Researchers of the NKI have been studying ATX for years and have helped unravel many of its secrets. Now they have unraveled the function of the mysterious tunnel incorporated in the enzyme. They were using crystallography techniques to study structural changes of the enzyme when they noticed that some unknown molecule occupied the tunnel. With clever deduction they were able to determine what type of molecule it must have been. It turned out to be a steroid. Further experiments, joining efforts with the AMC experts, showed that the tunnel has a high affinity for common bile salts. And that binding of bile salts inside the tunnel significantly slowed down the production of LPA. These results were published in the journal Nature Communications of April 14th.
First author of the study, Willem-Jan Keune, comments: "This is an exciting discovery, because up to now no natural regulators of ATX activity had been identified. Our findings support the hypothesis that the tunnel is the exit route of LPA once it is generated by the enzyme. And apparently, bile salts can block this exit, thus inhibiting LPA production."
Interestingly, bile salts used in this study or similar steroids (most importantly ursodeoxycholates) have been shown to alleviate symptoms of several diseases, including cholestatic disease and arthritis. Their anti-inflammatory effects have also been recognized in colitis, neurite growth impairment and neovascularization. Furthermore, these drugs are being explored as alleviators of the symptoms of several neurodegenerative diseases, including ALS, Parkinson's and Huntington's.
Anastassis Perrakis: "Our work provides a molecular basis that can explain at least part of the therapeutic effect of these drugs. Unwittingly, they might interfere with ATX functioning and LPA signaling. This certainly deserves further investigation. On top of that, our work may offer important clues on how to treat other diseases associated with abnormal ATX-LPA signaling. All in all, our work is a nice example of how very basal molecular research can have far-reaching and often unexpected clinical implications."