The Reduced Folate Carrier (RFC) Family
TC# 2.A.48 is a group of transport proteins that is part of the
major facilitator superfamily
The major facilitator superfamily (MFS) is a superfamily of membrane transport proteins that facilitate movement of small solutes across cell membranes in response to chemiosmotic gradients.
Function
The major facilitator superfamily (MFS) are ...
. RFCs take up
folate
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing and ...
, reduced folate, derivatives of reduced folate and the drug,
methotrexate
Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leuke ...
.
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. The large
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
ic 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 mold
Slime mold or slime mould is an informal name given to several kinds of unrelated eukaryotic organisms with a life cycle that includes a free-living single-celled stage and the formation of spores. Spores are often produced in macroscopic mu ...
s and ''
Giardia
''Giardia'' ( or ) is a genus of anaerobic flagellated protozoan parasites of the phylum Metamonada that colonise and reproduce in the small intestines of several vertebrates, causing the disease giardiasis. Their life cycle alternates between ...
''. They have been sequenced from several mammals and from the worm, ''
Caenorhabditis elegans
''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' (ro ...
,'' as well as the fly, ''
Drosophila melanogaster
''Drosophila melanogaster'' is a species of fly (the taxonomic order Diptera) in the family Drosophilidae. The species is often referred to as the fruit fly or lesser fruit fly, or less commonly the "vinegar fly" or "pomace fly". Starting with Ch ...
.'' 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:OH
−antiport 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).
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
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...
. In particular, RFC1, ThTr-1, and ThTr-2 have been shown to be downregulated in heart, liver and brain, causing malabsorption.
See also
*
Reduced folate carrier 1
References
Protein families
Membrane proteins
Transmembrane proteins
Transmembrane transporters
Transport proteins
Integral membrane proteins
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