The reduced folate carrier protein (RFC) is a transmembrane protein responsible for the transport of folate, or vitamin B9, into cells. It uses the large gradient of organic phosphate to move folate into the cell against its concentration gradient. The RFC protein can transport folates, reduced folates, the derivatives of reduced folate, and the drug methotrexate. The transporter is encoded by the SLC19A1 gene and is ubiquitously expressed in human cells. Its peak activity occurs at pH 7.4, with no activity occurring below pH 6.4. The RFC protein is critical because folates take the form of hydrophilic anions at physiological pH, so they do not diffuse naturally across biological membranes. Folate is essential for processes such as DNA synthesis, repair,and methylation, and without entry into cells, these could not occur.
Because folates are essential for various life-sustaining processes, a deficiency in this molecule can lead to fetal abnormalities, neurological disorders, cardiovascular disease, and cancer. Folates cannot be synthesized in the body, so it must be taken in through diet and moved into cells. Without the RFC protein facilitating this movement, processes such as embryological development and DNA repair cannot occur.
Adequate folate levels are required for the development of the neural tube in the fetus. Folate deficiency during pregnancy increases the risk of defects such as spina bifida and anencephaly. In mouse models, inactivating both alleles of the FRC protein gene causes death of the embryo. Even if folate is supplemented during gestation, the mice died within two weeks of birth from the failure of hematopoietic tissues.
Altered function of the RFC protein can increase folate deficiency, enhancing cardiovascular disease, neurodegenerative diseases, and cancer. In terms of cardiovascular issues, folate contributes to homocysteine metabolism. Low folate levels result in elevated homocysteine levels, which is a risk factor for cardiovascular diseases. In terms of cancer, folate deficiency is related to an increased risk, especially that of colorectal cancers. In mouse models with altered RFC protein expression showed increased transcripts of genes related to colon cancer and increased proliferation of colonocytes. The cancer risk is likely related to the FRC protein's role in DNA synthesis because inadequate levels of folate can lead to DNA damage and aberrant DNA methylation.