Potent Immunomodulators Developed from an Unstable Bacterial Metabolite of Vitamin B2 Biosynthesis

JYW Mak; RJD Rivero; HN Hoang; XY Lim; J Deng; HEG McWilliam; JA Villadangos; J McCluskey; AJ Corbett; DP Fairlie

Journal article

Potent Immunomodulators Developed from an Unstable Bacterial Metabolite of Vitamin B2 Biosynthesis

JYW Mak, RJD Rivero, HN Hoang, XY Lim, J Deng, HEG McWilliam, JA Villadangos, J McCluskey, AJ Corbett, DP Fairlie

Angewandte Chemie International Edition | WILEY-V C H VERLAG GMBH | Published : 2024

DOI: 10.1002/anie.202400632

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Abstract

Bacterial synthesis of vitamin B2 generates a by-product, 5-(2-oxopropylideneamino)-d-ribityl-aminouracil (5-OP-RU), with potent immunological properties in mammals, but it is rapidly degraded in water. This natural product covalently bonds to the key immunological protein MR1 in the endoplasmic reticulum of antigen presenting cells (APCs), enabling MR1 refolding and trafficking to the cell surface, where it interacts with T cell receptors (TCRs) on mucosal associated invariant T lymphocytes (MAIT cells), activating their immunological and antimicrobial properties. Here, we strategically modify this natural product to understand the molecular basis of its recognition by MR1. This culminated ..

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University of Melbourne Researchers

Jieru Deng Author

Hamish McWilliam Author

Jose Villadangos Author

McCluskey James Author

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Awarded by University of Melbourne

Funding Acknowledgements

We acknowledge grant support from University of Queensland UQECR1834385 (JYWM), Australian Research Council Centres of Excellence in Advanced Molecular Imaging CE140100011 and Innovations for Peptide and Protein Science CE200100012 (DPF), the Australian National Health and Medical Research Council of Australia for a Senior Principal fellowship 1117017 (DPF), Investigator fellowships 2009551 (DPF) and 1193745 (AJC), and an Ideas grant 2003192 (HMcW). JAV acknowledges grants from NHMRC (1113293, 1154502, 2016969) and ARC (DP170102471). AJC is supported by a Dame Kate Campbell Fellowship from University of Melbourne. JMc, JAV and DPF are supported by the US National Institutes of Health RO1 AI14807-01A1. Figure 2a was created with BioRender. Open Access publishing facilitated by The University of Queensland, as part of the Wiley - The University of Queensland agreement via the Council of Australian University Librarians.