Characterization of an Integral Protein of the Brush Border Membrane Mediating the Transport of Divalent Metal Ions

Abstract

The transport of Fe(2+) and other divalent transition metal ions across the intestinal brush border membrane (BBM) was investigated using brush border membrane vesicles (BBMVs) as a model. This transport is an energy-independent, protein-mediated process. The divalent metal ion transporter of the BBM is a spanning protein, very likely a protein channel, that senses the phase transition of the BBM, as indicated by a break in the Arrhenius plot. The transporter has a broad substrate range that includes Mn(2+), Fe(2+), Co(2+), Ni(2+), Cu(2+), and Zn(2+). Under physiological conditions the transport of divalent metal ions is proton-coupled, leading to the acidification of the internal cavity of BBMVs. The divalent metal ion transporter can be solubilized in excess detergent (30 mM diheptanoylphosphatidylcholine or 1% Triton X-100) and reconstituted into an artificial membrane system by detergent removal. The reconstituted membrane system showed metal ion transport characteristics similar to those of the original BBMVs. The properties of the protein described here closely resemble those of the proton-coupled divalent cation transporter (DCT1, Nramp2) described by, Nature. 388:482-488). We may conclude that a protein of the Nramp family is present in the BBM, facilitating the transport of Fe(2+) and other divalent transition metal ions.

Hereditary hemochromatosis is reflected in the iron isotope composition of blood

“…Iron is absorbed from 2 major dietary pools, that is, foods of animal origin containing primarily heme-bound iron [10][11] and plant foods containing nonheme iron. [13][14] Isotope effects (isotope fractionation) may be induced by preferential uptake of lighter isotopes of nonheme iron by DMT-1 and/or iron release from the epithelial cell into the circulatory system by IREG1 and/or preferential deposition of heavier iron isotopes into ferritin (which is removed from the body by regular apoptosis and shedding of epithelial cells into the lumen of the small intestine). In contrast to nonheme iron, it is unlikely that the iron isotopic composition of heme-bound iron is affected during uptake by the intestinal epithelial cell.…”

“…[8][9] Heme-bound iron such as myoglobin (and hemoglobin) in foods of animal origin is taken up by an endocytotic process in which the porphyrin ring of the heme molecule is broken up within the epithelial cell. [10][11] Uptake of nonheme iron, mostly from plant foods, is mediated by ferric reductase and divalent metal transporter-1 (DMT-1) [12][13][14] or, possibly, by the integrin-mobilferrinparaferritin pathway. [15][16] An iron-regulated transporter 1 (IREG1) is involved in subsequent iron transfer from the epithelial cell to blood circulation.…”

Nickel Toxicity and Carcinogenesis

“…The latter is likely to involve a proton-coupled divalent cation transporter DMT-1 (Nramp 2) that may account for the observed transport antagonism between nickel and other cations, including iron [91]. Ni 2ϩ interactions with iron transport and storage also seem possible at the transferrin/ferritin system [92].…”

Interaction of chemical species with biological regulation of the metabolism of essential trace elements

“…Although described mechanistically for several decades, knowledge about the molecular mode of homeostatic control of absorption has remained fragmentary. Recent findings indicate, however, that a major pathway of absorption is mediated by transport proteins located in the intestinal brush-border membrane; these collect Zn, Fe, Cu, and Mn as inorganic divalent cations more or less selectively from the mucus layer (Fe 3+ is probably reduced to Fe 2+ before it enters the transport system), whereas homeostatic control of absorption seems to be based on the expression of these proteins and/or of molecules of the subsequent transport line from the cell lumen towards the blood stream [2,3,4,5]. In contrast with absorption from the intestinal lumen, the adaptations of renal excretion are of minor relevance (Zn), or generally too small to contribute quantitatively to metabolic regulation (Fe, Cu, Mn).…”