Introduction: Trimethylamine N-Oxide (TMAO) is an important metabolite, which is synthesized from the dietary precursors’ choline, betaine, and carnitine in various organisms. In humans, TMAO is synthesized by the metabolism of these dietary precursors by the action of enzymes produced by gut microbiota, and its high levels are abundantly found in serum and cerebrospinal fluid (CSF). Although TMAO is a stress protectant, especially in urea-rich organisms, it is an atherogenic agent in humans and is associated with various diseases. Specifically, there has been a strong correlation between serum TMAO levels and the development of Dementia. We have investigated the effect of TMAO on Carbonic anhydrase (CA) as after repeated failure of drugs that target Aβ in clinical trials, CA is considered to be an alternative target.

Methods: In the present study, we have investigated the effect of TMAO on the structural and functional integrity of CA using various biophysical and biochemical approaches. Cellular approches are also used to confirm the effect.

Results: Our result indicates that TMAO acts as a ligand of CA that is specifically targeted to its folding intermediate, U_f. We discovered that TMAO inhibits the folding of CA by disrupting the U_f state and eventually impairing the cis/trans isomerization. Furthermore, TMAO is capable of inducing cell cycle arrest and eventually increasing ROS levels.

Conclusion: This study highlights a novel molecular insight into the involvement of TMAO in AD dementia and other proteopathy-associated diseases.