Proton-coupled folate transporter

Definition:

Proton-coupled folate symporter that mediates folate absorption using an H(+) gradient as a driving force. Involved in the intestinal absorption of folates at the brush-border membrane of the proximal jejunum, and the transport from blood to cerebrospinal fluid across the choroid plexus. Functions at acidic pH via alternate outward- and inward-open conformation states. Protonation of residues in the outward open state primes the protein for transport. Binding of folate promotes breaking of salt bridge network and subsequent closure of the extracellular gate, leading to the inward-open state and release of protons and folate. Also able to transport antifolate drugs, such as methotrexate and pemetrexed, which are established treatments for cancer and autoimmune diseases. Involved in FOLR1-mediated endocytosis by serving as a route of export of folates from acidified endosomes. Also acts as a lower-affinity, pH-independent heme carrier protein and constitutes the main importer of heme in the intestine. Imports heme in the retina and retinal pigment epithelium, in neurons of the hippocampus, in hepatocytes and in the renal epithelial cells. Hence, participates in the trafficking of heme and increases intracellular iron content.; [Isoform 2]: Inactive isoform which is not able to mediate proton-coupled folate transport.

References:

[1]. Srinivas Aluri, et al. Residues in the eighth transmembrane domain of the proton-coupled folate transporter (SLC46A1) play an important role in defining the aqueous translocation pathway and in folate substrate binding. Biochim Biophys Acta Biomembr. 2017 Nov;1859(11):2193-2202. [Content Brief]

[2]. Joanne L Parker, et al. Structural basis of antifolate recognition and transport by PCFT. Nature. 2021 Jul;595(7865):130-134. [Content Brief]

[3]. Hongxia Li, et al. SLC46A1 contributes to hepatic iron metabolism by importing heme in hepatocytes. Metabolism. 2020 Sep;110:154306. [Content Brief]

[4]. Gladys O Latunde-Dada, et al. Haem carrier protein 1 (HCP1): Expression and functional studies in cultured cells. FEBS Lett. 2006 Dec 22;580(30):6865-70. [Content Brief]

[5]. Andong Qiu, et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006 Dec 1;127(5):917-28. [Content Brief]

[6]. Miriam Erlacher, et al. Reversible pancytopenia and immunodeficiency in a patient with hereditary folate malabsorption. Pediatr Blood Cancer. 2015 Jun;62(6):1091-4. [Content Brief]

[7]. Tomoya Narawa, et al. Functional role of serine 318 of the proton-coupled folate transporter in methotrexate transport. Drug Metab Pharmacokinet. 2021 Dec;41:100421. [Content Brief]

[8]. Rongbao Zhao, et al. A role for the proton-coupled folate transporter (PCFT-SLC46A1) in folate receptor-mediated endocytosis. J Biol Chem. 2009 Feb 13;284(7):4267-74. [Content Brief]

[9]. Srinivas Aluri, et al. Hereditary folate malabsorption due to a mutation in the external gate of the proton-coupled folate transporter SLC46A1. Blood Adv. 2018 Jan 5;2(1):61-68. [Content Brief]

[10]. Srinivas Aluri, et al. Substitutions that lock and unlock the proton-coupled folate transporter (PCFT-SLC46A1) in an inward-open conformation. J Biol Chem. 2019 May 3;294(18):7245-7258. [Content Brief]

[11]. Takahiro Yamashiro, et al. Identification of the amino acid residue responsible for the myricetin sensitivity of human proton-coupled folate transporter. Sci Rep. 2019 Dec 2;9(1):18105. [Content Brief]

[12]. Rongbao Zhao, et al. Concentrative Transport of Antifolates Mediated by the Proton-Coupled Folate Transporter (SLC46A1); Augmentation by a HEPES Buffer. Mol Pharmacol. 2018 Mar;93(3):208-215. [Content Brief]

[13]. He-Qin Zhan, et al. A proton-coupled folate transporter mutation causing hereditary folate malabsorption locks the protein in an inward-open conformation. J Biol Chem. 2020 Nov 13;295(46):15650-15661. [Content Brief]

[14]. Rongbao Zhao, et al. The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier. Mol Pharmacol. 2008 Sep;74(3):854-62. [Content Brief]

[15]. Rongbao Zhao, et al. The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. Blood. 2007 Aug 15;110(4):1147-52. [Content Brief]

[16]. Yusuke Tozawa, et al. A deep intronic mutation of c.1166-285 T > G in SLC46A1 is shared by four unrelated Japanese patients with hereditary folate malabsorption (HFM). Clin Immunol. 2019 Nov;208:108256. [Content Brief]

[17]. Bradley L Urquhart, et al. The human proton-coupled folate transporter (hPCFT): modulation of intestinal expression and function by drugs. Am J Physiol Gastrointest Liver Physiol. 2010 Feb;298(2):G248-54. [Content Brief]

[18]. Ersin Selcuk Unal, et al. The functional roles of the His247 and His281 residues in folate and proton translocation mediated by the human proton-coupled folate transporter SLC46A1. J Biol Chem. 2009 Jun 26;284(26):17846-57. [Content Brief]

[19]. Michele Visentin, et al. Identification of Tyr residues that enhance folate substrate binding and constrain oscillation of the proton-coupled folate transporter (PCFT-SLC46A1). Am J Physiol Cell Physiol. 2015 Apr 15;308(8):C631-41. [Content Brief]

[20]. Yasuhiro Nakai, et al. Functional characterization of human proton-coupled folate transporter/heme carrier protein 1 heterologously expressed in mammalian cells as a folate transporter. J Pharmacol Exp Ther. 2007 Aug;322(2):469-76. [Content Brief]

[21]. Daniel Sanghoon Shin, et al. A P425R mutation of the proton-coupled folate transporter causing hereditary folate malabsorption produces a highly selective alteration in folate binding. Am J Physiol Cell Physiol. 2012 May 1;302(9):C1405-12. [Content Brief]

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