30-Year Mystery Solved: Hidden Nutrient Queuosine Protects Brain and Fights Cancer

The Discovery That Cracked a 30-Year Puzzle in Micronutrient Research

Researchers at leading universities have unveiled the mechanism behind a long-elusive micronutrient called queuosine, resolving a mystery that has puzzled scientists since the 1970s. Queuosine, often abbreviated as Q, is a vitamin-like compound that humans cannot produce on their own. Instead, it must be obtained through dietary sources or synthesized by beneficial gut bacteria. This breakthrough centers on the identification of the SLC35F2 gene, which encodes a high-specificity transporter responsible for shuttling queuine—the precursor to queuosine—and queuosine itself into human cells.

The SLC35F2 transporter operates with remarkable precision, exhibiting a Michaelis constant (K_m) of 174 nM for queuosine and 67 nM for queuine in human HeLa cells, ensuring efficient uptake even at low concentrations. This discovery not only explains how queuosine reaches cellular machinery but also opens avenues for understanding its profound effects on protein synthesis, particularly through modifications to transfer RNA (tRNA).

At the University of Florida's Institute of Food and Agricultural Sciences (UF/IFAS), microbiology professor Valérie de Crécy-Lagard, one of the study's principal investigators, described the finding as transformative: "This discovery opens up a whole new chapter in understanding how the microbiome and our diet can influence the translation of our genes." Collaborators at Trinity College Dublin, including Professor Vincent Kelly from the School of Biochemistry and Immunology, emphasized the nutrient's overlooked importance: "We have known for a long time that queuosine influences critical processes like brain health, metabolic regulation, cancer and even responses to stress."

A Brief History of Queuosine Research in Academia

Queuosine was first identified in the 1970s as a unique 7-deazaguanosine derivative found at the wobble position (position 34) of specific tRNAs that decode codons for histidine (His), tyrosine (Tyr), asparagine (Asn), and aspartic acid (Asp). These tRNA modifications, known as queuosine-tRNA or Q-tRNA, enhance the accuracy and speed of codon-anticodon pairing during translation, preventing errors that could lead to dysfunctional proteins.

Early studies in the 1980s and 1990s, conducted at institutions like the University of Chicago and European labs, noted queuosine deficiency in tumor tissues, hinting at its anti-cancer potential. By the 2000s, researchers at Ohio State University and San Diego State University began linking Q-tRNA levels to neurological functions. However, the critical gap—how queuosine enters eukaryotic cells—remained unsolved, stalling progress despite advanced genomic tools.

The persistence of this enigma underscores the challenges in interdisciplinary academic research, blending microbiology, genetics, and biochemistry. Cross-species bioinformatics finally bridged the gap, comparing organisms capable of Q-tRNA modification with those lacking it.

Unpacking the Breakthrough: Methods and Key Findings from the PNAS Study

Published on June 17, 2025, in the Proceedings of the National Academy of Sciences (PNAS), the landmark paper titled "The oncogene SLC35F2 is a high-specificity transporter for the micronutrients queuine and queuosine" details a multi-year effort. Lead authors Lyubomyr Burtnyak and colleagues employed phyletic profiling—a bioinformatic approach scanning transmembrane proteins across fungi, plants, and animals—to pinpoint SLC35F2 candidates. CRISPR-Cas9 knockouts in human HeLa cells, fission yeast (Schizosaccharomyces pombe), and trypanosomes (Trypanosoma brucei) confirmed its essential role.Read the full PNAS study here.

Liquid chromatography-mass spectrometry (LC-MS/MS) measured uptake kinetics, revealing SLC35F2's plasma membrane and Golgi localization via immunofluorescence. Knockout cells required 10-fold higher queuine concentrations for tRNA modification, detected by aniline-pyridine bisulfite (APB) Northern blots. Excess intracellular queuine is exported, maintaining homeostasis.

• SLC35F2 exclusively transports queuine/queuosine, rejecting other nucleobases.
• High expression in gut tissues supports dietary salvage.
• Knockouts impair cell proliferation, linking to its oncogene status.

University Collaborations Driving the Queuosine Revolution

This work exemplifies global academic synergy. UF/IFAS provided expertise in microbial genetics, while Trinity College Dublin contributed eukaryotic cell biology insights. San Diego State University handled structural analyses, and Ohio State focused on tRNA assays. Funding from the National Institutes of Health (NIH), Science Foundation Ireland, and others enabled this.

Such partnerships highlight how higher education institutions foster breakthroughs with real-world impact, from lab benches to clinical potential.

Photo by Kelly Sikkema on Unsplash

How Queuosine Fine-Tunes Protein Synthesis Step-by-Step

Queuosine modifies tRNA^{His,Tyr,Asn,Asp} at the anticodon wobble base, stabilizing pairing with ANN codons (where N is any nucleotide). Step 1: Gut bacteria or diet supply queuine. Step 2: SLC35F2 imports it into enterocytes. Step 3: Liver enzyme QNG1 converts queuosine to queuine monophosphate, then queuine. Step 4: Cytosolic TGT (QTRT1) inserts queuine into tRNA, followed by epoxyqueuosine reductase (QTRT2) maturation. This boosts translation efficiency by 2-3 fold for key proteins.

In the brain, high Q-tRNA levels in neurons support synaptic plasticity. A 2023 Luxembourg Institute of Health study showed queuosine-tRNA promotes sex-dependent learning and memory by regulating elongation speed.

Queuosine's Protective Role in Brain Health: Evidence from University Labs

Queuosine deficiency correlates with impaired cognitive function. Researchers at the Luxembourg Institute found female mice lacking Q-tRNA exhibit memory deficits due to slowed translation of plasticity-related proteins like BDNF (brain-derived neurotrophic factor). Human brain tissues show elevated Q levels, suggesting neuroprotection. A 2025 study in Journal of Molecular Biology linked mammalian Q-tRNA to myelination and stress resilience.

At Trinity College Dublin, ongoing work explores Q's gut-brain axis role, potentially informing Alzheimer's or Parkinson's research. "Queuosine modification regulates learning, memory, and neurological disorders," notes the PNAS team.

From Deficiency to Tumor Growth: Queuosine's Anti-Cancer Mechanisms

Cancer cells often hypomodify tRNA with queuosine, promoting the Warburg effect—aerobic glycolysis fueling rapid proliferation. A 2020 Queen's University Belfast study showed queuine deficiency in colon tumors accelerates metastasis via inefficient Tyr/His translation. SLC35F2 overexpression, seen in lung, bladder, and pancreatic cancers, acts as an oncogene by boosting Q uptake, aiding tumor survival.

Conversely, Q supplementation suppresses growth in preclinical models. University of Chicago findings indicate Q enhances immune recognition of tumors. Targeting SLC35F2 with inhibitors like YM155 (an anticancer agent) blocks Q entry, starving cancer cells.Explore queuine deficiency in cancer.

Dietary and Microbial Sources: Actionable Insights for Health

Primary sources include fermented dairy (yogurt, cheese), meats, and vegetables like spinach, where queuine concentrates. Gut producers: Bifidobacterium and Escherichia coli strains. To boost levels:

• Consume probiotic-rich foods (kefir, sauerkraut).
• Increase fiber for microbiome diversity.
• Eat queuine-containing plants post-bacterial synthesis.

UF researchers advocate microbiome-friendly diets to optimize Q salvage via SLC35F2.

Photo by 愚木混株 Yumu on Unsplash

Future Directions: Therapeutic Horizons in Academic Research

With SLC35F2 identified, universities are poised for trials: Q-mimetics for neurodegeneration, transporter inhibitors for oncology. Trinity and UF plan gut-brain studies; SDSU explores structural analogs. Challenges include bioavailability and specificity, but the foundation is set.

This breakthrough positions higher education at the forefront of precision nutrition, blending genomics, microbiology, and clinical translation for global health gains.