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PreprintCited by 17Drug Transport and Resistance MechanismsBiochemical Acid Research StudiesAlcoholism and Thiamine Deficiency

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Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3

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Qu, Qianhui, Li, Peipei, Zhu, Zhini, Wang, Yong, Zhang, Xuyuan, Zhou, Zixuan, Zhu, Yalan, Chao, Yulin, Long, Yonghui, Liu, Songqing, Zhang, Liguo, Gao, Pu·2024·Nature Communications
DOI 10.21203/rs.3.rs-4363986/v1PMC PMC11686366

Preprint — published as 10.1038/s41467-024-55359-8 · Paper page

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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 drug-nutrient interactions mediated by thiamine transporters.

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Metadata

Authors
Qu, Q., Li, P., Zhu, Z., Wang, Y., Zhang, X., Zhou, Z., Zhu, Y., Chao, Y., Long, Y., Liu, S., Zhang, L., & Gao, P.
Affiliations
  • Shanghai Medical College of Fudan University (CN)
  • Chinese Academy of Sciences (CN)
  • Beijing Institute of Technology (CN)
  • Institute of Biophysics, Chinese Academy of Sciences
Corresponding author
  • Qu, Qianhui
  • Wang, Yong
  • Zhang, Liguo
  • Gao, Pu
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-06-27
Volume
15
Issue
1
Pages
10924-10924
ISSN
2041-1723 (ISSN-L)
DOI
10.21203/rs.3.rs-4363986/v1
PMC
PMC11686366
OpenAlex
W4405895626
Cited by
17
References
1
Citations by year
2026: 7 · 2025: 10
FWCI
2.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Natural Science Foundation of China (32130057, 32371256, 32171194, 32325028)
  • Chinese Academy of Sciences (YSBR-074, XDB37030203)
  • Fudan University
  • National Science and Technology Major Project
  • Institute of Biophysics, Chinese Academy of Sciences
  • Shanghai Medical College, Fudan University
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
  • Health Sciences › Medicine › Clinical Neurology › Alcoholism and Thiamine Deficiency
Keywords
thiamine transporter, SLC19A2, SLC19A3, thiamine, pyridoxine, B vitamins, drug-nutrient interactions, metformin, fedratinib, amprolium, transporter conformational change, substrate recognition, translocation mechanism, cryo-EM structure, thiamine deficiency, vitamin B6 deficiency, neurometabolic disorders
MeSH terms
Biological Transport, Humans, Metformin, Models, Molecular, Pyridoxine, Pyrrolidines, Thiamine, Cryoelectron Microscopy, Membrane Transport Proteins, HEK293 Cells

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