2.A.55 The Metal Ion (Mn²⁺-iron) Transporter (Nramp) Family

The Smf1 protein of Saccharomyces cerevisiae appears to catalyze high-affinity (K_M = 0.3 μM) Mn²⁺ uptake while the closely related Smf2 protein may catalyze low affinity (K_M = 60 μM) Mn²⁺ uptake in the same organism. Both proteins also mediate H⁺-dependent Fe²⁺ uptake. These proteins are of 575 and 549 amino acyl residues in length and have 8-12 transmembrane α-helical spanners. They may be localized to the vacuole and/or the plasma membrane of the yeast cell. Indirect and some direct experiments suggest that they may be able to transport several heavy metals including Mn²⁺, Cu²⁺, Cd²⁺ and Co²⁺. This is true of the E. coli homologue which is of 412 aas and exhibits 11 putative and confirmed TMSs with the N-terminus in and the C-terminus out (Courville et al., 2004). A third yeast protein, Smf3p, appears to be exclusively intracellular, possibly in the Golgi.

The human broad specificity NRAMP2 (DMT1) which transports a range of divalent metal cations, transports Fe²⁺ and H⁺ with a 1:1 stoichiometry and apparent affinities of 6 µM and about 1 µM, respectively. The order of substrate preference for NRAMP2 is Fe²⁺ > Zn²⁺ > Mn²⁺ > Co²⁺ > Ca²⁺ > Cu²⁺ > Ni²⁺ > Pb²⁺. Many of these ions can inhibit iron absorption. The primary function of this transporter appears to be intestinal iron absorption.

The yeast proteins exhibit greater than 50% similarity to so-called 'natural resistance-associated' macrophage proteins (Nramp) found in mammals, birds, nematodes and insects. Homologues are also found in other yeast, plants, archaea, and Gram-negative and Gram-positive bacteria. The animal proteins play a role in resistance to intracellular bacterial pathogens such as Salmonella typhimurium, Leishmania clonovani and Mycobacterium bovis. It is hypothesized that a deficiency for Mn²⁺ or some other metal prevents the generation of reactive oxygenic and nitrogenic compounds that are used by macrophage to combat pathogens. Nramp family members are found in many animal tissues besides macrophages where they are expressed at low levels. One mammalian mutant species, Nramp2 of rat, has been shown to exhibit defective endosomal iron export within the ferritin cycle and plays roles in intestinal iron absorption. It has been reported to transport a number of different transition metals with similar affinities by a H⁺ symport mechanism. It is found in apical membranes of intestinal epithelial cells, but also in late endosomes and lysosomes.

The generalized transport reaction catalyzed by Nramp family proteins is:

Me²⁺ (out) + H⁺ (out) → Me²⁺ (in) + H⁺ (in).

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Examples: