Critical moieties of aromatic amino acids for the interaction with organic anion transporter OAT1: Implications for reducing the renal background in tumor imaging

We have isolated and characterized a novel human and rat organic anion transporter subtype, OATP-D. The isolated cDNA from human brain encodes a polypeptide of 710 amino acids ( Mr 76,534) with 12 predicted transmembrane domains. The rat clone encodes 710 amino acids ( Mr 76,821) with 97.6% amino acid sequence homology with human OATP-D. Human and rat OATP-D have moderate amino acid sequence homology with LST-1/rlst-1, the rat oatp family, the prostaglandin transporter, and moat1/MOAT1/KIAA0880/OATP-B. Phylogenetic tree analysis revealed that OATP-D is branched in a different position from all known organic anion transporters. OATP-D transports prostaglandin E1 ( Km 48.5 nM), prostaglandin E2 ( Km 55.5 nM), and prostaglandin F2α, suggesting that, functionally, OATP-D encodes a protein that has similar characteristics to those of the prostaglandin transporter. Rat OATP-D also transports prostaglandins. The expression pattern of OATP-D mRNA was abundant mainly in the heart, testis, brain, and some cancer cells. Immunohistochemical analysis further revealed that rat OATP-D is widely expressed in the vascular, renal, and reproductive system at the protein level. These results suggest that OATP-D plays an important role in translocating prostaglandins in specialized tissues and cells.

Download Full-text

Structure activity relations of aromatic amino acid derivatives to interact with organic anion transporter OAT1 reveal critical moieties for renal accumulation of tumor imaging probes

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.wcp2018.0_po1-8-40 ◽

2018 ◽

Vol WCP2018 (0) ◽

pp. PO1-8-40

Author(s):

Chunhuan Jin ◽

Ryuichi Ohgaki ◽

Hideyuki Tominaga ◽

Suguru Okuda ◽

Shushi Nagamori ◽

...

Keyword(s):

Amino Acid ◽

Aromatic Amino Acid ◽

Tumor Imaging ◽

Organic Anion ◽

Organic Anion Transporter ◽

Amino Acid Derivatives ◽

Structure Activity ◽

Anion Transporter ◽

Structure Activity Relations ◽

Imaging Probes

Download Full-text

Cationic Amino Acids Involved in Dicarboxylate Binding of the Flounder Renal Organic Anion Transporter

Journal of the American Society of Nephrology ◽

10.1681/asn.v12102012 ◽

2001 ◽

Vol 12 (10) ◽

pp. 2012-2018 ◽

Cited By ~ 2

Author(s):

NATASCHA A. WOLFF ◽

BETTINA GRÜNWALD ◽

BJÖRN FRIEDRICH ◽

FLORIAN LANG ◽

STEFAN GODEHARDT ◽

...

Keyword(s):

Amino Acids ◽

Organic Anion ◽

Surface Expression ◽

Organic Anion Transporter ◽

Site Directed Mutagenesis ◽

Cell Surface Expression ◽

Directed Mutagenesis ◽

Wild Type ◽

Anion Transporter ◽

Cationic Amino Acids

Abstract. Three conserved cationic amino acids in predicted transmembrane domains 1, 8, and 11, respectively, of the flounder renal organic anion transporter, fROAT, were changed by site-directed mutagenesis and the resulting mutants functionally characterized inXenopus laevisoocytes. Uptake ofp-aminohippurate (PAH) in oocytes that expressed mutant H34I, K394A, or R478D was markedly reduced compared with oocytes that expressed wild-type fROAT, but was still several-fold higher than that in water-injected control oocytes. Immunocytochemically, no decrease in cell surface expression of the mutants could be detected. Only mutant R478D appeared to have a lower PAH affinity than the wild type. Similar to wild-type—dependent PAH transport, uptake induced by mutant H34I was sensitive to glutarate (GA) cis-inhibition. In contrast, mutants K394A and R478D could not be significantly affected by up to 10 mM GA, although the cRNA-dependent PAH uptake could still be almost completely suppressed by probenecid. Moreover, again in contrast to the wild type, neither PAH influx nor PAH efflux mediated by these two mutants could be trans-stimulated by GA, nor did they induce GA transport. These data suggest that amino acids K394 and R478 in fROAT are required for dicarboxylate binding and PAH/dicarboxylate exchange.

Download Full-text