Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter.
Elevated serum levels of uric acid have been associated with an increased risk for gout, hypertension, cardiovascular disease, and renal failure. The molecular mechanisms for the diminished excretion of urate in these disorders, however, remain poorly understood. Human galectin 9, which is highly homologous to the rat urate transporter rUAT, has been reported to be a secreted or cytosolic protein. We provide data that galectin 9 is hUAT, the first identified human urate transporter. hUAT is a highly selective urate ion channel when inserted in lipid bilayers. When expressed in renal epithelial cells it is an integral plasma membrane protein with at least two transmembrane domains. The gene for hUAT consists of 11 exons and is mapped to chromosome 17; a highly homologous gene, hUAT2, maps to a nearby region of chromosome 17 and is also likely to be a urate transporter. hUAT is expressed in a wide variety of tissues and is present in at least three isoforms; hUAT2 is less widely expressed at severalfold lower levels than hUAT. Further knowledge about the functions of hUAT, its isoforms, and hUAT2, as well as mutational analysis of hUAT1 and hUAT2 in individuals or families with hyperuricemia, should significantly improve our understanding of the molecular mechanisms of urate homeostasis.
Lipkowitz
M S
MS
Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA. mike.lipkowitz@mssm.edu
Leal-Pinto
E
E
Rappoport
J Z
JZ
Najfeld
V
V
Abramson
R G
RG
D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D004847:Epithelial Cells; D037161:Galectins; D015894:Genome, Human; D006801:Humans; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D008051:Lipid Bilayers; D008958:Models, Molecular; D008969:Molecular Sequence Data; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D021382:Protein Sorting Signals; D021381:Protein Transport; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D014527:Uric Acid / Q000097:blood / Q000378:metabolism*
D002352:Carrier Proteins; D037161:Galectins; C105032:LGALS9 protein, human; D037102:Lectins; C491242:Lgals9 protein, rat; D008051:Lipid Bilayers; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; D021382:Protein Sorting Signals; D011994:Recombinant Proteins; C491241:SLC22A12 protein, human; C103862:urate transporter; D014527:Uric Acid