9u5a

Structural highlights

Function

S22AB_HUMAN Antiporter that mediates the transport of conjugated steroids and other specific organic anions at the basal membrane of syncytiotrophoblast and at the apical membrane of proximal tubule epithelial cells, in exchange for anionic compounds (PubMed:10660625, PubMed:11907186, PubMed:15037815, PubMed:15102942, PubMed:15291761, PubMed:15576633, PubMed:17229912, PubMed:18501590, PubMed:26277985, PubMed:28027879). May be responsible for placental absorption of fetal-derived steroid sulfates such as estrone sulfate (E1S) and the steroid hormone precursor dehydroepiandrosterone sulfate (DHEA-S), as well as clearing waste products and xenobiotics from the fetus (PubMed:12409283). Maybe also be involved in placental urate homeostasis (PubMed:17229912). Facilitates the renal reabsorption of organic anions such as urate and derived steroid sulfates (PubMed:15037815, PubMed:17229912). Organic anion glutarate acts as conteranion for E1S renal uptake (PubMed:15037815, PubMed:17229912). Possible transport mode may also include DHEA-S/E1S exchange (PubMed:28027879). Also interacts with inorganic anions such as chloride and hydroxyl ions, therefore possible transport modes may include E1S/Cl(-), E1S/OH(-), urate/Cl(-) and urate/OH(-) (PubMed:17229912). Also mediates the transport of prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may be involved in their renal excretion (PubMed:11907186). Also able to uptake anionic drugs, diuretics, bile salts and ochratoxin A (PubMed:10660625, PubMed:26277985). Mediates the unidirectional efflux of glutamate and aspartate (PubMed:28027879). Glutamate efflux down its transmembrane gradient may drive SLC22A11/OAT4-mediated placental uptake of E1S (PubMed:26277985).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]}

References

1. ↑ Cha SH, Sekine T, Kusuhara H, Yu E, Kim JY, Kim DK, Sugiyama Y, Kanai Y, Endou H. Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem. 2000 Feb 11;275(6):4507-12. PMID:10660625 doi:10.1074/jbc.275.6.4507
2. ↑ Kimura H, Takeda M, Narikawa S, Enomoto A, Ichida K, Endou H. Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J Pharmacol Exp Ther. 2002 Apr;301(1):293-8. PMID:11907186 doi:10.1124/jpet.301.1.293
3. ↑ Ugele B, St-Pierre MV, Pihusch M, Bahn A, Hantschmann P. Characterization and identification of steroid sulfate transporters of human placenta. Am J Physiol Endocrinol Metab. 2003 Feb;284(2):E390-8. PMID:12409283 doi:10.1152/ajpendo.00257.2002
4. ↑ Ekaratanawong S, Anzai N, Jutabha P, Miyazaki H, Noshiro R, Takeda M, Kanai Y, Sophasan S, Endou H. Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules. J Pharmacol Sci. 2004 Mar;94(3):297-304. PMID:15037815 doi:10.1254/jphs.94.297
5. ↑ Zhou F, Tanaka K, Pan Z, Ma J, You G. The role of glycine residues in the function of human organic anion transporter 4. Mol Pharmacol. 2004 May;65(5):1141-7. PMID:15102942 doi:10.1124/mol.65.5.1141
6. ↑ Zhou F, Pan Z, Ma J, You G. Mutational analysis of histidine residues in human organic anion transporter 4 (hOAT4). Biochem J. 2004 Nov 15;384(Pt 1):87-92. PMID:15291761 doi:10.1042/BJ20040751
7. ↑ Zhou F, Xu W, Hong M, Pan Z, Sinko PJ, Ma J, You G. The role of N-linked glycosylation in protein folding, membrane targeting, and substrate binding of human organic anion transporter hOAT4. Mol Pharmacol. 2005 Mar;67(3):868-76. PMID:15576633 doi:10.1124/mol.104.007583
8. ↑ Hagos Y, Stein D, Ugele B, Burckhardt G, Bahn A. Human renal organic anion transporter 4 operates as an asymmetric urate transporter. J Am Soc Nephrol. 2007 Feb;18(2):430-9. PMID:17229912 doi:10.1681/ASN.2006040415
9. ↑ Ugele B, Bahn A, Rex-Haffner M. Functional differences in steroid sulfate uptake of organic anion transporter 4 (OAT4) and organic anion transporting polypeptide 2B1 (OATP2B1) in human placenta. J Steroid Biochem Mol Biol. 2008 Jul;111(1-2):1-6. PMID:18501590 doi:10.1016/j.jsbmb.2008.04.001
10. ↑ Lofthouse EM, Brooks S, Cleal JK, Hanson MA, Poore KR, O'Kelly IM, Lewis RM. Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast. J Physiol. 2015 Oct 15;593(20):4549-59. PMID:26277985 doi:10.1113/JP270743
11. ↑ Skwara P, Schömig E, Gründemann D. A novel mode of operation of SLC22A11: Membrane insertion of estrone sulfate versus translocation of uric acid and glutamate. Biochem Pharmacol. 2017 Mar 15;128:74-82. PMID:28027879 doi:10.1016/j.bcp.2016.12.020
12. ↑ Hagos Y, Stein D, Ugele B, Burckhardt G, Bahn A. Human renal organic anion transporter 4 operates as an asymmetric urate transporter. J Am Soc Nephrol. 2007 Feb;18(2):430-9. PMID:17229912 doi:10.1681/ASN.2006040415