Researchers at EMBL Hamburg and CSSB have revealed the complex molecular processes involved in the body’s absorption of vitamin B1, which could lead to new approaches for preventing subtle yet dangerous deficiencies of this vital nutrient in patients. Vitamin B1, also known as thiamine, plays a crucial role in cell survival; however, it is not produced by the human body. To sustain healthy levels, it is essential to include foods like salmon, legumes, and brown rice in the diet. Maintaining sufficient vitamin B1 intake is critical, as a deficiency can result in serious issues, including cardiovascular problems, neurological disorders, disabilities, and even fatality.
Interestingly, certain medications can induce B1 deficiencies within the brain and other essential organs, even when blood levels appear normal. This often allows deficiencies to go unnoticed until they reach a critical stage. To delve into the underlying causes of these hidden deficiencies, the Löw Group at EMBL Hamburg and CSSB, alongside partners from the VIB-VUB Center for Structural Biology, employed structural biology and biophysical methods to explore how vitamin B1 is transported throughout the body and identify factors that may impede its distribution to various tissues.
The Journey of Vitamin B1: Overcoming Obstacles
As vitamin B1 traverses from the digestive system to the cells within the body, it encounters numerous barriers along the way. These include the gut wall, blood vessels, various organs, and ultimately, the membranes of individual cells. Among these obstacles, the blood-brain barrier is particularly formidable, as it protects the brain from harmful substances that could enter from the bloodstream. However, this protective barrier also complicates the passage of vital nutrients, such as vitamins.
To facilitate the transport of vitamins and other essential nutrients to cells throughout the body, these membranes contain specialized transporter molecules. For vitamin B1, two key transporters perform this role: SLC19A2 and SLC19A3. Although the significance of these transporters for human health is recognized, their precise molecular mechanisms have remained largely unknown.
To shed light on this process, the Löw Group focused on SLC19A3, the transporter crucial for allowing vitamin B1 to cross both the gut wall and the blood-brain barrier—two pivotal stages in its journey. To visually capture the activity of this transporter, the researchers utilized cryo-electron microscopy (cryo-EM) to create a ‘molecular movie’ comprising a series of detailed snapshots. “With this technique, we were able to capture the dynamics of the transport process and gain insights into how the transporter identifies and facilitates the movement of the B1 molecule across the cell membrane,” explained Christian Löw, the Group Leader and corresponding author of the study.
Understanding Rare Diseases
Recent molecular studies have allowed researchers to pinpoint the most essential components of the SLC19A3 transporter necessary for its proper functioning. When these critical elements fail, the transporter cannot perform its role effectively. This insight reveals why mutations in these vital regions obstruct the transport of Vitamin B1 to the brain, resulting in severe neurological issues. These infrequent disorders, which typically present symptoms during infancy, are managed with high doses of Vitamin B1 and other supportive substances. Nevertheless, approximately one in twenty patients do not survive, and nearly a third continue to experience symptoms.
To delve deeper into this issue, scientists engineered a version of the SLC19A3 transporter that harbors a mutation responsible for a debilitating brain disorder known as BTBGD. This model allows them to closely examine how the mutation alters the transporter’s molecular configuration, rendering it incapable of absorbing Vitamin B1. By uncovering this disease mechanism, researchers hope to pave the way for the development of more effective treatments for BTBGD in the future.
Drugs Linked to Hidden Vitamin B1 Deficiencies
Severe Vitamin B1 deficiency symptoms can stem not only from rare genetic mutations but also from certain medications. A number of widely prescribed drugs, including some antidepressants, antibiotics, and cancer treatments, can interfere with the function of SLC19A3. This interference may lead to potentially harmful deficiencies of Vitamin B1 in the body, particularly affecting specific organs or tissues. Brain-related deficiencies are especially perilous, as they can occur even when blood levels of Vitamin B1 appear normal, rendering them undetectable through standard blood tests. This concealed deficiency can gradually result in serious, potentially life-threatening brain dysfunction.
“While some medications known to cause hidden Vitamin B1 deficiencies are already documented, many others remain unidentified,” explained Florian Gabriel, a PhD student at EMBL Hamburg and the lead author of the study. “Detecting them is not an easy task, so our research aimed to simplify this process. We have revealed the molecular mechanisms by which certain drug molecules obstruct the SLC19A3 transporter and are currently leveraging this knowledge to screen all FDA- and EMA-approved medications for similar interactions.”
