Solute carrier family 46 member 1 (SLC46A1) (SLC46A1)

Solute carrier family 46 member 1 (SLC46A1), also known as the proton-coupled folate transporter (PCFT), is a critical transmembrane protein responsible for the absorption of dietary folates in the small intestine and their transport across the blood-cerebrospinal fluid barrier [1, 8]. It functions as a proton-coupled symporter, showing optimal activity in acidic environments, which distinguishes it from other folate transporters like the reduced folate carrier (RFC) [1, 5]. Mutations in the SLC46A1 gene lead to hereditary folate malabsorption, a rare disorder characterized by severe systemic and cerebral folate deficiency, megaloblastic anemia, and neurological dysfunction [10, 13]. In oncology, SLC46A1 is a significant therapeutic target because it is often highly expressed in solid tumors, where the acidic microenvironment enhances its activity [5, 15]. This property is exploited to deliver antifolate drugs like pemetrexed and methotrexate selectively to cancer cells while potentially minimizing systemic toxicity [1, 15]. Additionally, SLC46A1 has been identified as a heme transporter, further expanding its role in cellular iron and nutrient homeostasis [3, 9]. The transporter's expression is also linked to the risk of neural tube defects and oral clefts, highlighting its importance in embryonic development [14]. Therapeutic strategies targeting SLC46A1 aim to overcome drug resistance in cancer and provide effective folate supplementation in deficiency syndromes [5, 16]. Monitoring folate levels in serum and cerebrospinal fluid serves as a key biomarker for assessing the functional integrity of this transporter [13, 18]. Overall, SLC46A1 is a pivotal mediator of one-carbon metabolism with broad implications in nutrition, genetics, and cancer therapy [5, 17].

Other names

Proton-coupled folate transporterPCFTHeme carrier protein 1HCP1G21HsPCFT

Proton-coupled symport of folates and antifolates across cell membranes, particularly in acidic environments.