The rise and fall of anandamide: processes that control synthesis, degradation, and storage


Anandamide is a chemical compound that can be found in the human body. It was first discovered after being derived from arachidonic acid-containing membrane lipids and has many biological functions, including pain relief, appetite suppression, anxiety reduction as well as memory improvement; however, its most significant effect on humans may come through its ability to mimic THC or tetrahydrocannabinol which is one of over 100 different cannabinoids identified so far within cannabis plants (though not all are psychoactive).

Anandamide is a natural chemical that helps our body do things like sleep and eat. It also makes us feel good and take pain away. People make this in their body when they do these things, but sometimes people need more of it because it runs out too fast! If you want to know more about how this works, then read this review.


  • Anandamide
  • Endocannabinoid
  • Phospholipase
  • N-acyltransferase
  • Phosphatase


The endocannabinoid anandamide (AEA) is a molecule that mimics the effects of THC. AEA, or arachidonoylethanolamine, binds to cannabinoid receptors in our brain and initiates G-protein signaling through various biological pathways. The name given to it by its discoverers was derived from the Sanskrit word “ananda” which means joy – as this compound competes with exogenous cannabinoids for their specific receptors in the brain!

Subsequent research has revealed that anandamide activates both CB1 in the central nervous system, as well as receptors found throughout the body. This signaling causes a diverse set of biological responses including sleep patterns and short-term memory, mood alterations such as happiness or sadnesss, and modulation of how one perceives heat sensations. There are many excellent reviews on these subjects which I recommend reading if you want to know more!

AEA is a signaling molecule that typically maintains its concentration through synthesis and degradation, but it also has just as much potential to store the compound by synthesizing at high rates. The key enzymes involved in AEA homeostasis are described here with specific focus on human isoforms of these enzyme-encoding genes.

Anandamide biosynthesis

The release of AEA from the composite molecule is accomplished by a series of phospholipases. The process begins with an arachadonic acid being ligated to phosphatidylethanolamine and then ends in another membrane bound lipid which contains three fatty acids, one Omega-3 (eicosapentaenoic) and two Omega-6s(linoleic). (Fig. 1).

Reactions involved in the formation of Anandamide

Fig. 1 Reactions involved in the formation of Anandamide Metabolites: AEA anandamide, glycero-p-AEA 1-acyl-sn-glycero-3-(N-arachidonyl) phosphoethanolamine, and NArPE N-acylphosphatidylethanolamine, Enzymes: ABHD4 (lyso)-N-Acylphosphatidylethanolaminelipase, GDE1 Glycerophosphodiester phosphodiesterase 1, GDPD1,3 Lysophospholipase D isoforms 1 and 3, NAPE-PLD N-Acyl-Phosphatidylethanolamine-hydrolyzing Phospholipase D, PLAAT1,2,3,4,5 phospholipase A-Acyltransferases isoforms 1, 2, 3, 4, and 5, PLC phospholipase C, PTPN22 tyrosine-protein phosphatase non-receptor type 22, SHIP1 phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1, and sPLA2 secreted Phospholipase A2

Synthesis of Nacyl phosphatidylethanolamines (NAPEs)


The synthesis of NAPEs, including the calcium-independent ArPE and the more common phosphatidylethanolamine (PC), is accomplished through a transfer to PC from fatty acyl groups by one of several enzymes. It’s interesting that there are some forms which can be synthesized without relying on external factors such as enough calcium or sodium ions in order for it to happen.

The calcium-independent N-acyltransferases are represented by the H-RAS like suppressor proteins (HRASLS) and belongs to the subclass of enzymes called HRV107. These lipids derived from phospholipid hydrolysis were originally classified as tumor suppressing agents but have also been found to perform lipid transfer reactions, giving them a dual role in cancer prevention. All species except PLAAT5 contain a putative transmembrane helix that is known for being membrane associated which makes it difficult to study this class of protein due its apparent insolubility within EM samples and inability migrate through membranes during purification procedures used today.

Each of the enzymes catalyzes the hydrolysis of fatty acids from either the sn-1 or sn-2 position of glycerophospholipids, the sn-2 position being particularly important for anandamide synthesis, as arachidonic acid is typically found esterified to thesn-2 position in glycerophospholipids. Once the fatty acid is removed it is then a substrate for one of two secondary reactions, O-acyl transfer of the fatty acid to the free hydroxyl of a lysophospholipid or an N-acyl transfer to the primary amine on a phosphatidylethanolamine. These enzymes share a similar catalytic mechanism involving a thioester intermediate formed between an active site Cys and the fatty acid prior to transfer.

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