Reduced folate carrier family

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The Reduced Folate Carrier (RFC) Family (TC# 2.A.48) is a group of transport proteins that is part of the major facilitator superfamily. RFCs take up folate, reduced folate, derivatives of reduced folate and the drug, methotrexate.

Contents

Structure and Homology

These proteins are usually 500-600 amino acyl residues long and possess 12 putative transmembrane α-helical segments (TMSs). Residues in the first TMS and in the region between TMSs 1 and 2, and in TMS 11 appear to play roles in substrate recognition. [1] [2] The large cytoplasmic loop between TMSs 6 and 7 is required for stability and efficient transport.

Proteins of the RFC family have been characterized only from animals, but homologues can also be found in other eukaryotes such as slime molds and Giardia . They have been sequenced from several mammals and from the worm, Caenorhabditis elegans, as well as the fly, Drosophila melanogaster. Humans have at least two RFC family paralogues, and C. elegans has three. All homologues exhibit a high degree of sequence similarity with each other.

Proposed Mechanisms

The RFC members appear to transport reduced folate by an energy-dependent, pH-dependent, Na+-independent mechanism. Folate:H+ symport, folate:OHantiport and folate:anion antiport mechanisms have been proposed. Intracellular anions are able to promote folate derivative uptake. A bidirectional anion antiport mechanism for RFC family members is favored. In support of this notion, RFC1 has been shown to catalyze efflux of thiamin pyrophosphate (TPP). [3] [4]

Transport Reactions

The generalized transport reactions catalyzed by the proteins of the RFC family are:

Folate derivative (out) + anion (in) ⇌ folate derivative (in) + anion (out)
Thiamine (out) + H+ (out) ⇌ thiamine (in) + H+ (in)
TPP (in) + H+ (in) ⇌ TPP (out) + H+ (out)

Medical relevance

Several human RFCs have been linked to chronic kidney disease. In particular, RFC1, ThTr-1, and ThTr-2 have been shown to be downregulated in heart, liver and brain, causing malabsorption. [5]

See also

Related Research Articles

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The Nucleobase:Cation Symporter-1 (NCS1) Family (TC# 2.A.39) consists of over 1000 currently sequenced proteins derived from Gram-negative and Gram-positive bacteria, archaea, fungi and plants. These proteins function as transporters for nucleobases including purines and pyrimidines. Members of this family possess twelve transmembrane α-helical spanners (TMSs). At least some of them have been shown to function in uptake by substrate:H+ symport mechanism.

Sodium-solute symporter Group of transport proteins

Members of the Solute:Sodium Symporter (SSS) Family (TC# 2.A.21) catalyze solute:Na+ symport. The SSS family is within the APC Superfamily. The solutes transported may be sugars, amino acids, organo cations such as choline, nucleosides, inositols, vitamins, urea or anions, depending on the system. Members of the SSS family have been identified in bacteria, archaea and eukaryotes. Almost all functionally well-characterized members normally catalyze solute uptake via Na+ symport.

Ammonia transporter

Ammonia transporters are structurally related membrane transport proteins called Amt proteins in bacteria and plants, methylammonium/ammonium permeases (MEPs) in yeast, or Rhesus (Rh) proteins in chordates. In humans, the RhAG, RhBG, and RhCG Rhesus proteins constitute solute carrier family 42 whilst RhD and RhCE form the Rh blood group system. The three-dimensional structure of the ammonia transport protein AmtB from Escherichia coli has been determined by x-ray crystallography revealing a hydrophobic ammonia channel. The human RhCG ammonia transporter was found to have a similar ammonia-conducting channel structure. It was proposed that the erythrocyte Rh complex is a heterotrimer of RhAG, RhD, and RhCE subunits in which RhD and RhCE might play roles in anchoring the ammonia-conducting RhAG subunit to the cytoskeleton. Based on reconstitution experiments, purified RhCG subunits alone can function to transport ammonia. RhCG is required for normal acid excretion by the mouse kidney and epididymis.

Cation diffusion facilitators (CDFs) are transmembrane proteins that provide tolerance of cells to divalent metal ions, such as cadmium, zinc, and cobalt. These proteins are considered to be efflux pumps that remove these divalent metal ions from cells. However, some members of the CDF superfamily are implicated in ion uptake. All members of the CDF family possess six putative transmembrane spanners with strongest conservation in the four N-terminal spanners. The Cation Diffusion Facilitator (CDF) Superfamily includes the following families:

Members of the organic solute transporter (OST) family have been characterized from a small bottom feeding species of fish called the little skate, Raja erinacea. Members have also been characterized from humans and mice. The OST family is a member of the larger group of secondary carriers, the APC superfamily.

The amino acid-polyamine-organocation (APC) superfamily is the second largest superfamily of secondary carrier proteins currently known, and it contains several Solute carriers. Originally, the APC superfamily consisted of subfamilies under the transporter classification number. This superfamily has since been expanded to include eighteen different families.

The cation-chloride cotransporter (CCC) family is part of the APC superfamily of secondary carriers. Members of the CCC family are found in animals, plants, fungi and bacteria. Most characterized CCC family proteins are from higher eukaryotes, but one has been partially characterized from Nicotiana tabacum, and homologous ORFs have been sequenced from Caenorhabditis elegans (worm), Saccharomyces cerevisiae (yeast) and Synechococcus sp.. The latter proteins are of unknown function. These proteins show sequence similarity to members of the APC family. CCC family proteins are usually large, and possess 12 putative transmembrane spanners (TMSs) flanked by large N-terminal and C-terminal hydrophilic domains.

The anion exchanger family is a member of the large APC superfamily of secondary carriers. Members of the AE family are generally responsible for the transport of anions across cellular barriers, although their functions may vary. All of them exchange bicarbonate. Characterized protein members of the AE family are found in plants, animals, insects and yeast. Uncharacterized AE homologues may be present in bacteria. Animal AE proteins consist of homodimeric complexes of integral membrane proteins that vary in size from about 900 amino acyl residues to about 1250 residues. Their N-terminal hydrophilic domains may interact with cytoskeletal proteins and therefore play a cell structural role. Some of the currently characterized members of the AE family can be found in the Transporter Classification Database.

The sulfate permease (SulP) family is a member of the large APC superfamily of secondary carriers. The SulP family is a large and ubiquitous family of proteins derived from archaea, bacteria, fungi, plants and animals. Many organisms including Bacillus subtilis, Synechocystis sp, Saccharomyces cerevisiae, Arabidopsis thaliana and Caenorhabditis elegans possess multiple SulP family paralogues. Many of these proteins are functionally characterized, and most are inorganic anion uptake transporters or anion:anion exchange transporters. Some transport their substrate(s) with high affinities, while others transport it or them with relatively low affinities. Others may catalyze SO2−
4
:HCO
3
exchange, or more generally, anion:anion antiport. For example, the mouse homologue, SLC26A6, can transport sulfate, formate, oxalate, chloride and bicarbonate, exchanging any one of these anions for another. A cyanobacterial homologue can transport nitrate. Some members can function as channels. SLC26A3 and SLC26A6 can function as carriers or channels, depending on the transported anion. In these porters, mutating a glutamate, also involved in transport in the CIC family, created a channel out of the carrier. It also changed the stoichiometry from 2Cl/HCO
3
to 1Cl/HCO
3
.

Natural resistance-associated macrophage protein Family of transport proteins

Natural resistance-associated macrophage proteins (Nramps), also known as metal ion (Mn2+-iron) transporters (TC# 2.A.55), are a family of metal transport proteins found throughout all domains of life. Taking on an eleven-helix LeuT fold, the Nramp family is a member of the large APC Superfamily of secondary carriers. They transport a variety of transition metals such as manganese, cadmium, and manganese using an alternating access mechanism characteristic of secondary transporters.

The Ca2+:cation antiporter (CaCA) family (TC# 2.A.19) is a member of the cation diffusion facilitator (CDF) superfamily. This family should not be confused with the Ca2+:H+ Antiporter-2 (CaCA2) Family (TC# 2.A.106) which belongs to the Lysine Exporter (LysE) Superfamily. Proteins of the CaCA family are found ubiquitously, having been identified in animals, plants, yeast, archaea and divergent bacteria. Members of this family facilitate the antiport of calcium ion with another cation.

The Nickel/Cobalt Transporter (NicO) Family is a member of the Lysine Exporter (LysE) Superfamily.

Divalent anion:Na+ symporters were found in bacteria, archaea, plant chloroplasts and animals.

The arsenical resistance-3 (ACR3) family is a member of the BART superfamily. Based on operon analyses, ARC3 homologues may function either as secondary carriers or as primary active transporters, similarly to the ArsB and ArsAB families. In the latter case ATP hydrolysis again energizes transport. ARC3 homologues transport the same anions as ArsA/AB homologues, though ArsB homologues are members of the IT Superfamily and homologues of the ARC3 family are within the BART Superfamily suggesting they may not be evolutionarily related.

Monovalent cation:proton antiporter-1 Family of proteins

The Monovalent Cation:Proton Antiporter-1 (CPA1) Family (TC# 2.A.36) is a large family of proteins derived from Gram-positive and Gram-negative bacteria, blue-green bacteria, archaea, yeast, plants and animals. The CPA1 family belongs to the VIC superfamily. Transporters from eukaryotes have been functionally characterized to catalyze Na+:H+ exchange. Their primary physiological functions are thought to be in (1) cytoplasmic pH regulation, extruding the H+ generated during metabolism, and (2) salt tolerance (in plants), due to Na+ uptake into vacuoles. Bacterial homologues have also been found to facilitate Na+:H+ antiport, but some also catalyze Li+:H+ antiport or Ca2+:H+ antiport under certain conditions.

The Chloroplast Envelope Anion Channel-forming Tic110 (Tic110) Family consists of proteins of the inner chloroplast envelope membrane. This family consists of the inner membrane protein import apparatus, and appears to be a protein import-related anion-selective channel. It has also been designated (1) IEP110, (2) IAP100 and (3) protein import-related anion channel (PIRAC).

References

  1. Flintoff, Wayne F.; Williams, Frederick M. R.; Sadlish, Heather (2003-10-17). "The region between transmembrane domains 1 and 2 of the reduced folate carrier forms part of the substrate-binding pocket". The Journal of Biological Chemistry. 278 (42): 40867–40876. doi: 10.1074/jbc.M302102200 . ISSN   0021-9258. PMID   12909642.
  2. Hou, Zhanjun; Stapels, Sarah E.; Haska, Christina L.; Matherly, Larry H. (2005-10-28). "Localization of a substrate binding domain of the human reduced folate carrier to transmembrane domain 11 by radioaffinity labeling and cysteine-substituted accessibility methods". The Journal of Biological Chemistry. 280 (43): 36206–36213. doi: 10.1074/jbc.M507295200 . ISSN   0021-9258. PMID   16115875.
  3. Zhao, R.; Gao, F.; Wang, Y.; Diaz, G. A.; Gelb, B. D.; Goldman, I. D. (2001-01-12). "Impact of the reduced folate carrier on the accumulation of active thiamin metabolites in murine leukemia cells". The Journal of Biological Chemistry. 276 (2): 1114–1118. doi: 10.1074/jbc.M007919200 . ISSN   0021-9258. PMID   11038362.
  4. Visentin, Michele; Zhao, Rongbao; Goldman, I. David (2012-08-01). "Augmentation of reduced folate carrier-mediated folate/antifolate transport through an antiport mechanism with 5-aminoimidazole-4-carboxamide riboside monophosphate". Molecular Pharmacology. 82 (2): 209–216. doi:10.1124/mol.112.078642. ISSN   1521-0111. PMC   3400841 . PMID   22554803.
  5. Bukhari, Farhan J.; Moradi, Hamid; Gollapudi, Pavan; Ju Kim, Hyun; Vaziri, Nosratola D.; Said, Hamid M. (2011-07-01). "Effect of chronic kidney disease on the expression of thiamin and folic acid transporters". Nephrology, Dialysis, Transplantation. 26 (7): 2137–2144. doi:10.1093/ndt/gfq675. ISSN   1460-2385. PMC   3164444 . PMID   21149507.

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