queuine (STEL-101) / Stellate Therap - LARVOL DELTA

Disrupted tRNA modification leads to intestinal mitochondrial dysfunction and microbial dysbiosis. (PubMed, bioRxiv) - "Our previous study demonstrated tRNA modopathies and altered queuine-related metabolites in inflammatory bowel diseases...Restoring mitochondrial function leads to enhanced QTRT1. Targeting tRNA-Q modification in enhancing mitochondrial function will be a novel method to maintain intestinal health."

IO biomarker • Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Metabolic Disorders • BAX • BCL2 • CASP3 • CD14 • CDC42 • MUC2 • TJP1

Decoding tRNA dynamics in neuroimmune disorders: mechanistic insights, diagnostic innovations, and therapeutic opportunities. (PubMed, Front Immunol) - "We highlight innovative diagnostic biomarkers (e.g., plasma tsRNAs, aminoacyl-tRNA synthetase-interacting multifunctional protein 1) and therapeutic strategies targeting tRNA modification pathways (e.g., queuine analogs, tRNA ligase inhibitors). By bridging tRNA biology with neuroimmunology, this work underscores the translational potential of tRNA-centric approaches in managing complex neurological diseases."

Biomarker • Journal • Review • Alzheimer's Disease • CNS Disorders • Immunology • Inflammation • Movement Disorders • Multiple Sclerosis • Neuromyelitis Optica Spectrum Disorder • Parkinson's Disease • Rare Diseases

Microbial metabolites shape mammalian protein translation. (PubMed, Cell Metab) - "In a recent issue of Nature Cell Biology, Zhang et al. show that pre-queuosine 1 (preQ1), an intermediate of the bacterial queuine biosynthesis pathway, competes with queuine for the same mammalian tRNA targets to antagonistically modulate protein translation and cell proliferation."

Journal

In silico screening and in vitro biological evaluation reveal Queuine as a promising MAP4K4 inhibitor for treating pancreatic cancer. (PubMed, BMC Biotechnol) - No abstract available

Journal • Preclinical • Oncology • Pancreatic Cancer • Solid Tumor

Two microbiome metabolites compete for tRNA modification to impact mammalian cell proliferation and translation quality control. (PubMed, Nat Cell Biol) - "The microbiome affects eukaryotic host cells via many metabolites, including the well-studied queuine as substrate for host tRNA queuosine modification...We identify the endoplasmic reticulum-localized inositol-requiring enzyme 1 (IRE1) ribonuclease as the enzyme responsible for the selective degradation of preQ1-modified tRNAs on translating ribosomes. Our results identify two microbial metabolites competing for host tRNA modification, which elicits translation quality control and impacts cell proliferation."

Journal • Oncology • ERN1

Selective Chemical Manipulation of Mannosyl- and Galactosyl-Queuosine in tRNAs of Living Cells. (PubMed, Angew Chem Int Ed Engl) - "Here, we performed feeding experiments with synthetic deoxyqueuine derivatives that lack either the allylic, the homoallylic, or both hydroxyl groups. Analysis of the queuosine derivatives that are found in the corresponding tRNAs shows that the glycosylases attach the sugar with precise specificity, suggesting decisive functions of the galactose and mannose sugar moieties in the decoding process."

Journal

The oncogene SLC35F2 is a high-specificity transporter for the micronutrients queuine and queuosine. (PubMed, Proc Natl Acad Sci U S A) - "Ectopic expression of labeled SLC35F2 reveals localization to the cell membrane and Golgi apparatus via immunofluorescence. Competition uptake studies show that SLC35F2 is not a general transporter for other canonical ribonucleobases or ribonucleosides but selectively imports q and Q. The identification of SLC35F2, an oncogene, as the transporter of both q and Q advances our understanding of how intracellular levels of queuine and queuosine are regulated and how their deficiency contributes to a variety of pathophysiological conditions, including neurological disorders and cancer."

Journal • CNS Disorders • Oncology • Psychiatry • Schizophrenia • SLC35F2

Mammalian queuosine tRNA modification impacts translation to enhance cell proliferation and MHC-II expression. (PubMed, J Mol Biol) - "Eukaryotic tRNA Q-modification requires the metabolite queuine - derived from diet or catabolism of the gut microbiome - and a host-genome encoded enzyme complex, QTRT1/QTRT2...We also find that tRNA Q-modification increases surface presentation of MHC-II in BMDCs. Our results provide insights into the broader implications of tRNA Q-modifications in regulating diverse biological functions."

Journal

Metabolomic and Molecular Insights into ATP Synthase Inhibitors from Micromonospora sp. as Novel Antimicrobial Agents Against Multidrug-Resistant Gram-Negative Pathogens of Enteric Origin. (PubMed, Lett Appl Microbiol) - "Further analysis using LC-QTOF-MS/MS non-targeted metabolomics identified six bioactive compounds-melibiose, oligomycin A, queuine, heptelidic acid, diethyl phthalate, and 2'-deoxyguanosine-linked to the inhibition of bacterial enzymes essential for proliferation...This study integrates metabolomics, molecular docking, and genomics, offering robust mechanistic insights into ATP synthase inhibition. Future research will include fecal isolate testing, detailed structural elucidation using NMR, and experimental validation to explore the therapeutic potential of Micromonospora-derived compounds."

Journal • Infectious Disease

Queuine: A Bacterial Nucleobase Shaping Translation in Eukaryotes. (PubMed, J Mol Biol) - "This review discusses our current understanding of the cellular and organismal impacts of Q deficiency in eukaryotes. Additionally, it examines recent advancements in technologies for detecting Q modifications at single-base resolution and explores the potential applications of the Q modification system in biotechnology."

Journal • Review • CNS Disorders • Oncology

Queuosine tRNA Modification: Connecting the Microbiome to the Translatome. (PubMed, Bioessays) - "In eukaryotes, queuosine is synthesized by the tRNA-guanine trans-glycosylase (TGT) complex, which incorporates the nucleobase queuine (or Qbase) into guanine of the GUN anticodons...Q's role in neuropsychiatric diseases and cancer is highlighted and discussed. Given the recent interest in Q, and the new findings, more research is needed to fully comprehend its biological function and disease relevance, especially in neurobiology."

Journal • Review • CNS Disorders • Mental Retardation • Oncology • Psychiatry

Exploring the Interactome of the Queuine Salvage Protein DUF2419 in Entamoeba histolytica. (PubMed, Cells) - "Entamoeba histolytica causes amebiasis, a significant global health issue, with millions affected annually, especially in developing countries. The reduction in the EhDUF2419 protein levels was regulated by proteasome-mediated degradation, as evidenced by the reduced degradation in the presence of MG132, a proteasome inhibitor. Our study uncovers the novel interaction of EhDUF2419 with ribosomal proteins and its regulation by the proteasome machinery, providing new insights into its role in E. histolytica and potential therapeutic strategies."

Journal

The utilization of Lysinibacillus bacterial powder to induce Fe plaque formation mitigates cadmium and chromium levels in rice. (PubMed, J Hazard Mater) - "Our findings suggest that Lysinibacillus sp. OR-15 exhibits stable and effective properties as a factor for Cd and Cr adsorb on rice iron plaque, thus mitigating the levels of Cd and Cr in rice grains."

Journal

Queuosine salvage in Bartonella henselae Houston 1: a unique evolutionary path. (PubMed, Microbiology (Reading)) - "Organisms such as the facultative intracellular pathogen Bartonella henselae, which possess only bTGT and QPTR but lack predicted enzymes for converting preQ1 to Q, would be expected to salvage the queuine (q) base, mirroring the scenario for the obligate intracellular pathogen Chlamydia trachomatis...Complementation analysis demonstrates that B. henselae bTGT and QPTR not only utilize preQ1, akin to their Escherichia coli counterparts, but can also process q when provided at elevated concentrations. The experimental and phylogenomic analyses suggest that the Q pathway in B. henselae could represent an evolutionary transition among intracellular pathogens - from ancestors that synthesized Q de novo to a state prioritizing the salvage of q. Another possibility that will require further investigations is that the insertion of preQ1 confers fitness advantages when B. henselae is growing outside a mammalian host."

Journal • Infectious Disease

Queuine ameliorates impaired mitochondrial function caused by mt-tRNAAsn variants. (PubMed, J Transl Med) - "The study not only confirmed the pathogenicity of the m.5708 C > T variant but also explored the therapeutic potential of queuine in individuals with mt-tRNAAsn variants. The recognition of the novel m.5708 C > T variant's pathogenic nature contributes to our comprehension of mitochondrial disorders. Furthermore, the results emphasize queuine supplementation as a promising approach to enhance the stability of mt-tRNAAsn and rescue mitochondrial dysfunction caused by mt-tRNAAsn variants, indicating potential implications for the development of targeted therapies for patients with mt-tRNAAsn variants."

Journal • Metabolic Disorders

Development, validation and application of an LC-MS/MS method quantifying free forms of the micronutrients queuine and queuosine in human plasma using a surrogate matrix approach. (PubMed, Anal Bioanal Chem) - "Q was not detected in human plasma. This validated method can now be used to further substantiate the role of q/Q in nutrition, physiology and pathology."

Journal

Deciphering the Diversity in Bacterial Transporters That Salvage Queuosine Precursors. (PubMed, Epigenomes) - "Three genes encoding transporters from three different Pfam families, a ureide permease (PF07168) from Acidobacteriota bacterium, a hemolysin III family protein (PF03006) from Bifidobacterium breve, and a Major Facilitator Superfamily protein (PF07690) from Bartonella henselae, were found to allow the transport of both preQ0 and preQ1 in this heterologous system. This work suggests that many transporter families can evolve to transport Q precursors, reinforcing the concept of transporter plasticity."

Journal

A new class of 7-deazaguanine agents targeting autoimmune diseases: dramatic reduction of synovial fibroblast IL-6 production from human rheumatoid arthritis patients and improved performance against murine experimental autoimmune encephalomyelitis. (PubMed, RSC Med Chem) - "A simple in vitro assay involving the measurement of IL-6 production in human synovial fibroblasts from rheumatoid arthritis patients has been utilised to select candidates from a targeted library of queuine tRNA ribosyltransferase (QTRT) substrates for subsequent in vivo screening in murine experimental autoimmune encephalomyelitis (EAE - a model of multiple sclerosis)...Two molecules were of significant promise: one rigidified analogue of the lead, and another considerably simpler structure incorporating an oxime motif which differs structurally from the lead to a considerable extent. These studies provide data from human cells for the first time and have expanded both the chemical space and current understanding of the structure-activity relationship underpinning the remarkable potential of 7-deazguanines in a Multiple Sclerosis disease model."

Journal • Preclinical • CNS Disorders • Immunology • Inflammatory Arthritis • Multiple Sclerosis • Rheumatoid Arthritis • Rheumatology • IL6

Transcriptomic and metabolomic dissection of skeletal muscle of crossbred Chongming white goats with different meat production performance. (PubMed, BMC Genomics) - "This study benefits to dissection candidate genes and regulatory networks related to goat meat production performance, and the joint analysis of transcriptomic and metabolomic data provided insights into the study of goat muscle development."

Journal • Metabolic Disorders • FABP3 • LMO2 • MYBPC2 • TNNI3 • TNNT1 • TPM3

IHIBITION OF TRNA QUEUOSINE MODIFICATION CAUSE MITOCHONDRIAL DYSFUNCTION AND APOPTOSIS IN THE INTESTINAL EPITHELIAL CELLS (CCCongress 2024) - "Queuine tRNA-ribosyltransferase catalytic subunit 1 (QTRT1) and QTRT 2 co-localize in mitochondria and form a heterodimeric TGT participating in tRNA Queuosine (tRNA-Q) modification... Reduced QTRT1 induced dysfunctional mitochondria and Caspase-3 dependent apoptosis. tRNA-Q modification plays an unexplored role in the pathogenesis of mitochondrial function in the intestine. Our upcoming research will employ N-acetyl-l-cysteine, a mitochondrial ROS inhibitor, and a Caspase 3 specific inhibitor to ascertain the role of tRNA modification in mitochondrial function in the intestinal inflammation."

Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Metabolic Disorders • BAX • BCL2 • CASP3

Structural and functional insights into tRNA recognition by human tRNA guanine transglycosylase. (PubMed, Structure) - "Eukaryotic tRNA guanine transglycosylase (TGT) is an RNA-modifying enzyme which catalyzes the base exchange of the genetically encoded guanine 34 of tRNAs for queuine, a hypermodified 7-deazaguanine derivative...Here, we report a cryo-EM structure of eukaryotic TGT in complex with a complete tRNA, revealing the crucial role of the non-catalytic subunit in tRNA binding. We decipher the functional significance of these additional tRNA-binding sites, analyze solution state conformation, flexibility, and disorder of apo TGT, and examine conformational transitions upon tRNA binding."

Journal

Queuine as a potential multi-target drug for alzheimer's disease: insights from protein dynamics. (PubMed, J Biomol Struct Dyn) - "We propose that the neuroprotective effect of Queuine may stem from its prominent inhibitory action on enzymes BACE-1 and AChE. Our results suggest that Queuine may serve as a promising MTD candidate for the treatment of AD.Communicated by Ramaswamy H. Sarma."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Impacts of maternal microbiota and microbial metabolites on fetal intestine, brain, and placenta. (PubMed, BMC Biol) - "The maternal microbiota has a major impact on the developing fetus, with male fetuses potentially more susceptible to microbial modulation. The expression of genes important for the immune system, neurophysiology, translation, and energy metabolism are strongly affected by the maternal microbial status already before birth. These impacts are associated with microbially modulated metabolites. We identified several microbial metabolites which have not been previously observed in this context. Many of the potentially important metabolites remain to be identified."

Journal

Queuosine-tRNA promotes sex-dependent learning and memory formation by maintaining codon-biased translation elongation speed. (PubMed, EMBO J) - "In mammals, queuosinylation is facilitated by queuine uptake from the gut microbiota and is introduced into tRNA by the QTRT1-QTRT2 enzyme complex...Proteomics analysis confirmed deregulation of synaptogenesis and neuronal morphology. Together, our findings provide a link between tRNA modification and brain functions and reveal an unexpected role of protein synthesis in sex-dependent cognitive performance."

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Queuine analogues incorporating the 7-aminomethyl-7-deazaguanine core: structure-activity relationships in the treatment of experimental autoimmune encephalomyelitis. (PubMed, ChemMedChem) - "A library of queuine analogues targeting the modification of tRNA isoacceptors for Asp, Asn, His and Tyr catalysed by queuine tRNA ribosyltransferase (QTRT, also known as TGT) was evaluated in the treatment of a chronic multiple sclerosis model--murine experimental autoimmune encephalomyelitis. Several active 7-deazaguanines emerged, together with a structure activity relationship involving the necessity for a flexible alkyl chain of fixed length."

Journal • CNS Disorders • Immunology • Multiple Sclerosis