Study of queuosine salvage and function in eukaryotes; a forgotten micronutrient
Lead Research Organisation:
Queen's University Belfast
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
Queuine is the only micronutrient that directly affects translation efficiency and accuracy in eukaryotes, with roles in metabolism and healthy-aging of the brain (Fig. 1). It is a precursor of the tRNA modification Queuosine (Q) and is exclusively retrieved from ingested food or provided by the gut microbiota1. The Q modification is found at the wobble base (position 34) of cytoplasmic and mitochondrial tRNAs for the amino acids Tyr, Asp, Asn and His. Absence of Q in tRNAs of mice or human HepG2 cells lowers biopterin (BH4) pools and leads to serious tyrosine metabolic defect and eventually death2, highlighting the importance of Q in mammalian physiology. Cognisant of the fact that tRNA of rapidly-proliferating cells is hypomodified with respect to Q, chemical analogues have been developed that induce complete remission of multiple sclerosis in an animal model3. The realization that tRNA modifications are associated with neurological and mitochondrial diseases4–6 has led to renewed interest and in the biosynthesis and function of Q1. A common goal of the Crécy and Kelly laboratories is to characterize the Q synthesis pathways and explore the functional importance of this modification in all kingdoms of life, leading to 15 publications and laying the groundwork for this proposal. The bacterial Q synthesis pathway and the human tRNA Q addition enzyme, tRNA-guanine transglycosylase (hTGT), are well characterized7,8.
However, many gaps in knowledge of eukaryotic Q metabolism remain1. These include unknown transporters, hydrolases and sugar transferases. The lead PIs have gathered a multidisciplinary team taking advantage of the US-Ireland R&D Partnership, where funds are provided by each jurisdiction for their investigations (see commitment letters), to identify the “missing” human players in Q biosynthesis and elucidate the biologicalrole of this overlooked micronutrient in metabolism and neuronal function.
However, many gaps in knowledge of eukaryotic Q metabolism remain1. These include unknown transporters, hydrolases and sugar transferases. The lead PIs have gathered a multidisciplinary team taking advantage of the US-Ireland R&D Partnership, where funds are provided by each jurisdiction for their investigations (see commitment letters), to identify the “missing” human players in Q biosynthesis and elucidate the biologicalrole of this overlooked micronutrient in metabolism and neuronal function.
Publications
Dixit S
(2021)
Dynamic queuosine changes in tRNA couple nutrient levels to codon choice in Trypanosoma brucei.
in Nucleic acids research
Hung SH
(2023)
Structural basis of Qng1-mediated salvage of the micronutrient queuine from queuosine-5'-monophosphate as the biological substrate.
in Nucleic acids research
Description | (CITI-GENS) - Collaboration In Training and Innovation for Growing, Evolving and Networked Societies |
Amount | € 3,254,400 (EUR) |
Funding ID | 945231 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 03/2020 |
End | 03/2025 |
Description | Are the impairments of arginine metabolism as found in Alzheimer's disease also present in patients developing post-operative delirium and cognitive decline? |
Amount | $1,054,957 (USD) |
Organisation | National Institutes of Health (NIH) |
Department | National Institute on Aging |
Sector | Public |
Country | United States |
Start | 09/2020 |
End | 10/2022 |
Title | LC-MS/MS method for detecting and quantifying queuine and queuosine. |
Description | We have developed a method for quantifying both queuine and queuine simultaneously. It can do this in precise and accurate manner and it performs well in samples derived from cells. |
Type Of Material | Technology assay or reagent |
Year Produced | 2020 |
Provided To Others? | No |
Impact | We have only recently commenced the project but we have some generated data, it will require further cell studies and replications before we will have sufficient data for a publication. |
Description | Bioinformatics of proteins involved in queuine or queuosine metabolism |
Organisation | University of Florida |
Country | United States |
Sector | Academic/University |
PI Contribution | My group will soon be testing the protein candidate suggestions identifies by bioinformatic techniques. |
Collaborator Contribution | Prof Valerie de Crecy Legard's group are performing bioinformatic searching techniques to identify proteins/enzymes involved in queuine or queuosine metabolism |
Impact | No outputs or outcome as yet - project still in the early stages. |
Start Year | 2019 |
Description | British and Irish Longitudinal Studies of ageing |
Organisation | Trinity College Dublin |
Department | Discipline of Medical Gerontology |
Country | Ireland |
Sector | Academic/University |
PI Contribution | My group provide the metabolomics and data analysis support to this consortium. We have collectively submitted a large scale funding application, for which my group will lead one of the proposed WPs. |
Collaborator Contribution | This unique team emerged from collaborative discussions between PI/CoIs of three nationally representative British Isles Longitudinal Studies (ELSA, NICOLA and TILDA). Collectively we offer both systems-based expertise and an interdisciplinary approach through a collaboration between Bioanalytical, Social, and Health Scientists, with expertise in population epidemiology, social and medical gerontology, molecular network analysis and systems biology. |
Impact | Submission of a BBSRC grant proposal for the establishment of a consortia of British and Irish Longitudinal Studies of ageing using unique longitudinal interdisciplinary data on human ageing, with repositories of biological samples and/or derived data to examine the influence of key exposures of nutritional status (WP 1), physiological capacity (WP 2) and stress (WP 3) on trajectories in the pillars of healthy ageing. We will then use metabolomic (WP 4) and genetic (WP 5) profiles and to identify precise biological mechanisms that mediate the relationship between later life health and these exposures (WP 6). |
Start Year | 2015 |
Description | British and Irish Longitudinal Studies of ageing |
Organisation | University of Manchester |
Department | Manchester Interdisciplinary Biocentre |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | My group provide the metabolomics and data analysis support to this consortium. We have collectively submitted a large scale funding application, for which my group will lead one of the proposed WPs. |
Collaborator Contribution | This unique team emerged from collaborative discussions between PI/CoIs of three nationally representative British Isles Longitudinal Studies (ELSA, NICOLA and TILDA). Collectively we offer both systems-based expertise and an interdisciplinary approach through a collaboration between Bioanalytical, Social, and Health Scientists, with expertise in population epidemiology, social and medical gerontology, molecular network analysis and systems biology. |
Impact | Submission of a BBSRC grant proposal for the establishment of a consortia of British and Irish Longitudinal Studies of ageing using unique longitudinal interdisciplinary data on human ageing, with repositories of biological samples and/or derived data to examine the influence of key exposures of nutritional status (WP 1), physiological capacity (WP 2) and stress (WP 3) on trajectories in the pillars of healthy ageing. We will then use metabolomic (WP 4) and genetic (WP 5) profiles and to identify precise biological mechanisms that mediate the relationship between later life health and these exposures (WP 6). |
Start Year | 2015 |
Description | British and Irish Longitudinal Studies of ageing |
Organisation | University of Manchester |
Department | School of Chemistry Manchester |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | My group provide the metabolomics and data analysis support to this consortium. We have collectively submitted a large scale funding application, for which my group will lead one of the proposed WPs. |
Collaborator Contribution | This unique team emerged from collaborative discussions between PI/CoIs of three nationally representative British Isles Longitudinal Studies (ELSA, NICOLA and TILDA). Collectively we offer both systems-based expertise and an interdisciplinary approach through a collaboration between Bioanalytical, Social, and Health Scientists, with expertise in population epidemiology, social and medical gerontology, molecular network analysis and systems biology. |
Impact | Submission of a BBSRC grant proposal for the establishment of a consortia of British and Irish Longitudinal Studies of ageing using unique longitudinal interdisciplinary data on human ageing, with repositories of biological samples and/or derived data to examine the influence of key exposures of nutritional status (WP 1), physiological capacity (WP 2) and stress (WP 3) on trajectories in the pillars of healthy ageing. We will then use metabolomic (WP 4) and genetic (WP 5) profiles and to identify precise biological mechanisms that mediate the relationship between later life health and these exposures (WP 6). |
Start Year | 2015 |
Description | Cell-based studies of queuine and queuosine transport and metabolism |
Organisation | Trinity College Dublin |
Country | Ireland |
Sector | Academic/University |
PI Contribution | My group have developed a bespoke method for accurately measuring the levels of queuine and queuosine (q&Q). We have extracted and analysed a large number of samples from Trinity College Dublin, to determine the mechanism of q & Q uptake and incorporation. This is very helpful to the aims of the project. |
Collaborator Contribution | Prof Vincent Kelly's group in TCD are performing studies in human cells and are providing samples to us. |
Impact | We are in the early stages of the project and there are as yet no outputs. However, in terms of outcomes we have demonstrated that human cells take up and convert queuine to queuosine, and we have also demonstrated the occurence of natural stereoisomers of queuosine - something which has not been dicovered befor. |
Start Year | 2019 |
Description | Identifying the enzyme responsible for queuine and queuosine. |
Organisation | San Deigo State University |
Country | United States |
Sector | Academic/University |
PI Contribution | My group are utilising purified proteins provided by SDSU to perform experiments which determine whether queuine or queuosine are structurally modified by the presence of these. |
Collaborator Contribution | Dr Manal Swairjo's laboratory are synthesising, purifying and supplying proteins which are enzyme candidates for modifying queuine or queuosine. |
Impact | No outputs or outcomes yet, but this is a recently commenced collaboration. |
Start Year | 2020 |
Description | Mapping shifts in the brain lipidome during the development and progression of Alzheimer's disease |
Organisation | King's College London |
Department | Randall Division of Cell & Molecular Biophysics |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Myself and my team have co-written a grant proposal with the King's College group which is currently undergoing peer-review. We seek to develop an open-access database mapping shifts in the brain lipidome during the development and progression of Alzheimer's disease. |
Collaborator Contribution | The Legido-Quigley group have put extensive efforts into this new collaboration and have provided support in terms of post-doctoral researcher time for the scoping and writing of the proposal. The group have all shared their bespoke methods with us which we hope to independently validate for them. |
Impact | Early stages - the writing and submission of a competitive grant proposal. |
Start Year | 2016 |
Company Name | Aramune Technologies |
Description | Aramune Technologies develops aramune, a immune-boosting compound, for farm animal feed. |
Year Established | 2021 |
Impact | Recently formed company, and has not yet had impact. |
Website | http://www.qubis.co.uk |
Description | Enrollment in BBSRC ICURe programme to explore commercialisation of the the methods developed during the project. |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Reaching out to as many potential users of the technology developed, inquiring about its utility in the policy/economy, holding up to 100 conversations and performing 'digital testing' to better understand the commercialization options. |
Year(s) Of Engagement Activity | 2023 |
URL | https://www.icureprogramme.com/ |