Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3
Abstract Thiamine and pyridoxine are essential B vitamins that serve as enzymatic cofactors in energy metabolism, protein and nucleic acid biosynthesis, and neurotransmitter production. In humans, thiamine transporters SLC19A2 and SLC19A3 primarily regulate cellular uptake of both vitamins. Genetic...
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55359-8 |
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| author | Peipei Li Zhini Zhu Yong Wang Xuyuan Zhang Chuanhui Yang Yalan Zhu Zixuan Zhou Yulin Chao Yonghui Long Yina Gao Songqing Liu Liguo Zhang Pu Gao Qianhui Qu |
| author_facet | Peipei Li Zhini Zhu Yong Wang Xuyuan Zhang Chuanhui Yang Yalan Zhu Zixuan Zhou Yulin Chao Yonghui Long Yina Gao Songqing Liu Liguo Zhang Pu Gao Qianhui Qu |
| author_sort | Peipei Li |
| collection | DOAJ |
| description | Abstract Thiamine and pyridoxine are essential B vitamins that serve as enzymatic cofactors in energy metabolism, protein and nucleic acid biosynthesis, and neurotransmitter production. In humans, thiamine transporters SLC19A2 and SLC19A3 primarily regulate cellular uptake of both vitamins. Genetic mutations in these transporters, which cause thiamine and pyridoxine deficiency, have been implicated in severe neurometabolic diseases. Additionally, various prescribed medicines, including metformin and fedratinib, manipulate thiamine transporters, complicating the therapeutic effect. Despite their physiological and pharmacological significance, the molecular underpinnings of substrate and drug recognition remain unknown. Here we present ten cryo-EM structures of human thiamine transporters SLC19A3 and SLC19A2 in outward- and inward-facing conformations, complexed with thiamine, pyridoxine, metformin, fedratinib, and amprolium. These structural insights, combined with functional characterizations, illuminate the translocation mechanism of diverse chemical entities, and enhance our understanding of drug-nutrient interactions mediated by thiamine transporters. |
| format | Article |
| id | doaj-art-d5c1e1d6b6614fbf83a041512441b9eb |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d5c1e1d6b6614fbf83a041512441b9eb2025-01-05T12:34:50ZengNature PortfolioNature Communications2041-17232024-12-0115111310.1038/s41467-024-55359-8Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3Peipei Li0Zhini Zhu1Yong Wang2Xuyuan Zhang3Chuanhui Yang4Yalan Zhu5Zixuan Zhou6Yulin Chao7Yonghui Long8Yina Gao9Songqing Liu10Liguo Zhang11Pu Gao12Qianhui Qu13ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Department of Systems Biology for Medicine, Fudan UniversityENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Department of Systems Biology for Medicine, Fudan UniversityKey Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of SciencesKey Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of SciencesENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Department of Systems Biology for Medicine, Fudan UniversitySchool of Life Sciences, Beijing Institute of TechnologyENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Department of Systems Biology for Medicine, Fudan UniversityENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Department of Systems Biology for Medicine, Fudan UniversityENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Department of Systems Biology for Medicine, Fudan UniversityKey Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of SciencesKey Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of SciencesKey Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of SciencesKey Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of SciencesENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, Institutes of Biomedical Sciences, Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Department of Systems Biology for Medicine, Fudan UniversityAbstract Thiamine and pyridoxine are essential B vitamins that serve as enzymatic cofactors in energy metabolism, protein and nucleic acid biosynthesis, and neurotransmitter production. In humans, thiamine transporters SLC19A2 and SLC19A3 primarily regulate cellular uptake of both vitamins. Genetic mutations in these transporters, which cause thiamine and pyridoxine deficiency, have been implicated in severe neurometabolic diseases. Additionally, various prescribed medicines, including metformin and fedratinib, manipulate thiamine transporters, complicating the therapeutic effect. Despite their physiological and pharmacological significance, the molecular underpinnings of substrate and drug recognition remain unknown. Here we present ten cryo-EM structures of human thiamine transporters SLC19A3 and SLC19A2 in outward- and inward-facing conformations, complexed with thiamine, pyridoxine, metformin, fedratinib, and amprolium. These structural insights, combined with functional characterizations, illuminate the translocation mechanism of diverse chemical entities, and enhance our understanding of drug-nutrient interactions mediated by thiamine transporters.https://doi.org/10.1038/s41467-024-55359-8 |
| spellingShingle | Peipei Li Zhini Zhu Yong Wang Xuyuan Zhang Chuanhui Yang Yalan Zhu Zixuan Zhou Yulin Chao Yonghui Long Yina Gao Songqing Liu Liguo Zhang Pu Gao Qianhui Qu Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3 Nature Communications |
| title | Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3 |
| title_full | Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3 |
| title_fullStr | Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3 |
| title_full_unstemmed | Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3 |
| title_short | Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3 |
| title_sort | substrate transport and drug interaction of human thiamine transporters slc19a2 a3 |
| url | https://doi.org/10.1038/s41467-024-55359-8 |
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