Superfund Research Program

Mechanisms of Arsenic Transport in Kidney and Bladder

Project Leader: Stephen Wright
Grant Number: P42ES004940
Funding Period: 2000 - 2005

Project-Specific Links

Final Progress Reports

Year:   2004 

Dr. Wright’s group is identifying and characterizing the specific transport processes involved in the movement of arsenic and arsenic-containing conjugates into and out of cells along the urinary tract.  This year they made substantial progress on elucidating the 3D structure of the OAT transport proteins that are the pathways by which metal chelators used to treat arsenic toxicity enter renal cells.  The researchers focused on determining why OAT1 is 10-times more sensitive to inhibition from metals (e.g., arsenic and mercury) that bind to sulfur-containing amino acids (i.e., cysteine) than is OAT3.  They propose that the difference reflects the interaction with one or cysteine residues that are present in OAT1, but not at the homologous location(s) in OAT3.  In additional studies they have developed ‘homology models’ of the structures of OAT1 and OAT3 based upon the anticipated similarity in structure of all OAT transporters to the closely related glycerol-phosphate transporter of E. coli.  These structures revealed in OAT1 a single cysteine residue in the extracellular loop found between the third and fourth transmembrane-spanning domains; the OAT3 structure shows this homologous site to be occupied by the amino acid methionine.  Direct tests (employing site-directed mutagenesis) of the influence of these sites to differential interaction with arsenic are currently underway.  These studies hold the promise of validating a structural model that may allow accurate predictions of the extent to which metals and drugs bind to OAT transporters.