What are endocannabinoid enzymes? - Cannactiva

Endocannabinoid enzymes: What are they and their therapeutic potential?

Endocannabinoid System

Endocannabinoid enzymes are components produced by our body with the function of synthesizing and degrading cannabinoids. They are intrinsically related to the endocannabinoid system, offer enormous therapeutic potential and expand our knowledge of cannabidiol (CBD). cannabidiol (CBD) and its effects.

However, probably because it presents some complexity, endocannabinoid enzymes often do not receive all the attention they deserve. If you dare to learn, today on the Cannactiva blog we tell you more about the enzymes responsible for the metabolism of endocannabinoids in our body. You will discover the effects of phytocannabinoids, such as CBD and THC, on these enzymes and their therapeutic potential. Get ready for this post of cannabinoid science with some CBD flowers . Inside post!

Introduction to cannabinoid enzymes

What are endocannabinoid enzymes?

Endocannabinoid enzymes play a crucial role in the synthesis and degradation of endocannabinoids. endocannabinoids which are the cannabinoids produced naturally by our body.

Endocannabinoid enzymes are responsible for the production and regulation of endocannabinoids, which are the cannabinoids produced by our body.

An enzyme is a specialized protein that performs a function, that does something. In this case, endocannabinoid enzymes are responsible for synthesizing and transforming endocannabinoids.

Endocannabinoids in our body are produced by endocannabinoid enzymes.

Cannabinoid enzymes are involved in biochemical processes that convert precursor substances into active endocannabinoids, and are also responsible for the degradation of these compounds, to finalize their effect. Thus, endocannabinoid enzymes are responsible for the production and regulation of endocannabinoids.

Differences between endocannabinoid enzymes and cannabinoid enzymes

These enzymes are not to be confused with those found in the cannabis plant, which are responsible for the biosynthesis of phytocannabinoids. biosynthesis of phytocannabinoids. . The endocannabinoid enzymes we are talking about today are produced and found in our body, not in the cannabis plant.

How do endocannabinoid enzymes work?

Well, let’s start from the beginning: endocannabinoids. Endocannabinoids are cannabinoids produced by the human body that bind to receptors of the endocannabinoid system, called cannabinoid receptors, that we have inside our body [1]. The CB1 receptor is found in the brain, while the CB2 receptor is mainly associated with the immune system [1-4].

Endocannabinoids have been found in various organisms, and apparently, endocannabinoid receptors originated approximately 500 million years ago [5, 6]. Surprisingly, invertebrate organisms have also been found to possess endocannabinoid receptors and produce endocannabinoids [7]. It is interesting to know that humans share an ancestor with invertebrates approximately 600 million years ago! In addition to vertebrate animals, it appears that we also share cannabinoid receptors with invertebrate animals.

As mentioned in previous writings, endocannabinoids play an important role in functions such as neurotransmission [1, 8], appetite and stress regulation, metabolic and immune system functions [9], among many, many others. The two best known endocannabinoids are anandamide and 2-AG (2-arachidonylglycerol) [10].

Endocannabinoid enzymes function by playing two main roles: the synthesis, “activation” and degradation or “inactivation” of endocannabinoids in the body.

In terms of synthesis, these enzymes catalyze specific chemical reactions that convert precursors into “active endocannabinoids,” ready to bind to cannabinoid receptors in the body.

As for degradation, endocannabinoid enzymes are responsible for breaking down endocannabinoids once they have fulfilled their function, or for their function to end. To do so, they catalyze reactions that convert endocannabinoids into other products, allowing precise regulation of endocannabinoid levels in the body.

This topic is quite complex, since, according to my summary of the literature, there are still many unknowns about how these enzymes act, what exactly they produce and whether they might interact with other compounds not yet known or studied [10].

How many cannabinoid enzymes are there?

There appear to be five (5) enzymes related to endocannabinoid metabolism [10]:

  • NAPE-PLD (N-acylphosphati-dilethanolamine-selective phospholipase D)
  • DAGL α and β (diacylglycerol lipases)
  • FAAH (fatty acid amide hydrolase, which in Spanish should be something likefatty acid amide hydrolase).
  • MAGL (monoacylglycerol lipase)

Endocannabinoids and their enzymes

As I mentioned, anandamide is one of the best known endocannabinoids. NAPE-PLD and FAAH enzymes act on it.

The other known endocannabinoid is 2-AG (2-araquidonylglycerol), and physiological levels of 2-AG are higher than those of anandamide [13]. DAGL α and β enzymes and MAGL act on 2-AG [10, 14].

Types of endocannabinoid enzymes

FAAH (Fatty Acid Amide Hydrolase)

The enzyme FAAH is a cell membrane-bound protein whose main known function is to degrade anandamide.

It has been found in the brain and liver of mice, while in pigs it has been detected in the brain [15]. In humans, FAAH is found in the brain, liver and also in the placenta, together with the CB1 receptor. This suggests that the human placenta responds to molecules that bind to these receptors [16]. Therefore, the FAAH enzyme may play a critical role in the control of anandamide levels and pregnancy outcome. However, it is not yet known what happens with high levels of anandamide or levels of other cannabinoids that can bind to CB1 receptors in the placenta [16].

The phytocannabinoids THC, CBD and CBN inhibit the activity of the FAAH enzyme [15], which could have therapeutic implications. By inhibiting FAAH, phytocannabinoids could increase the levels of endocannabinoids, such as anandamide, in the body, as well as their effects. Increased endocannabinoids could have effects on pain sensation, inflammation, mood and appetite. This provides a basis for further research into the potential therapeutic use of these phytocannabinoids in the treatment of various medical conditions.

Another curious fact about FAAH is that the genes encoding it in humans and mice are very similar [17], and they also have many exons and introns, which I told you about in a previous writing.

See the article about CBG

MAGL (Monoacylglycerol Lipase)

The MAGL enzyme catalyzes the hydrolysis of glycerol to fatty acids, and in the endocannabinoid system, it is responsible for the degradation of 2-AG (2-arachidonylglycerol). It is found in the brain and other peripheral tissues, such as kidneys, ovaries, testes and heart [18].

This enzyme has been associated with conditions such as pain, inflammation, neuronal degeneration and diseases such as Parkinson’s disease. Parkinson’s or Alzheimer’s . In addition, elevated levels of this enzyme have been found in breast, ovarian and melanoma cancers [19].

DAGL α and β (diacylglycerol lipases)

DAGL α and β enzymes (alpha and beta) break down diacylglycerol into 2-AG, which is the endocannabinoid with the highest affinity for CB1 and CB2 receptors. .

This enzyme is involved in regulation during embryonic development and is required for the generation of neurons in the brain. In addition, it is related to a metabolic pathway linked to neuronal degeneration in Parkinson’s disease. [20].

Potential therapeutic implications of endocannabinoid enzymes

Endocannabinoid enzymes play a crucial role in the endocannabinoid system of the human body.

Inhibition of these endocannabinoid enzymes may have important therapeutic implications and potential medicinal uses for the development of drugs with new pharmacological targets.

Two key enzymes, FAAH and MAGL, play a prominent role and are the most studied.

Inhibition of the MAGL enzyme results in the non-degradation of the endocannabinoid 2-AG and thus increases its levels. This endocannabinoid has the ability to bind to CB1 and CB2 receptors, leading to decreased pain [13].

On the other hand, inhibition of the FAAH enzyme increases anandamide levels in the brain, which also results in analgesic effects led by the CB1 receptor, in addition to anxiolytic and antidepressant effects [21]. Inhibition of both FAAH and MAGL increases the levels of both anandamide and 2-AG in the brain, which produces a similar effect to when the CB1 receptor is directly activated with CB1 receptor-like substances (called agonists) [21].

Inhibition of endocannabinoid enzymes may have potential therapeutic uses

Inhibition of these enzymes can control signals in the endocannabinoid system which may result in therapeutic possibilities. For example, inhibition of the FAAH enzyme can produce analgesic, anxiolytic, antidepressant, sleep-inducing, and inflammation-reducing effects. These effects occur without adverse consequences such as weight gain, or cognitive alterations. Therefore FAAH inhibition could be a strategy to induce CB1 receptor properties without many side effects which have been observed with direct receptor agonists [22].

What are the benefits of endocannabinoid enzymes?

Endocannabinoid enzymes have the potential to offer a variety of health and wellness benefits. By regulating endocannabinoid production and degradation, these enzymes can influence neurotransmission, pain control, inflammatory response, immune function, mood and appetite regulation, among other physiological mechanisms. By maintaining a proper balance of endocannabinoids in the body, endocannabinoid enzymes may have therapeutic implications in the treatment of various medical conditions. However, it is important to keep in mind that data on the specific benefits of endocannabinoid enzymes are ongoing and more research is needed to fully understand their therapeutic potential.

What is the future of cannabinoid enzymes?

As the understanding of these enzymes and their interaction with phytocannabinoids and endocannabinoids deepens, new perspectives open up in terms of possible therapeutic applications.

Inhibition of these endocannabinoid enzymes offers therapeutic promise, and since phytocannabinoids produced by the Cannabis sativa plant inhibit some of these enzymes, new medical possibilities open up.

I hope this article has opened a door of knowledge for you about this fascinating field of study that is cannabis and its effects. See you next time!

Referencias
  1. Iversen, L., Cannabis and the brain. Brain, 2003. 126(6): p. 1252-1270.
  2. Matsuda, L.A., et al., Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 1990. 346(6284): p. 561-564.
  3. Munro, S., K.L. Thomas, and M. Abu-Shaar, Molecular characterization of a peripheral receptor for cannabinoids. 1993.
  4. Pertwee, R.G., Pharmacology of cannabinoid receptor ligands. Current medicinal chemistry, 1999. 6(8): p. 635-664.
  5. Salzet, M., et al., Comparative biology of the endocannabinoid system. European Journal of Biochemistry, 2000. 267(16): p. 4917-4927.
  6. McPartland, J.M., et al., Evolutionary origins of the endocannabinoid system. Gene, 2006. 370: p. 64-74.
  7. Salzet, M. and G. Stefano, The endocannabinoid system in invertebrates. Prostaglandins, Leukotrienes and Essential Fatty Acids (Plefa), 2002. 66(2-3): p. 353-361.
  8. Miller, L.L. and R.J. Branconnier, Cannabis: Effects on memory and the cholinergic limbic system. Psychological Bulletin, 1983. 93(3): p. 441.
  9. Szaflarski, J.P. and E.M. Bebin, Cannabis, cannabidiol, and epilepsy-from receptors to clinical response. Epilepsy & Behavior, 2014. 41: p. 277-282.
  10. Di Marzo, V. and F. Piscitelli, The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics, 2015. 12: p. 692-698.
  11. Rog, D.J., Cannabis-based medicines in multiple sclerosis-a review of clinical studies. Immunobiology, 2010. 215(8): p. 658-672.
  12. Reggio, P.H., Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Current medicinal chemistry, 2010. 17(14): p. 1468-1486.
  13. Gil-Ordóñez, A., et al., Monoacylglycerol lipase (MAGL) as a promising therapeutic target. Biochemical pharmacology, 2018. 157: p. 18-32.
  14. Ligresti, A., M.G. Cascio, and V.D. Marzo, Endocannabinoid metabolic pathways and enzymes. Current Drug Targets-CNS & Neurological Disorders, 2005. 4(6): p. 615-623.
  15. Deutsch, D., N. Ueda, and S. Yamamoto, The fatty acid amide hydrolase (FAAH). Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA), 2002. 66(2-3): p. 201-210.
  16. Park, B., et al., Identification of the CB1 cannabinoid receptor and fatty acid amide hydrolase (FAAH) in the human placenta. Placenta, 2003. 24(5): p. 473-478.
  17. Basavarajappa, B.S., Critical enzymes involved in endocannabinoid metabolism. Protein and peptide letters, 2007. 14(3): p. 237-246.
  18. Fowler, C.J., Monoacylglycerol lipase-a target for drug development? British journal of pharmacology, 2012. 166(5): p. 1568-1585.
  19. Jha, V., et al., Discovery of monoacylglycerol lipase (MAGL) inhibitors based on a pharmacophore-guided virtual screening study. Molecules, 2020. 26(1): p. 78.
  20. Reisenberg, M., et al., The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling. Philosophical Transactions of the Royal Society B: Biological Sciences, 2012. 367(1607): p. 3264-3275.
  21. Marrs, W.R., et al., The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors. Nature neuroscience, 2010. 13(8): p. 951-957.

Ahn, K., D.S. Johnson, and B.F. Cravatt, Fatty acid amide hydrolase as a potential therapeutic target for the treatment of pain and CNS disorders. Expert opinion on drug discovery, 2009. 4(7): p. 763-784.

Andrea Rezes Esmeraldino
Cannabis researcher and trainer : Expert in CBD products of Cannactiva. With extensive experience in the cannabis world, Andrea is an expert in Cannactiva's CBD products. He deals every day [...]

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