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      Ammonium Homeostasis and Human Rhesus Glycoproteins

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          The brain ammonium production is detoxified by astrocytes, the gut ammonium production is detoxified by hepatic cells, and the renal ammonium production plays a major role in renal acid excretion. As a result of ammonium handling in these organs, the ammonium and pH values are strictly regulated in plasma. Up until recently, it was accepted that mammalian cell transmembrane ammonium transport was due to NH<sub>4</sub><sup>+</sup> transport by non-specific transporting systems, and to non-ionic NH<sub>3</sub> diffusion, whereas lower organisms (such as bacteria, yeasts and plants) were endowed with specific ammonium transporters (Amts). Sequence homologies between Amts and human Rhesus (Rh) glycoproteins (RhAG, from erythroid cells, and RhBG and RhCG from epithelial cells) raised the hypothesis that Rh glycoproteins act as specific ammonium transporters, further sustained by the polarized distribution of RhBG and RhCG in gut, kidney and liver. Results from functional studies agree that Rh glycoproteins are the first ammonium transporters reported in mammals. However, the nature of the transported specie(s) is much debated: in particular, it is proposed that Rh glycoproteins mediate a direct NH<sub>3</sub> transport, or that they mediate an indirect NH<sub>3</sub> transport (resulting from NH<sub>4</sub><sup>+</sup> for H<sup>+</sup> exchange). Direct NH<sub>3</sub> transport (associated or not with NH<sub>4</sub><sup>+</sup> transport) raises the exciting hypothesis that Rh glycoproteins may also transport other gasses than NH<sub>3</sub> (namely, CO<sub>2</sub>).

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          Most cited references 23

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          Mechanism of ammonia transport by Amt/MEP/Rh: structure of AmtB at 1.35 A.

          The first structure of an ammonia channel from the Amt/MEP/Rh protein superfamily, determined to 1.35 angstrom resolution, shows it to be a channel that spans the membrane 11 times. Two structurally similar halves span the membrane with opposite polarity. Structures with and without ammonia or methyl ammonia show a vestibule that recruits NH4+/NH3, a binding site for NH4+, and a 20 angstrom-long hydrophobic channel that lowers the NH4+ pKa to below 6 and conducts NH3. Favorable interactions for NH3 are seen within the channel and use conserved histidines. Reconstitution of AmtB into vesicles shows that AmtB conducts uncharged NH3.
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            Individual Activity Coefficients of Ions in Aqueous Solutions

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              The mechanism of ammonia transport based on the crystal structure of AmtB of Escherichia coli.

              Ammonium is one of the most important nitrogen sources for bacteria, fungi, and plants, but it is toxic to animals. The ammonium transport proteins (methylamine permeases/ammonium transporters/rhesus) are present in all domains of life; however, functional studies with members of this family have yielded controversial results with respect to the chemical identity (NH(4)(+) or NH(3)) of the transported species. We have solved the structure of wild-type AmtB from Escherichia coli in two crystal forms at 1.8- and 2.1-A resolution, respectively. Substrate transport occurs through a narrow mainly hydrophobic pore located at the center of each monomer of the trimeric AmtB. At the periplasmic entry, a binding site for NH(4)(+) is observed. Two phenylalanine side chains (F107 and F215) block access into the pore from the periplasmic side. Further into the pore, the side chains of two highly conserved histidine residues (H168 and H318) bridged by a H-bond lie adjacent, with their edges pointing into the cavity. These histidine residues may facilitate the deprotonation of an ammonium ion entering the pore. Adiabatic free energy calculations support the hypothesis that an electrostatic barrier between H168 and H318 hinders the permeation of cations but not that of the uncharged NH(3.) The structural data and energetic considerations strongly indicate that the methylamine permeases/ammonium transporters/rhesus proteins are ammonia gas channels. Interestingly, at the cytoplasmic exit of the pore, two different conformational states are observed that might be related to the inactivation mechanism by its regulatory partner.

                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                December 2006
                10 November 2006
                : 105
                : 1
                : p11-p17
                Inserm, U806 et Université Paris Descartes, Faculté de Médecine René Descartes, Paris, France
                96979 Nephron Physiol 2007;105:p11–p17
                © 2007 S. Karger AG, Basel

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                Page count
                Figures: 2, References: 38, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/96979


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