Little-Known Gut Nutrient Is Emerging Player in Cancer Fight

An under-the-radar micronutrient is having a moment.

Queuosine — just call it “Q” — is a molecule that humans can only get from foods and gut bacteria. It’s has been known to microbiologists for decades, who know it plays a role in protein synthesis — as well as cancer growth, brain health, and inflammation. Yet, it hasn’t been clear how Q moves from the gut into cells throughout the body. Now the curtain has been pulled back.

The authors of a study published in Proceedings of the National Academy of Sciences (PNAS) have pinpointed a gene (SLC35F2) that helps transport Q to cells. The researchers say the new finding could help scientists figure out how to use the micronutrient to fight disease.

“It’s 70 years ago now that Q was discovered,” said study author Vincent P. Kelly, PhD, Professor of Biochemistry in the School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. “What’s exciting about this study is the fact that we never understood how we actually took that molecule from bacteria in our body and transported it into our cells, and this explains how we do it.”

Q: A Brief Primer

The PNAS study looked at both queuine (q), a modified nucleobase, and its nucleoside Q. A quick refresher: A nucleobase is a nitrogen-containing molecule that is one of the building blocks of DNA and RNA. And a nucleoside is a molecule made of sugar (either ribose or deoxyribose) plus a nitrogenous base (purine or pyrimidine) — also a building block of DNA. 

All of the cells in the human body are eukaryotes — they have a nucleus — and they rely on the micronutrients Q and q, which lurk in the human gut. They come from gut bacteria or a person’s diet (most commonly meat, eggs, dairy, fruits and vegetables, and fermented foods), said Kelly.

Prior studies had given hints that cellular uptake of Q and q is mediated by a selective transporter, but Kelly said that this transporter’s identity “remained elusive” until now.

“Almost all eukaryotes take the Q molecule and incorporate it into the transfer RNA (tRNA) in the body,” said Kelly. “tRNA is critical for making protein. It’s essential — essential for everything,” he said, pointing out that the average adult human is composed of about 12 kilograms (26 pounds) of protein.

How does Q get into gut bacteria and the food we eat? The Q molecule is more or less everywhere, Kelly said. “It’s in the oceans, it’s in the soil. Plants, which are eukaryotic, take it from the soil. And yet, very little is known about it. I’m surprised more people aren’t knowledgeable about it,” he said, especially considering public interest over the years in health-oriented micronutrients like vitamins and “macros” like carbohydrates, fats, and proteins.

What They Found, What It Means

Collaborating with researchers from Germany, Northern Ireland, the United States, and his own colleagues in Ireland, Kelly said they used a cross-species bioinformatic search and genetic validation — research techniques that enable scientists to analyze vast amounts of genomic data from across different species — to determine that Q and q are “salvaged” from the gut by SLC35F2 and ferried to different tissues throughout the body. 

“There’s a whole biology built around this micronutrient,” said Kelly.

Cracking the identity of the transporter of Q and q opens up opportunities for important research, Kelly said. It will lead to a deeper understanding of how intracellular levels of both micronutrients are regulated and how their deficiency is associated with diseases.

The study findings “represent an important leap in our understanding of queuosine biology. Queuosine is a unique tRNA modification to its precursor, queuine, which is not synthesized de novo in mammalian cells,” said Sherif Rashad, MD, PhD, associate professor in the Graduate School of Biomedical Engineering and the Graduate School of Medicine at Tohoku University in Sendai, Japan.

Rashad said scientists’ understanding of how q is imported into cells was “virtually nonexistent” until now and that the authors of the PNAS study used “an elegant but grounded approach” to identify the first q importer. The finding “paves the way for new discoveries in the many fields at the crossroads of queuosine biology,” he said.

Zdeněk Paris, PhD, Head of Laboratory, in the Laboratory of RNA Biology of Protists, at the Institute of Parasitology in Ceske Budejovice, Czech Republic, agreed. “This study advances the field of queuosine research by identifying the primary transporter and establishing a direct link between the function of SLC35F2, intracellular queuosine levels, and vital cellular processes, which can explain how a deficiency of Q and/or its free base, queuine (q), contributes to various conditions, including neurological disorders and cancer.”

Paris said, “Prior to this study, no specific transporters for the intracellular uptake of Q or q had been identified in any eukaryote.” He said the research is “high-quality.” He pointed out that the researchers also demonstrated that SLC35F2 is the sole high-affinity plasma membrane transporter for the Q nucleoside and the primary high-affinity transporter for the nucleobase q in human cells. 

“Its high expression in the human alimentary canal strongly suggests a critical role in Q/q uptake from the gut during digestion,” he said. “This reveals how these micronutrients, which are synthesized exclusively by bacteria, are salvaged from the gut microbiome and/or diet and delivered to various body tissues. Based on the obtained data, the authors propose a model in which Q is transported from the gut to the liver by SLC35F2. There, QNG1 cleaves Q to release the q base, which enters the serum for wider distribution.”

The Cancer Connection

Paris said that SLC35F2 was characterized as an oncogene in previous research and is known to contribute to the progression of various cancers through its overexpression, including non-small cell lung cancer, papillary thyroid cancer, and bladder cancer. 

Paris added that SLC35F2’s role in Q and q transport provides a significant mechanistic explanation for its oncogenic activity. “High SLC35F2 expression is an unfavorable prognostic factor for patient survival in multiple cancers. SLC35F2 overexpression increases cellular Q/q levels, promoting higher Q34 modification of tRNAs. Consequently, Q modification may offer malignant cells a selective advantage through codon-biased translation,” he said.

Additionally, the study identified SLC35F2 (or its homologs) as the unique Q/q transporter in the yeast Schizosaccharomyces pombe and the human parasite Trypanosoma brucei, Paris said. “While the physiological importance of Q-tRNA varies by species — for example, loss of Qtp1 does not affect growth in S pombe or T brucei — this comparative analysis strengthens the evidence for SLC35F2’s role in humans and reveals its conserved function in eukaryotes that salvage Q and q.”

He said, “In essence, the study provides the missing link in the queuine salvage pathway, significantly advancing our understanding of how this essential micronutrient is acquired, distributed, and regulated, and its profound impact on health and disease, particularly in the context of cancer.”