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The evolving biology of the proton‐coupled folate transporter: New insights into regulation, structure, and mechanism

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...

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Autores principales: Hou, Zhanjun, Gangjee, Aleem, Matherly, Larry H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8978580/
https://www.ncbi.nlm.nih.gov/pubmed/35061292
http://dx.doi.org/10.1096/fj.202101704R
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author Hou, Zhanjun
Gangjee, Aleem
Matherly, Larry H.
author_facet Hou, Zhanjun
Gangjee, Aleem
Matherly, Larry H.
author_sort Hou, Zhanjun
collection PubMed
description 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.
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spelling pubmed-89785802022-04-04 The evolving biology of the proton‐coupled folate transporter: New insights into regulation, structure, and mechanism Hou, Zhanjun Gangjee, Aleem Matherly, Larry H. FASEB J Reviews 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. John Wiley and Sons Inc. 2022-01-21 2022-02 /pmc/articles/PMC8978580/ /pubmed/35061292 http://dx.doi.org/10.1096/fj.202101704R Text en © 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Reviews
Hou, Zhanjun
Gangjee, Aleem
Matherly, Larry H.
The evolving biology of the proton‐coupled folate transporter: New insights into regulation, structure, and mechanism
title The evolving biology of the proton‐coupled folate transporter: New insights into regulation, structure, and mechanism
title_full The evolving biology of the proton‐coupled folate transporter: New insights into regulation, structure, and mechanism
title_fullStr The evolving biology of the proton‐coupled folate transporter: New insights into regulation, structure, and mechanism
title_full_unstemmed The evolving biology of the proton‐coupled folate transporter: New insights into regulation, structure, and mechanism
title_short The evolving biology of the proton‐coupled folate transporter: New insights into regulation, structure, and mechanism
title_sort evolving biology of the proton‐coupled folate transporter: new insights into regulation, structure, and mechanism
topic Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8978580/
https://www.ncbi.nlm.nih.gov/pubmed/35061292
http://dx.doi.org/10.1096/fj.202101704R
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