Structural basis of antifolate recognition and transport by PCFT.

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-adenylsmethionine^1,2. Folate deficiency is associated with a number of developmental, immune and neurological disorders^3-5. Mammals cannot synthesize folates de novo; several systems have therefore evolved to take up folates from the diet and distribute them within the body^3,6. The proton-coupled folate transporter (PCFT) (also known as SLC46A1) mediates folate uptake across the intestinal brush border membrane and the choroid plexus^4,7, and is an important route for the delivery of antifolate drugs in cancer chemotherapy^8-10. 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.

SUBMITTER: Parker JL 

PROVIDER: S-EPMC9990147 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature