Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3
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.
Authors
- Yong Wang (ORCID: https://orcid.org/0000-0003-1100-697X)
- Yalan Zhu
- Songqin Liu (ORCID: https://orcid.org/0000-0002-4686-5291)
- Qianhui Qu (ORCID: https://orcid.org/0000-0002-5753-2599)
- Yina Gao
- Yulin Chao (ORCID: https://orcid.org/0009-0005-2230-1167)
- Pu Gao (ORCID: https://orcid.org/0000-0002-5328-9755)
- Chuanhui Yang (ORCID: https://orcid.org/0009-0002-4084-1966)
- Peipei Li (ORCID: https://orcid.org/0009-0002-6665-7526)
- Liguo Zhang (ORCID: https://orcid.org/0000-0002-9795-0314)
- Xuyuan Zhang (ORCID: https://orcid.org/0000-0002-6305-1556)
- Zixuan Zhou (ORCID: https://orcid.org/0000-0002-6004-182X)
- Yonghui Long (ORCID: https://orcid.org/0000-0001-6412-8415)
- Zhini Zhu (ORCID: https://orcid.org/0009-0001-8750-7300)
Institutions
- Beijing Institute of Technology (CN)
- Chinese Academy of Sciences (CN)
- Fudan University (CN)
- Eye & ENT Hospital of Fudan University (CN)
- Institute of Biophysics (CN)
- Ministry of Science and Technology (LA)
- Shandong First Medical University (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-12-30
- DOI
- https://doi.org/10.1038/s41467-024-55359-8
- Citations
- 13
- Primary Topic
- Alcoholism and Thiamine Deficiency
- Type
- article
- Field-Weighted Citation Impact
- 4.80
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Fudan University
- National Science and Technology Major Project
- Institute of Biophysics, Chinese Academy of Sciences
- Shanghai Medical College, Fudan University