A gut feeling about plasmablasts.

6 conserved aspartate residues (designated " D " in amino acid notation) in the molecule (see figure) are permissive to change, but the other 2 (D109 and D156) are critical for function with resulting marked impairment or total loss of function when mutated. Why aspartate? This amino acid is more highly conserved than others because of several attributes that include a short side chain, a high charge density, strong polar interactions, and molecular rigidity. 2 Recently, the same laboratory were the first to identify that PCFT plays a critical role in folate absorption from the relatively acidic milieu of the upper small intestine and transports folate into the brain through the blood, choroid plexus, cerebrospinal fluid conduit. 3 Unlike the reduced folate receptor, PCFT has a similar affinity for reduced folate and folic acid, at pH 5.5, ambient in the upper small intestine. A loss-of-function mutation affecting the pcft gene coding for this transmem-brane protein was identified as the cause of hereditary folate malabsorption, 3,4 an uncommon cause of folate deficiency of previously obscure etiology that presents within the first few months of life and leads to death during early infancy if not treated. Since then, several mutations affecting various other critical amino acid residues have been described in individuals with hereditary folate malabsorp-tion (HFM) and these have been reviewed recently. 5,6 Using a HELA cell subclone that lacks membrane folate transporters including PCFT, Shin and coworkers transiently trans-fected the cells with site-directed mutants of PCFTs and monitored functionality using tritiated methotrexate as surrogate cargo for the transporter. 1 The overall conclusions from these studies were that D156, located in the fourth transmembrane domain, is critical for PCFT protein stability. In addition, D109, in the first intracellular loop (between the second and third transmembrane domains) is absolutely essential for PCFT function, perhaps to maintain flexibility at what may be a critical hinge point in the molecule allowing for inward or outward flip-flop during the transport cycle. Recommended treatment for HFM consists of parenteral injection of folate, preferably with folinic acid (5-formyl tetrahydrofo-late), for correction of the anemia and central nervous system problems. 6,7 As emphasized in the recent comprehensive review of this topic, 6 the fact that folinic acid (leucovorin) has a much higher affinity than folic acid for the reduced folate carrier proves important in the management of HFM. In addition, as further pointed out by the same group, …