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2.A.65 The Bilirubin Transporter (BRT) Family

The BRT family consists of a single protein, the 'bilitranslocase', a hepatic plasma membrane bilirubin transporter involved in the uptake of bilirubin and other organic anions from the blood into liver cells. The protein contains a bilirubin-binding motif, and it binds bilirubin with exceptionally high affinity (2 nM) (Battiston et al., 1998). This motif is also present in α-phycocyanines, biliproteins present in cyanobacteria. BRT also takes up a variety of cholephilic organic anions such as bromosulphophthalein (BSP), the related phthalein thymol blue, the antibiotic, rifamycin, and the vitamin precursor, nicotinic acid (Župerl et al., 2011). Sulfobromophthalein has been shown to be transported electrogenically (Passamonti et al., 2005). The carrier may exist in two interchangeable forms with high (5 μM for BSP) and low (37 μM for BSP) affinities for its substrates. Phenylmethylsulfonyl fluoride inactivates bilitranslocase (Passamonti et al., 1999).

The bilitranslocase exhibits 3-5 peaks of hydrophobicity, each of a length sufficient to pass through the membrane as an α-helix. The first is a 'certain' transmembrane α-helix spanner (TMS) according to the TopPred program, and the amphipathicity of two more have been reported (Choudhury et al. 2013). The topology is therefore uncertain. The rat bilitranslocase shows sequence similarity with no other protein in the NCBI database as of July 2012, not even in mice or humans. However, it may be more wide spread (Petrussa et al., 2010). One of the putative TMSs has been shown to be α-helical (Perdih et al., 2012). Rat liver shows increased expression of bilitranslocase from animals with obstructive cholestasis (Brandoni et al., 2010). Bilitranslocase mediates the uptake of some flavenoids such as cyanidin-3-glucoside which may have a protective effect against oxidative stress (Ziberna et al., 2012).

The presumed transport reaction catalyzed by bilitranslocase is:

Bilirubin (out) + nNa+ (out) → bilirubin (in) + nNa+ (in)

References associated with 2.A.65 family:

Battiston, L., S. Passamonti, A. Macagno, and G.L. Sottocasa. (1998). The bilirubin-binding motif of bilitranslocase and its relation to conserved motifs in ancient biliproteins. Biochem. Biophys. Res. Commun. 247: 687-692. 9647754
Brandoni, A., G. Di Giusto, R. Franca, S. Passamonti, and A.M. Torres. (2010). Expression of kidney and liver bilitranslocase in response to acute biliary obstruction. Nephron Physiol 114: p35-40. 20110735
Passamonti, S., L. Battiston, and G.L. Sottocasa. (1999). On the mechanism of bilitranslocase transport inactivation by phenylmethylsulphonyl fluoride. Mol. Membr. Biol. 16: 167-172. 10417981
Passamonti, S., M. Terdoslavich, A. Margon, A. Cocolo, N. Medic, F. Micali, G. Decorti, and M. Franko. (2005). Uptake of bilirubin into HepG2 cells assayed by thermal lens spectroscopy. Function of bilitranslocase. FEBS J. 272: 5522-5535. 16262692
Perdih, A., A. Roy Choudhury, S. Zuperl, E. Sikorska, I. Zhukov, T. Solmajer, and M. Novič. (2012). Structural analysis of a Peptide fragment of transmembrane transporter protein bilitranslocase. PLoS One 7: e38967. 22745694
Petrussa, E., E. Braidot, M. Zancani, C. Peresson, A. Bertolini, S. Patui, V. Casolo, S. Passamonti, F. Macrì, and A. Vianello. (2010). Immunohistochemical localisation of a putative flavonoid transporter in grape berries. Methods Mol Biol 643: 291-306. 20552459
Roy Choudhury, A., A. Perdih, S. Zuperl, E. Sikorska, T. Solmajer, S. Jurga, I. Zhukov, and M. Novič. (2013). Structural elucidation of transmembrane transporter protein bilitranslocase: conformational analysis of the second transmembrane region TM2 by molecular dynamics and NMR spectroscopy. Biochim. Biophys. Acta. 1828: 2609-2619. 23774522
Roy Choudhury, A., E. Sikorska, J. van den Boom, P. Bayer, &.#.3.2.1.;. Popenda, K. Szutkowski, S. Jurga, M. Bonomi, A. Sali, I. Zhukov, S. Passamonti, and M. Novič. (2015). Structural Model of the Bilitranslocase Transmembrane Domain Supported by NMR and FRET Data. PLoS One 10: e0135455. 26291722
Szutkowski, K., E. Sikorska, I. Bakanovych, A.R. Choudhury, A. Perdih, S. Jurga, M. Novič, and I. Zhukov. (2019). Structural Analysis and Dynamic Processes of the Transmembrane Segment Inside Different Micellar Environments-Implications for the TM4 Fragment of the Bilitranslocase Protein. Int J Mol Sci 20:. 31454948
Ziberna, L., F. Tramer, S. Moze, U. Vrhovsek, F. Mattivi, and S. Passamonti. (2012). Transport and bioactivity of cyanidin 3-glucoside into the vascular endothelium. Free Radic Biol Med 52: 1750-1759. 22387282
Župerl, &.#.3.5.2.;., S. Fornasaro, M. Novič, and S. Passamonti. (2011). Experimental determination and prediction of bilitranslocase transport activity. Anal Chim Acta 705: 322-333. 21962375