The evolving biology of the proton-coupled folate transporter: New insights into regulation, structure, and mechanism.
antifolate
major facilitator superfamily
membrane transporter
proton-coupled folate transporter
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
revised:
15
12
2021
received:
10
11
2021
accepted:
03
01
2022
entrez:
21
1
2022
pubmed:
22
1
2022
medline:
15
2
2022
Statut:
ppublish
Résumé
The human proton-coupled folate transporter (PCFT; SLC46A1) or hPCFT was identified in 2006 as the principal folate transporter involved in the intestinal absorption of dietary folates. A rare autosomal recessive hereditary folate malabsorption syndrome is attributable to human SLC46A1 variants. The recognition that hPCFT was highly expressed in many tumors stimulated substantial interest in its potential for cytotoxic drug targeting, taking advantage of its high-level transport activity under acidic pH conditions that characterize many tumors and its modest expression in most normal tissues. To better understand the basis for variations in hPCFT levels between tissues including human tumors, studies have examined the transcriptional regulation of hPCFT including the roles of CpG hypermethylation and critical transcription factors and cis elements. Additional focus involved identifying key structural and functional determinants of hPCFT transport that, combined with homology models based on structural homologies to the bacterial transporters GlpT and LacY, have enabled new structural and mechanistic insights. Recently, cryo-electron microscopy structures of chicken PCFT in a substrate-free state and in complex with the antifolate pemetrexed were reported, providing further structural insights into determinants of (anti)folate recognition and the mechanism of pH-regulated (anti)folate transport by PCFT. Like many major facilitator proteins, hPCFT exists as a homo-oligomer, and evidence suggests that homo-oligomerization of hPCFT monomeric proteins may be important for its intracellular trafficking and/or transport function. Better understanding of the structure, function and regulation of hPCFT should facilitate the rational development of new therapeutic strategies for conditions associated with folate deficiency, as well as cancer.
Identifiants
pubmed: 35061292
doi: 10.1096/fj.202101704R
pmc: PMC8978580
mid: NIHMS1789301
doi:
Substances chimiques
Folic Acid Antagonists
0
Proton-Coupled Folate Transporter
0
Transcription Factors
0
Folic Acid
935E97BOY8
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
e22164Subventions
Organisme : NCI NIH HHS
ID : R01 CA053535
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA250469
Pays : United States
Informations de copyright
© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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