ATP-binding Cassette Transporter Superfamily

Wilcox. L.J., Balderes, D.A., Wharton, B., Tinkelenberg. A.H.. Rao, G, and Sturley, S.L. (2002) Transcriptional profiling identifies two members of the ATP-binding cassette transporter superfamily required for sterol uptake in yeast. The Journal of Biological Chemistry, 277, 32466-32472. 

ABC, ATP-binding cassette transporter superfamily ASBT, apical sodium-dependent bile salt transporter BCRP, breast cancer resistance protein BSEP, bile salt export pump MDRl, multidrug resistance MRR multidrug resistance-related protein NTCP, sodium taurocholate cotransporting polypeptide OAT, organic anion transporter OCT, organic cation transporter SLC, solute-linked carrier transporter family SLCO, solute-linked carrier organic anion transporter family. 

The ATP-binding cassette (ABC) superfamily and the major facilitator (MF) superfamily account for the majority of membrane transporters. 

MDR is a major issue for cancer chemotherapy that must be overcome for the successful use of many anti-cancer agents. One member of the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily of membrane transporters that has been studied extensively for molecular imaging purposes has been the 170 kDa transmembrane glycoprotein, P-glycoprotein (Pgp). Two widely studied Tc-labeled agents that have been used for SPECT imaging of MDR... 

To date more than 400 membrane proteins have been annotated in the human genome. Two major superfamilies - which are also intensively investigated in our group - are the ATP- binding cassette transporters (ABC, e.g. P-glycoprotein), and the solute carrier superfamily (SLC). They will be discussed into more detail in section 3 of this chapter. 

Currently, five different molecular classes of mdr efflux pumps are known [5], While pumps of the the ATP-binding cassette (ABC) transporter superfamily are driven by ATP hydrolysis, the other four superfamilies called resistance-nodulation-division (RND), major facilitator superfamily (MFS), multidrug and toxic compound extrusion (MATE), and small multidrag resistance transporter (SMR) are driven by the proton-motive force across the cytoplasmic membrane. Usually a single pump protein is located within the cytoplasmic membrane. However, the RND-type pumps which are restricted to Gram-negative bacteria consist of two additional components, a periplasmic membrane fusion protein (MFP) which connects the efflux pump to an outer... 

The presence at the BBB of members of the multidrug resistance-associated protein (MRPs) family, whose members preferentially transport anionic compounds, is still controversial. The seven members of the MRP family belong, like P-gp, to the ATP-binding cassette (ABC) protein superfamily. Mrpl has been found at the BBB in isolated rat brain capillaries, primary cultures of brain capillary endothelial cells and in immortalized capillary endothelial cells, but not in human brain capillaries [59]. Another member, MRP2 has been found at the luminal membrane of the brain endothelial cells [60]. However, further studies are required to show that there are MRP transporters at the BBB (Figure 15.5). As for P-gp, a functional Mrpl was found in primary cultured rat astrocytes [56] and it has been shown to take part in the release of glutathione disulfide from brain astrocytes under oxidative stress [61]. 

ABC transporters are multidomain systems that translocate substrates across membranes. A common characteristic is the well-conserved ATP binding cassette (ABC) domain that couples ATP hydrolysis to transport. Members of this group of proteins constitute the largest superfamily of transport components, and they are found in all organisms from Archaea to humans. According to the work of Dassa, who developed a classification based on the ATPase components, the ABC systems can be divided into a number of subfamilies (for details see http //www.pasteur.fr/recherche/unites/pmtg/abc/) [136]. 

Dean, M., Rzhetsky, A. and Allikmets, R. (2001) The human ATP-binding cassette (ABC) transporter superfamily. Genome Research, 11, 1156-1166. 

Hinoshita, E., Uchiumi, T., Taguchi, K., Kinukawa, N., Tsuneyoshi, M., Maehara, Y., Sugimachi, K. and Kuwano, M. (2000) Increased expression of an ATP-binding cassette superfamily transporter, multidrug resistance protein 2, in human colorectal carcinomas. Clinical Cancer Research, 6, 2401-2407. 

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