New insights on the structural biology of medical cannabis

European Molecular Biology Laboratory (EMBL), Grenoble, France, researchers have investigated the interaction between D9-tetrahydrocannabinol (THC) and some proteins it might bind to.

In a recent study, they showed in vitro that THC inhibits an important human enzyme called autotaxin. This enzyme is involved in many different cellular functions, specifically producing a molecule called lysophosphatidic acid (LPA), which stimulates cell proliferation. A dysregulation of LPA production can lead to development of cancer, inflammation, or pulmonary fibrosis. Autotaxin is therefore a major target for drug development.

In various European countries and North America, medical cannabis or medicines based on cannabinoids are authorised for therapeutic purposes. Cannabis plant contains over 100 cannabinoids, THC and cannabidiol (CBD).

THC and CBD are administered under different pharmaceutical forms, showing therapeutic effects such as pain and inflammation relief.

Based on previous clinical trials, cannabinoid-containing medications can help to alleviate symptoms of mental disorders such as epilepsy, Alzheimer’s disease, asthma, and cancer, and help prevent weight loss during clinically challenging treatments for AIDS and different forms of cancer.

Yet, understanding how THC and other cannabinoids interact in our cells would help to administer THC more efficiently in therapeutic contexts.

Structural biologists focus on elucidating at the atomic scale the three-dimensional structure of molecules, like proteins or enzymes, and how they interact with each other. These structural results further lead to understanding molecules’ particular function and how to modulate their activities with specific compounds – which are crucial insights to develop effective drugs.

During their investigation of THC, the team obtained the three-dimensional structure of the THC cannabinoid bound with autotaxin. By employing macromolecular crystallography with EMBL’s beamline at the PETRA III synchrotron in Hamburg, they could lay the molecular basis of how THC inhibits this enzyme.

Identifying this enzyme as a binding target for THC expands the knowledge on this cannabinoid and provides more data on its possible therapeutic effects at the molecular level and how medical cannabis might contribute to therapy.

“Autotaxin is an essential enzyme in human beings,” said Mathias Eymery, PhD student on the team.

“It is responsible for the production of LPA, a major membrane-derived lipid signalling molecule that mediates many different cellular functions. Dysregulations of LPA production by autotaxin are known to have a role in the development of cancer, inflammation, or pulmonary fibrosis.”

In vivo studies are necessary to confirm that the binding between autotaxin and THC is linked to the therapeutic effects of THC administration – as the main known targets of THC in the human body are the CB1 and CB2 cannabinoid receptors, that mediate the psychoactive and pain relieve effects of cannabinoids.

Further investigation will help determine further potential of cannabinoids for medical research and drug development.