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Structural basis of antifolate recognition and transport by PCFT

Author

Listed:
  • Joanne L. Parker

    (University of Oxford)

  • Justin C. Deme

    (University of Oxford
    University of Oxford
    National Cancer Institute)

  • Gabriel Kuteyi

    (University of Oxford)

  • Zhiyi Wu

    (University of Oxford)

  • Jiandong Huo

    (The Rosalind Franklin Institute
    University of Oxford
    The Research Complex at Harwell)

  • I. David Goldman

    (Albert Einstein College of Medicine)

  • Raymond J. Owens

    (The Rosalind Franklin Institute
    University of Oxford
    The Research Complex at Harwell)

  • Philip C. Biggin

    (University of Oxford)

  • Susan M. Lea

    (University of Oxford
    University of Oxford
    National Cancer Institute)

  • Simon Newstead

    (University of Oxford
    University of Oxford)

Abstract

Folates (also known as vitamin B9) have a critical role in cellular metabolism as the starting point in the synthesis of nucleic acids, amino acids and the universal methylating agent S-adenylsmethionine1,2. Folate deficiency is associated with a number of developmental, immune and neurological disorders3–5. Mammals cannot synthesize folates de novo; several systems have therefore evolved to take up folates from the diet and distribute them within the body3,6. The proton-coupled folate transporter (PCFT) (also known as SLC46A1) mediates folate uptake across the intestinal brush border membrane and the choroid plexus4,7, and is an important route for the delivery of antifolate drugs in cancer chemotherapy8–10. How PCFT recognizes folates or antifolate agents is currently unclear. Here we present cryo-electron microscopy structures of PCFT in a substrate-free state and in complex with a new-generation antifolate drug (pemetrexed). Our results provide a structural basis for understanding antifolate recognition and provide insights into the pH-regulated mechanism of folate transport mediated by PCFT.

Suggested Citation

  • Joanne L. Parker & Justin C. Deme & Gabriel Kuteyi & Zhiyi Wu & Jiandong Huo & I. David Goldman & Raymond J. Owens & Philip C. Biggin & Susan M. Lea & Simon Newstead, 2021. "Structural basis of antifolate recognition and transport by PCFT," Nature, Nature, vol. 595(7865), pages 130-134, July.
    • Handle: RePEc:nat:nature:v:595:y:2021:i:7865:d:10.1038_s41586-021-03579-z
    DOI: 10.1038/s41586-021-03579-z
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    Cited by:

    1. Yi C. Zeng & Meghna Sobti & Ada Quinn & Nicola J. Smith & Simon H. J. Brown & Jamie I. Vandenberg & Renae M. Ryan & Megan L. O’Mara & Alastair G. Stewart, 2023. "Structural basis of promiscuous substrate transport by Organic Cation Transporter 1," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Dohyun Im & Mika Jormakka & Narinobu Juge & Jun-ichi Kishikawa & Takayuki Kato & Yukihiko Sugita & Takeshi Noda & Tomoko Uemura & Yuki Shiimura & Takaaki Miyaji & Hidetsugu Asada & So Iwata, 2024. "Neurotransmitter recognition by human vesicular monoamine transporter 2," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

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