to the fatty acid chain. After deleting these 21 amino acids, Faah completely loses its activity. Ile-491 has recently been shown to be a key amino acid residue involved in the binding of acyl substrates. 307-315 of Faah is a proline-rich region, and deleting this part will also make it lose its catalytic activity.

Faah and N-arachidonic Ethanolamine (Anandamied)

Cannabis as a cultivated plant can be used to treat various diseases, such as arthritis and menstrual pain. There are about 60 kinds of natural active ingredients in cannabis, collectively referred to as cannabinoids. N-arachidonic ethanolamine (AEA) and 2-arachidonic acid (2-AG) glycerol are the first endocannabinoids to be isolated and identified, and they are also important neurotransmitters in the brain. In addition, these endocannabinoids It has a protective effect on a variety of central nervous system injury models. AEA is synthesized from the phospholipid precursor N-acylphosphatidylethanolamine (NAPE) via N-acyltransferase and separated from NAPE after being catalyzed by phospholipase D. AEA mainly works by binding and activating the cannabinoid receptors CB1 and CB2 on the cell surface. By adjusting the activity of AEA degrading enzymes, increasing the level of endogenous AEA can also play a neuroprotective effect. Faah is the main hydrolase of AEA. By inhibiting the activity of Faah, the level of AEA in the body can be up-regulated, thereby producing a series of biological activities. Faah inhibitor URB597 can inhibit carrageenan-induced inflammatory pain in rats by acting on PPARα. The irreversible Faah inhibitor AM374 can also inhibit kainic acid-induced seizures and neuronal death by activating the extracellular regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway. Therefore, inhibiting the hydrolysis of endocannabinoids has become a new target for the treatment of central nervous system diseases.

Figure 1. AEA is degraded intracellularly.

Faah and Cancer

A large number of studies have found that AEA has the effects of inhibiting proliferation, inhibiting adhesion and invasion, inhibiting tumor angiogenesis, and inducing apoptosis on a variety of tumors including liver cancer. However, because AEA in the body can be rapidly metabolized by the hydrolase Faah located in the cytoplasm, the effect of exogenous supplementation of AEA is weak and short-lived, and it has no drug-making properties. URB5789 is a selective inhibitor of AEA metabolic enzymes, which can up-regulate the level of AEA, and has a significant inhibitory effect on melanoma, glioma, and prostate cancer.

References:

Otrubova, K., Ezzili, C., & Boger, D. L. (2011). 'The discovery and development of inhibitors of fatty acid amide hydrolase (Faah).' Bioorganic & medicinal chemistry letters, 21(16), 4674–4685.
Tripathi, R. K. P. (2019). 'A perspective review on fatty acid amide hydrolase (Faah) inhibitors as potential therapeutic agents.' European Journal of Medicinal Chemistry, 188, 111953.
Fu, J., Bottegoni, G., Sasso, O., Bertorelli, R., Rocchia, W., Masetti, M., Guijarro, A., Lodola, A., Armirotti, A., Garau, G., Bandiera, T., Reggiani, A., Mor, M., Cavalli, A., & Piomelli, D. (2011). 'A catalytically silent Faah-1 variant drives anandamide transport in neurons.' Nature neuroscience, 15(1), 64–69.

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