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1.A.28 The Urea Transporter (UT) Family

Members of the UT family are found in vertebrate animals and bacteria but not in other eukaryotes or in archaea (Minocha et al., 2003). In a single species (i.e., rat or human) there are at least seven isoforms. These isoforms are splice variants of two adjacent genes in humans and mice, Slc14a2, which encodes the type UT-A variants, and Slc14a1, which encodes the UT-B variants. UT-A1-4 are expressed mainly in the renal tubules while UT-A5 is expressed only in the testis. UT-B1 is expressed in red blood cells, in endothelial cells of the descending vasa recta irrigating renal medulla and in other tissues (Minocha et al., 2003). The physiology of UT family members is described by Sands (2003).

One of the human UT family members (UT-B1) is the Kidd (JK) blood group glycoprotein. The JKa/JKb antigenic polymorphism in human UT-B1 is due to an Asp280Asn substitution on the external loop separating TMSs 7 and 8, while the ABO blood group type is due to a glycan linked to Asn211 in the large, central, extracellular loop between TMSs 5 and 6 (Lucien et al., 2002).

Most of the UT proteins vary in size from 380-400 residues and exhibit 10 putative transmembrane helical spanners, but mammalian urea transporters such as UT-A1 of the rat are 920-930 residues long. They exhibit an internal duplication with a total of 20 TMSs (Minocha et al., 2003). This duplication is lacking in the other forms. Isoforms A2-A5 are splice variants of A1. B1 and B2 are of the same size as A2-A5. At least one of these proteins (UTB or UT3) can transport water as well as urea (Yang and Verkman, 2002). A channel-type mechanism is probable. UT1 and UT2 may be derived from a single gene by alternative splicing. A human protein (spQ15849) is 397 residues long, exhibits 10 putative TMSs and is internally duplicated.

Homologues of the mammalian UT family members have been identified in several bacteria. The gene encoding the Actinobacillus pleuropneumoniae homologue, Utp, is in the urea utilization gene cluster which also encodes a Ni2+-ABC transporter and urease (Bosse et al., 2001). Utp is 300 aas long and has ten putative TMSs. The first 129 residues of this bacterial protein are homologous to residues 55-187 and 220-349 of the frog protein, thus demonstrating the presence of a putative 5 TMS repeat element.

Urea is highly concentrated in the mammalian kidney to produce the osmotic gradient necessary for water re-absorption. Free diffusion of urea across cell membranes is slow owing to its high polarity, and specialized urea transporters have evolved to achieve rapid and selective urea permeation. Levin et al. (2009) presented a 2.3 A structure of a functional urea transporter from the bacterium Desulfovibrio vulgaris. The transporter is a homotrimer, and each subunit contains a continuous membrane-spanning pore formed by the two homologous halves of the protein. The pore contains a constricted selectivity filter that can accommodate several dehydrated urea molecules in single file. Backbone and side-chain oxygen atoms provide continuous coordination of urea as it progresses through the filter, and well-placed alpha-helix dipoles provide further compensation for dehydration energy. Thus, the urea transporter operates by a channel-like mechanism. The structure reveals the physical and chemical basis of urea selectivity (Levin et al., 2009).

 

References associated with 1.A.28 family:

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Bosse, J.T., H.D. Gilmour, and J.I. MacInnes. (2001). Novel genes affecting urease activity in Actinobacillus pleuropneumoniae. J. Bacteriol. 183: 1242-1247. 11157936
Couriaud, C., C. Leroy, M. Simon, C. Silberstein, P. Bailly, P. Ripoche, and G. Rousselet. (1999). Molecular and functional characterization of an amphibian urea transporter. Biochim. Biophys. Acta 1421: 347-352. 10518704
Couriaud, C., P. Ripoche, and G. Rousselet. (1998). Cloning and functional characterization of a rat urea transporter-expression in the brain. Biochim. Biophys. Acta 1309: 197-199. 8982255
Levin EJ., Quick M. and Zhou M. (2009). Crystal structure of a bacterial homologue of the kidney urea transporter. Nature. 462(7274):757-61. 19865084
Lucien, N. F. Sidoux-Walter, N. Roudier, P. Ripoche, M. Huet, M.-M. Trinh-Trang-Tan, J.-P. Cartron, and P. Bailly. (2002). Antigenic and functional properties of the human red blood cell urea transporter hUT-B1. J. Biol. Chem. 277: 34101-34108. 12093813
Lucien, N., F. Sidoux-Walter, B. Olives, J. Moulds, P.-Y. Le Pennec, J.-P. Cartron, and P. Bailly. (1998). Characterization of the gene encoding the human Kidd blood group/urea transporter protein. J. Biol. Chem. 273: 12973-12980. 9582331
Minocha, R., K. Studley, and M.H. Saier, Jr. (2003). The urea transporter (UT) family: bioinformatic analyses leading to structural, functional, and evolutionary predictions. Receptors & Channels 9: 345-352. 14698962
Mistry, A.C., R. Mallick, O. Fröhlich, J.D. Klein, A. Rehm, G. Chen, and J.M. Sands. (2007). The UT-A1 urea transporter interacts with snapin, a SNARE-associated protein. J. Biol. Chem. 282: 30097-30106. 17702749
Olives, B., P. Neau, P. Bailly, M.A. Hediger, G. Rousselet, J.P. Cartron, and P. Ripoche. (1994). Cloning and functional expression of a urea transporter from human bone marrow cells. J. Biol. Chem. 269: 31649-31652. 7989337
Raunser, S., J.C. Mathai, P.D. Abeyrathne, A.J. Rice, M.L. Zeidel, and T. Walz. (2009). Oligomeric structure and functional characterization of the urea transporter from Actinobacillus pleuropneumoniae. J. Mol. Biol. 387: 619-627. 19361419
Sands, J.M. (2003). Molecular mechanisms of urea transport. J. Membrane Biol. 191: 149-163. 12571750
Shayakul, C., A. Steel, and M.A. Hediger. (1996). Molecular cloning and characterization of the vasopressin-regulated urea transporter of rat kidney collecting ducts. J. Clin. Invest. 98: 2580-2587. 8958221
Smith, C.P. and G. Rousselet. (2001). Facilitative urea transporters. J. Membrane Biol. 183: 1-14. 11547347
Yang, B. and A.S. Verkman. (1998). Urea transporter UT3 functions as an efficient water channel. J. Bacteriol. 272: 9369-9372. 9545259
Yang, B. and A.S. Verkman. (2002). Analysis of double knockout mice lacking aquaporin-1 and urea transporter UT-B. Evidence for UT-B-facilitated water transport in erythrocytes. J. Biol. Chem. 277: 36782-36786. 12133842
Zhao, D., N.D. Sonawane, M.H. Levin, and B. Yang. (2007). Comparative transport efficiencies of urea analogues through urea transporter UT-B. Biochim. Biophys. Acta. 1768: 1815-1821. 17506977