Enzymes - Living Machines that Control Nature’s Chemical Diversity

If receptors are like switches that control different systems and functions, then enzymes are like different tools in the tool belt to construct, break apart, and modify molecules. All of the molecules in cannabis we enjoy like cannabinoids and terpenes are created by enzymes and this is also going on inside our own bodies too where enzymes play a key role in the endocannabinoid system! Read on to learn more about the amazing, but often underappreciated living machines that control nature’s chemical diversity.

Image of a homology model of human ABHD6, an endocannabinoid hydrolyzing enzyme and a representative phospholipid membrane.

What are enzymes and what are enzyme inhibitors?

There are millions upon millions of chemical reactions going on every second in all living beings. These chemical reactions are essential for life, because they create and break down all the different molecules that come together to power the brain and body. Enzymes speed up certain chemical reactions depending on their type. Some enzymes are very specific, only altering one or two chemical reactions, while others can work on a huge array of similar chemical reactions. Changing the enzymes changes the levels of all the molecules that are involved in those chemical reactions. Blocking an enzyme will “stop” that chemical reaction and there will be a build-up of some molecules and a reduction in others. And this is a common type of pharmaceutical drug: an enzyme inhibitor.

Many drugs work by targeting a specific enzyme and turning it off, which changes the balance of molecules in the chemical reaction for that enzyme. If you’ve ever taken ibuprofen (Advil) or naproxen (Aleve), then you’ve taken an enzyme inhibitor. Both of those molecules work by stopping two similar enzymes called the cyclooxygenase enzymes (COX-1 and COX-2). This prevents the creation of molecules that are associated with causing inflammation and increases the number of molecules in the body that reduce inflammation.

Enzymes are an essential part of all life, including the endocannabinoid system in our bodies and the biosynthetic pathways in cannabis.

From endocannabinoids to phytocannabinoids, enzymes make and break it all.

Every warm-blooded animal, which includes every single human in existence, has an endocannabinoid system revolving around fatty, sticky signaling molecules called endocannabinoids. The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2AG) are created and broken down by enzymes. Here is an image of the chemical reaction of breaking down endocannabinoids:

Preventing the breakdown of endocannabinoids by blocking enzymes has therapeutic potential for a huge number of issues from metabolic disorders like diabetes and obesity to mental health. The enzymes often get overshadowed by the receptors, but they contribute to the effects of all drugs.

And there is even early evidence that molecules in cannabis can act as enzyme inhibitors for endocannabinoids! We have only just started to scratch the surface investigating how the unlimited combinations of molecules found in cannabis and cannabis products affects the enzymes. There are still hundreds of uncharacterized molecules.

And almost all of the unique molecules in cannabis are created by enzymes. Different strains will have different aroma and cannabinoid content depending on the different biosynthetic enzymes. For example, only strains that have the enzyme THCA synthase will create THC!

From regulating the levels of our endocannabinoid system in our brain and body to creating all the wonderful molecules that make cannabis so special, enzymes are at the core.

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REFERENCES

Gagne, S. J., Stout, J. M., Liu, E., Boubakir, Z., Clark, S. M., & Page, J. E. (2012). Identification of olivetolic acid cyclase from Cannabis sativa reveals a unique catalytic route to plant polyketides. Proceedings of the National Academy of Sciences of the United States of America, 109(31), 12811–12816. https://doi.org/10.1073/pnas.1200330109

Hillard C. J. (2018). Circulating Endocannabinoids: From Whence Do They Come and Where are They Going?. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 43(1), 155–172. https://doi.org/10.1038/npp.2017.130

Klawitter, J., Weissenborn, W., Gvon, I., Walz, M., Klawitter, J., Jackson, M., Sempio, C., Joksimovic, S. L., Shokati, T., Just, I., Christians, U., & Todorovic, S. M. (2024). β-Caryophyllene Inhibits Monoacylglycerol Lipase Activity and Increases 2-Arachidonoyl Glycerol Levels In Vivo: A New Mechanism of Endocannabinoid-Mediated Analgesia?. Molecular pharmacology, 105(2), 75–83. https://doi.org/10.1124/molpharm.123.000668

Viegas, A., Manso, J., Corvo, M. C., Marques, M. M., & Cabrita, E. J. (2011). Binding of ibuprofen, ketorolac, and diclofenac to COX-1 and COX-2 studied by saturation transfer difference NMR. Journal of medicinal chemistry, 54(24), 8555–8562. https://doi.org/10.1021/jm201090k