Vitamin B1, or thiamine, is vital for cellular survival, yet the human body is unable to synthesize it independently. Instead, individuals must derive this essential nutrient from their diet, with sources such as salmon, legumes, and brown rice being particularly beneficial. Maintaining adequate vitamin B1 levels is crucial, as deficiencies can lead to severe impairments in both cardiovascular and central nervous system functions, resulting in disability or even death.
The Hidden Dangers of Vitamin B1 Deficiency
In some cases, vitamin B1 deficiency can occur in critical organs like the brain, often as a side effect of certain medications. Notably, this can transpire even when blood levels of B1 appear normal, making it challenging to detect before significant harm has occurred.
To investigate these hidden deficiencies, researchers from the Löw Group at EMBL Hamburg and CSSB, in collaboration with the VIB-VUB Center for Structural Biology, utilized structural biology and biophysical techniques to explore how vitamin B1 traverses the body and the various factors that impede its transport. Their findings have been published in the journal Nature Communications.
Navigating the Body’s Barriers
The journey of vitamin B1 from the digestive system to cells requires it to navigate multiple cell membranes, each acting as a barrier. This path begins with the gut wall, progresses through blood vessels and organs, and culminates at the membranes of individual cells. The blood-brain barrier presents one of the most formidable challenges, safeguarding the brain from toxins but also complicating the passage of essential nutrients like vitamins.
To facilitate this nutrient transport, membranes are equipped with specialized transporter molecules. In the case of vitamin B1, two transporters—SLC19A2 and SLC19A3—primarily undertake this role. While their importance in human health is acknowledged, the precise molecular mechanisms underlying their function have remained elusive.
To elucidate these mechanisms, the Löw Group focused on SLC19A3, a transporter critical for transporting vitamin B1 across both the gut wall and the blood-brain barrier—two pivotal steps in its journey.
Capturing the Transport Process
Using cryo-electron microscopy (cryo-EM), the researchers constructed a “molecular movie,” enabling them to visualize the dynamics of the transport process and gain insights into how the transporter recognizes and facilitates the movement of the B1 molecule across cell membranes.
“With this, we could capture the dynamics of the transport process and visualize molecular details of how the transporter recognizes and pushes the B1 molecule across the cell membrane,” said Christian Löw, Group Leader and corresponding author of the study.
Implications for Rare Diseases
The molecular snapshots produced during this investigation allowed scientists to identify the critical components of the SLC19A3 transporter necessary for its function. Malfunctions in these areas can impair the transport of vitamin B1 to the brain, leading to severe neurological symptoms. Rare conditions manifesting in infancy are often treated with high doses of vitamin B1 and other compounds; however, the prognosis is dire, with one in 20 patients succumbing to the disease, and nearly one-third continuing to experience symptoms.
To further explore this issue, the researchers created a version of the SLC19A3 transporter that carries a mutation associated with a severe brain condition known as BTBGD. This model allowed them to observe how the mutation alters the transporter’s molecular structure, rendering it ineffective in transporting vitamin B1. Understanding this disease-causing mechanism could inform the development of more effective treatments for BTBGD.
Medications and Hidden Deficiencies
In addition to genetic mutations, certain medications can also induce severe vitamin B1 deficiency symptoms. Commonly prescribed drugs, including certain antidepressants, antibiotics, and oncology medications, have been found to impair the function of SLC19A3. This can potentially lead to dangerous deficiencies, particularly in the brain, which may occur even when blood levels of B1 remain normal, evading standard blood tests.
“While medicine already knows a few drugs that have the potential to cause hidden B1 deficiencies, there may be many more that we’re unaware of,” noted Florian Gabriel, Ph.D. student at EMBL Hamburg and the study’s first author.
The researchers aimed to simplify the identification of these drugs, uncovering the molecular basis for how various drug molecules obstruct the SLC19A3 transporter. They are currently screening all FDA- and EMA-approved medications for similar effects.
Identifying New Drug Interactions
By analyzing how known inhibitors interact with SLC19A3, the Löw Group identified seven new drugs likely to impair vitamin B1 transport in vitro and potentially in the human body. These include several antidepressants, the antiparasitic hydroxychloroquine, and three cancer treatments.
While further studies in humans are necessary, these findings represent a significant step toward protecting patients from potentially harmful drug-induced vitamin B1 deficiencies in the future.
The research could lay the groundwork for understanding how medications interact with similar transporters in the human body, potentially guiding the development of future drugs that utilize these transporters to achieve more effective targeting of organs.
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