Monoacylglycerol Lipase (MAGL) is the specialized enzyme that breaks down the endocannabinoid 2-AG, and it represents the point at which the endocannabinoid system dovetails with a system of signaling agents called eicosanoids.

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This is a schematic illustration of the three-dimensional structure of MAGL. 2-AG fits into the spaces formed by the structure and is hydrolyzed to break down.

Eicosanoids are different kinds of fat-based molecules that promote inflammation or reduce it, mount immune responses, control blood pressure, playing roles in pregnancy and delivery and controlling blood flow to different tissues. Inflammation is the source of most disease symptoms — whether it’s histamines causing your hay fever-sensitive nose to run or specific eicosanoids that cascade around your brain and cause damage after a stroke. 

Sometimes, inflammation is good. Inflammation in your intestines causing diarrhea may be unpleasant, but it helps you expel the E. Coli infection that could be in your gut. Other times, like after a head injury, it’s inflammation that causes long-term damage rather than the initial trauma.

But eicosanoids also may help attenuate kidney function, cardiovascular function and a lot of other important processes. Some eicosanoids may inhibit inflammation; it’s a large class of different molecules.

One thing all eicosanoids have in common is they are made from the breakdown of arachidonic acid. If that sounds familiar, it’s because arachidonic acid is the prime component of both of the important endocannabinoids in your body —  2-AG and anandamide

MAGL impact on 2-AG and anandamide and arachidonic acid

In fact, it seems that the eicosanoid system gets most of its arachidonic acid from the breakdown of 2-AG by MAGL, according to a 2013 paper published in Life Sciences.

The paper is a meta-analysis of other studies that show when you lock up MAGL and prevent it from breaking down 2-AG, it can reduce a variety of different types of pain and inflammation, including tumor growth.

So if you tamp down the action of MAGL in a diseased organism, a cascade of positive things can happen, depending on the disease. 

One, more 2-AG is floating around to reduce anxiety, improve mood, modulate stress response and all the other benefits demonstrated by robust function of the endocannabinoid system. Two, the pro-inflammatory eicosanoids are robbed of their ingredients to make all the little chemicals that cause inflammation in specific tissues.

Some of these eicosanoids also promote tumor growth in cancer patients, so anything that can reduce the amount of those particular lipid signallers is thought to be helpful.

“MAGL inhibitors have also been shown to exert anti-inflammatory action in the brain and protect against neurodegeneration through lowering eicosanoid production,” the Life Sciences study states. “In cancer, MAGL inhibitors have been shown to have anti-cancer properties not only through modulating the endocannabinoid—eicosanoid network, but also by controlling fatty acid release for the synthesis of protumorigenic signaling lipids. Thus, MAGL serves as a critical node in simultaneously coordinating multiple lipid signaling pathways in both physiological and disease contexts.”

What are the genetics of MAGL synthesis?

The MGLL protein gene is responsible for encoding MAGL, according to the GeneCards database of human DNA mapping.

“The encoded protein plays a critical role in several physiological processes including pain and nociperception through hydrolysis of the endocannabinoid 2-arachidonoylglycerol,” according to GeneCards. “Expression of this gene may play a role in cancer tumorigenesis and metastasis.”

Mutations or abnormal expression of the MAGL gene is linked to a predilection for cannabis dependence, according to GeneCards.

How does MAGL work in the endocannabinoid system?

MAGL operates in the same way FAAH, a different enzyme of the endocannabinoid system, breaks down anandamide

According to the current understanding of how the endocannabinoid system works, researchers theorize that cellular uptake of anandamide and 2-AG is governed by a concentration gradient under control of MAGL and FAAH. MAGL lives inside little sacks within the cell. Once 2-AG from outside the cell enters the cell after docking with the cannabinoid receptors (CB1 and CB2) on the cell membrane, fatty acid binding proteins grab onto the 2-AG and carry it to the little vesicle or sack full of MAGL. The MAGL enzyme locks onto the 2-AG and alters it by adding a hydrogen group or “hydrolyzes” the molecule.

How MAGL works

Once MAGL does its job, there’s suddenly less 2-AG inside the cell, and based on simple fluid mechanics, the 2-AG in the intercellular space gets sucked inside the cell as the fluid solution inside you seeks homogeny. 

This process follows simple rules of fluid mechanics, and other more heavily documented body systems also use this technique to move molecules around. Still, this model isn’t the final word on how the endocannabinoid system shuttles its components around the body. One cadre of endocannabinoid researchers still insist there must be an as-yet undiscovered theoretical transporter molecule dubbed “the anandamide transporter” that acts to shepherd anadamide or 2-AG from the intercellular space to the cell membrane.

But, until further research proves the existence of an intercellular endocannabinoid transporter, StrainGenie for its informational content will assume the concentration gradient model is correct. This decision is based on a convincing 2016 defense of the theory in Frontiers in Pharmacology by Dale G. Deutsch of Stonybrook University. Deutsch was integral in early mapping of the endocannabinoid system — he was part of the team in 1993 who discovered FAAH, the enzyme that breaks down anandamide

And no matter how the details of transport in the endocannabinoid system ultimately shake out, research has already proven profound effects of manipulating MAGL.

“Upon administration to mice, (the MAGL blocker) raises brain 2-AG by 8-fold without altering anandamide. (blocker)-treated mice exhibited a broad array of CB1-dependent behavioral effects, including analgesia, hypothermia, and hypomotility,” according to the 2009 study in Nature Chemical Biology. “These data indicate that 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo.”

Another enzyme, and another role for 2-AG

Interestingly, 2-AG is vital in the function of male reproduction, and a specialized enzyme in the testes, ABHD2, breaks down 2-AG in the sperm cell membrane in testicle tissue. ABHD2 also breaks down a minor percentage of 2-AG throughout the rest of the body. 

Scientists aren’t sure why your body makes this secondary enzyme to hydrolyze 2-AG, but it probably has something to do with reproductive function.

ABHD2 is coded by a gene of the same name.

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