Open AccessStructural basis of antifolate recognition and transport by PCFT
Author(s) -
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
Publication year - 2021
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-021-03579-z
Subject(s) - antifolate , biochemistry , pemetrexed , biology , chemistry , genetics , antimetabolite , cancer , chemotherapy , cisplatin
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.