NEW YORK, Oct 20: Vitamin B1, also known as thiamine, is crucial for the survival of cells; however, the human body is unable to produce it. To maintain optimal levels, it’s important to include foods like salmon, legumes, and brown rice in your diet. Ensuring sufficient intake of vitamin B1 is essential, as a deficiency can result in severe cardiovascular and nervous system issues, disability, or even death.

In some cases, a deficiency in vitamin B1 may occur in the brain and other vital organs due to the side effects of certain medications. This can happen even when blood levels of B1 are normal, often leading to undetected deficiencies until they become serious.

To uncover the reasons behind these hidden deficiencies, the Löw Group at EMBL Hamburg, in collaboration with the CSSB and the VIB-VUB Center for Structural Biology, employed structural biology and biophysical techniques to explore how vitamin B1 is transported within the body and what factors can impede its movement.

As vitamin B1 travels from the gut to the body's cells, it must navigate several barriers, starting with the gut wall, followed by blood vessels, organs, and finally, the membranes of individual cells. The most significant barrier is the blood-brain barrier, which protects the brain from toxins in the bloodstream but also restricts the passage of essential nutrients like vitamins.

To facilitate the transfer of vitamins and nutrients across these membranes, specialized transporter molecules are present. For vitamin B1, this task is primarily handled by two transporters: SLC19A2 and SLC19A3. While their importance to human health is acknowledged, the exact molecular mechanisms behind their function have remained unclear.

To elucidate this, the Löw Group focused on SLC19A3, a transporter vital for B1’s passage through the gut wall and the blood-brain barrier—both critical phases in the vitamin's journey.

To observe the transporter in action, the researchers created a 'molecular movie' by compiling a series of images obtained through cryo-electron microscopy (cryo-EM).

“With this approach, we captured the dynamics of the transport process and visualized molecular details of how the transporter recognizes and moves the B1 molecule across the cell membrane,” said Christian Löw, Group Leader and corresponding author of the study.

These molecular images allowed scientists to identify which sections of the SLC19A3 transporter are crucial for its proper function. Malfunctions in these areas can hinder the transporter’s effectiveness. This is significant because mutations in these critical regions disrupt B1 transport to the brain, resulting in severe neurological symptoms. These rare disorders typically manifest during infancy and are treated with high doses of B1 and other compounds; however, one in 20 patients may die, and nearly one-third continue to experience symptoms.

To further investigate, the researchers created a version of the SLC19A3 transporter carrying a mutation responsible for a severe brain disorder known as BTBGD. This model allows them to observe how the mutation alters the transporter’s molecular structure and reduces its ability to bind to B1. Understanding this mechanism may pave the way for developing more effective treatments for BTBGD in the future.

In addition to rare genetic mutations, severe symptoms of B1 deficiency can also result from certain medications. Various commonly prescribed drugs, including some antidepressants, antibiotics, and cancer treatments, have been found to impair SLC19A3 function. This impairment can lead to dangerous deficiencies in B1, affecting the entire body or specific organs.

Brain-related deficiencies are particularly concerning, as they can arise even with normal blood levels of B1, making them undetectable through standard blood tests. Such hidden deficiencies can quietly result in serious and potentially life-threatening brain dysfunction.

“While there are already known drugs that can induce hidden B1 deficiencies, there may be many others yet to be identified,” stated Florian Gabriel, a PhD student at EMBL Hamburg and the study's first author. “Finding these drugs isn’t straightforward, which is why our research aimed to simplify this process. We have uncovered the molecular basis of how certain drug molecules obstruct the SLC19A3 transporter and are currently using this knowledge to screen all FDA- and EMA-approved medications for similar interactions.”

The Löw Group also identified specific structural characteristics that increase the likelihood of a drug interfering with B1 transport. Utilizing cryo-EM and biophysical techniques, they analyzed how known blockers interact with SLC19A3.

This research has led to the identification of seven new drugs that block the B1 transporter in vitro, which are likely to do so in the human body as well. These include several antidepressants, the antiparasitic hydroxychloroquine, and three cancer medications.

While these findings require further confirmation in humans, they represent a crucial step toward protecting patients from potentially harmful drug-induced B1 deficiencies in the future.

“These results will not only help improve monitoring of patients taking these medications but could also assist in developing new drugs that do not have this side effect,” Löw explained. “We believe our research could also serve as a foundation for studying how medications interact with similar transporters in the human body. In the long term, it might also guide the design of future drugs that could effectively target specific organs.”