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Updated: May 21, 2025

Author Spotlight: Expression and Purification of Human Solute Carrier Transporters Using Codon-Optimized Genes
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Author Spotlight: Expression and Purification of Human Solute Carrier Transporters Using Codon-Optimized Genes

Published on: September 29, 2023

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Transport mechanism and drug discovery of human monocarboxylate transporter 1

Sai Shi1,2, Jia-Chen Li2, Xiao-Yu Zhou2

  • 1Department of Medical and Pharmaceutical Informatics, Hebei Medical University, Shijiazhuang, 050011, China.

Acta Pharmacologica Sinica
|March 18, 2025
PubMed

Insights

Researchers elucidated the lactate transport mechanism of monocarboxylate transporter 1 (MCT1), identifying silybin as a selective MCT1 inhibitor. This discovery offers a new strategy for developing targeted cancer therapies by inhibiting tumor cell glycolysis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Monocarboxylate transporters (MCTs) are vital for tumor cell glycolysis and immune response.
  • Understanding the molecular mechanism of MCT1-mediated lactate transport is crucial for developing targeted cancer therapies.
  • The precise mechanism of lactate transport by MCT1 has remained elusive.

Purpose of the Study:

  • To elucidate the allosteric mechanisms and lactate transport mechanism of human MCT1.
  • To identify selective inhibitors of MCT1 for potential anticancer drug development.

Main Methods:

  • Principal component analysis and enhanced sampling to study MCT family allosteric mechanisms.
  • Quantum chemical calculations and umbrella sampling to determine lactate and proton co-transport mechanism.
  • Drug screening targeting MCT1's core pocket.

Main Results:

  • Identified key residue pairs (E46-K289, E376-R143) essential for MCT1 conformational changes.
  • Demonstrated sequential co-transport of lactate and protons by MCT1, involving residues K38 and R313.
  • Discovered silybin as a selective MCT1 inhibitor with significant effects on tumor cells expressing high MCT1 levels.

Conclusions:

  • Provided a comprehensive understanding of MCT1's lactate transport mechanism.
  • Laid the groundwork for rational drug design targeting MCT1 for anticancer therapies.
  • Silybin shows promise as a selective MCT1 inhibitor for treating cancers with high MCT1 expression.
Keywords:
MCT1allosteric mechanismdrug discoverymonocarboxylate transportersilybin

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