SLC11 family of H+-coupled metal-ion transporters NRAMP1 and DMT1

NRAMP1 (natural resistance-associated macrophage protein-1) and DMT1 (divalent metal-ion transporter-1) make up the SLC11 gene family of metal-ion transporters that are energized by the H+ electrochemical gradient. Long known to confer resistance to bacterial infection, NRAMP1 functions at the phagolysosomal membrane of macrophages and neutrophils. NRAMP1 most likely contributes to macrophage antimicrobial function by extruding essential metal ions (including Mn2+) from the phagolysosome via H+/metal-ion cotransport. An alternative hypothesis in the literature proposes that NRAMP1 concentrate Fe2+ within the phagolysosome by means of H+/Fe2+ antiport, resulting in the generation of toxic free radicals. DMT1 is expressed widely and accepts as substrates a broad range of transition metal ions, among which Fe2+ is transported with high affinity (K(0.5)approximate to2 muM). DMT1 accounts both for the intestinal absorption of free Fe2+ and for transferrin-associated endosomal Fe2+ transport in erythroid precursors and many other cell types. DMT1 is up-regulated dramatically in the intestine by dietary iron restriction and, despite high serum iron levels, is not appropriately down-regulated in hereditary hemochromatosis.