2.A.2.3.8
Major Facilitator Superfamily Domain containing 2A, MFSD2A or SLC59A1 (543aas, 12 TMSs). It is the omega-3-fatty acid transporter that plays a role in thermogenesis via β-adrenergic signaling. It takes up Tunicamycin (TM), a mixture of related species of nucleotide sugar analogs fatty-acylated with alkyl chains of varying lengths and degrees of unsaturation, produced by several Streptomyces species (Bassik and Kampmann, 2011; Reiling et al., 2011).  It is a sodium-dependent lysophosphatidylcholine (LPC) symporter expressed at the blood-brain barrier endothelium. It is the primary route for import of docosahexaenoic acid and other long-chain fatty acids into foetal and adult brain, and is essential for mouse and human brain growth and function (Quek et al. 2016). In addition to a conserved sodium-binding site, three structural features were identified: A phosphate headgroup binding site, a hydrophobic cleft to accommodate a hydrophobic hydrocarbon tail, and three sets of ionic locks that stabilize the outward-open conformation. Ligand docking studies and biochemical assays identified Lys436 as a key residue for transport. It forms a salt bridge with the negative charge on the phosphate headgroup. Mfsd2a transports structurally related acylcarnitines but not a lysolipid without a negative charge, demonstrating the necessity of a negative charged headgroup interaction with Lys436 for transport. These findings support a novel transport mechanism by which LPCs are flipped within the transporter cavity by pivoting about Lys436 leading to net transport from the outer to the inner leaflet of the plasma membrane (Quek et al. 2016). Docosahexaenoic acid is an omega-3 fatty acid that is essential for neurological development and function, and it is supplied to the brain and eyes predominantly from dietary sources. This nutrient is transported across the blood-brain and blood-retina barriers as lysophosphatidylcholine. The structure of MFSD2A has been determined using single-particle cryo-EM (Cater et al. 2021). The transporter is in an inward-facing conformation and features a large amphipathic cavity that contains the Na⁺-binding site and a bound lysolipid substrate. This structure reveals details of how MFSD2A interacts with substrates and how Na⁺-dependent conformational changes allow for the release of these substrates into the membrane through a lateral gate. This atypical MFS transporter mediates the uptake of lysolipids into the brain. Homozygous variants in the MFSD2A gene cause severe primary microcephaly, brain malformations, developmental delay, and epilepsy (Khuller et al. 2021). Bi-allelic MFSD2A variants cause autosomal recessive primary microcephaly type 15 and broaden the phenotypic spectrum associated with these pathogenic variants, emphasizing the role of MFSD2A in early brain development. Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A have been documented (Bergman et al. 2023).  Automated collective variables have been discovered for MFSD2A from molecular dynamics simulations (Oh et al. 2024).  Omega-3 fatty acids, such as docosahexaenoic acid (DHA), are essential nutrients required to support the growth, maintenance, and function of the central nervous system (CNS). Circulating DHA is primarily obtained from dietary sources and is transported across the blood-brain barrier (BBB) in the form of lysophosphatidylcholine (LPC-DHA) by the transmembrane transporter major facilitator superfamily domain containing 2A (MFSD2A) This transporter mediates uptake of LPC-DHA, and lysolipids more broadly, highlighting different conformational states, substrate entry and release pathways, and the ligand binding sites (Blades et al. 2025).