ArticleThe Biochemical journal2020
Functional analysis of a species-specific inhibitor selective for human Na+-coupled citrate transporter (NaCT/SLC13A5/mINDY).
Article in The Biochemical journal, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 24 citations in OpenAlex.
- Structures of the human sodium-citrate cotransporter NaCT with and without substrates.bioRxiv : the preprint server for biology · 2026Article
- Technology-enabled insights into SLC transporters in MAFLD: redefining the multi-hit pathogenesis and therapeutic landscape.Acta pharmacologica Sinica · 2026Review
- Discovery and Characterization of a Nonacidic Small-Molecule Inhibitor of the Sodium-Coupled Dicarboxylate Transporter NaCT.Journal of medicinal chemistry · 2026Article
- Cryo-EM structures reveal the HLife science alliance · 2025Article
- Molecular Phenotypes Segregate Missense Mutations in SLC13A5 Epilepsy.Journal of molecular biology · 2024Article
- Role of sodium dependent SLC13 transporter inhibitors in various metabolic disorders.Molecular and cellular biochemistry · 2023Review
- Mapping the Metabolic Niche of Citrate Metabolism andMetabolites · 2023Review
- A Novel and Cross-Species Active Mammalian INDY (NaCT) Inhibitor Ameliorates Hepatic Steatosis in Mice with Diet-Induced Obesity.Metabolites · 2022Article
- Untargeted Metabolomics of Slc13a5 Deficiency Reveal Critical Liver-Brain Axis for Lipid Homeostasis.Metabolites · 2022Article
- L-Arginine and Cardioactive Arginine Derivatives as Substrates and Inhibitors of Human and Mouse NaCT/Nact.Metabolites · 2022Article
- Review
- A home run for human NaCT/SLC13A5/INDY: cryo-EM structure and homology model to predict transport mechanisms, inhibitor interactions and mutational defects.The Biochemical journal · 2021Article
- Consequences of NaCT/SLC13A5/mINDY deficiency: good versus evil, separated only by the blood-brain barrier.The Biochemical journal · 2021Review
- INDY-From Flies to Worms, Mice, Rats, Non-Human Primates, and Humans.Frontiers in aging · 2021Review
- The growing research toolbox for SLC13A5 citrate transporter disorder: a rare disease with animal models, cell lines, an ongoing Natural History Study and an engaged patient advocacy organization.Therapeutic advances in rare diseaseReview
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Na+-coupled citrate transporter (NaCT/SLC13A5/mINDY) in the liver delivers citrate from the blood into hepatocytes. As citrate is a key metabolite and regulator of multiple biochemical pathways, deletion of Slc13a5 in mice protects against diet-induced obesity, diabetes, and metabolic syndrome. Silencing the transporter suppresses hepatocellular carcinoma. Therefore, selective blockers of NaCT hold the potential to treat various diseases. Here we report on the characteristics of one such inhibitor, BI01383298. It is known that BI01383298 is a high-affinity inhibitor selective for human NaCT with no effect on mouse NaCT. Here we show that this compound is an irreversible and non-competitive inhibitor of human NaCT, thus describing the first irreversible inhibitor for this transporter. The mouse NaCT is not affected by this compound. The inhibition of human NaCT by BI01383298 is evident for the constitutively expressed transporter in HepG2 cells and for the ectopically expressed human NaCT in HEK293 cells. The IC50 is ∼100 nM, representing the highest potency among the NaCT inhibitors known to date. Exposure of HepG2 cells to this inhibitor results in decreased cell proliferation. We performed molecular modeling of the 3D-structures of human and mouse NaCTs using the crystal structure of a humanized variant of VcINDY as the template, and docking studies to identify the amino acid residues involved in the binding of citrate and BI01383298. These studies provide insight into the probable bases for the differential effects of the inhibitor on human NaCT versus mouse NaCT as well as for the marked species-specific difference in citrate affinity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.