Membrane transport proteins superfamily

Membrane transport proteins having the ABC molecular domain (ATP-binding cassette), characteristic of a large superfamily of proteins that hydrolyse ATP and transport a diverse array of small molecules across membranes. 

Paulsen and colleagues (114, 115) determined the distribution of membrane transport proteins for all organisms with completely sequenced genomes and identified 81 distinct families. Two superfamilies, the ATP-binding cassette (ABC) and major facilitator... 

A FIGURE 18-1 Overview of synthesis of major membrane lipids and their movement into and out of cells. Membrane lipids (e.g., phospholipids, cholesterol) are synthesized through complex multienzyme pathways that begin with sets of water-soluble enzymes and intermediates in the cytosol (D) that are then converted by membrane-associated enzymes into water-insoluble products embedded in the membrane (B), usually at the interface between the cytosolic leaflet of the endoplasmic reticulum (ER) and the cytosol. Membrane lipids can move from the ER to other organelles (H), such as the Golgi apparatus or the mitochondrion, by either vesicle-mediated or other poorly defined mechanisms. Lipids can move into or out of cells by plasma-membrane transport proteins or by lipoproteins. Transport proteins similar to those described in Chapter 7 that move lipids (0) include sodium-coupled symporters that mediate import CD36 and SR-BI superfamily proteins that can mediate... 

P-glycoprotein (P-gp) is a member of the ATP-binding cassette superfamily of membrane transport proteins responsible for the efflux of many drugs. It represents a major component of the blood-brain barrier and the intestinal barrier, and contributes to renal and biliary elimination of drugs. At the blood-brain barrier, P-gp is localized in the apical membrane of brain capillary endothelial cells and transports substrates into the blood. Therefore, P-gp limits the penetration into and retention of numerous compounds, including the antidepressants, within the brain and, thus, modulate their effectiveness and CNS toxicity. 

The ABC-transporter superfamily represents a large group of transmembrane proteins. Members of this family are mainly involved in ATP-dependent transport processes across cellular membranes. These proteins are of special interest from a pharmacological point of... 

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]. 

Figure 15.2 Transport proteins involved in the intestinal absorption and the renal and hepatic excretion of drugs. In the intestine, drugs are taken up from the luminal side into enterocytes before the subsequent elimination into blood. In hepatocytes, drugs are taken up from the blood over the basolateral membrane and excreted over the canalicular membrane into bile. In the renal epithelium, drugs undergo secretion (drugs are taken up from the blood and excreted into the urine) or reabsorption (drugs are taken up from the urine and are excreted back into blood). Uptake transporters belonging to the SLC transporter superfamily are shown in red and export pumps...

Juranka PF, Zastawny RL, Ling V. P-glycoprotein multidrug-resistance and a superfamily of membrane-associated transport proteins. FASEB J 1989 3(14) 2583-2592. 

Conjugation of lipophilic xenobiotics to polar cellular constituents renders the xenobiotic more water-soluble. While the lipophilic parent xenobiotics could readily diffuse into the cells, the increase in polarity associated with conjugation greatly reduces the ability of the compound to diffuse across the lipid bilayer of the cell membrane thus trapping the compound within the cell. The polar conjugates must therefore rely upon active transport processes to facilitate efflux from the cell. Hepatocytes, as well as other cells involved in chemical detoxification, are rich with members of the ATP-binding cassette superfamily of active transport proteins (ABC transporters). Cellular efflux of xenobiotics by these transporters is often referred to as Phase III elimination because Phase I or II detoxification processes often precede and are a requirement of Phase III elimination. A detailed description and discussion of elimination and transporters is presented in Chapter 15. 

The Na +/taurocholate cotransport system Ntcp belongs to the "solute carrier superfamily (SLC) and represents one of the best-studied transport proteins in the basolateral membrane. It transports taurocholate and other conjugated bile acids from the blood into hepatocytes. In addition, an ontogenetically presumably older and Na-independent protein (Oatpl) is expressed in the basolateral membrane. 

This family of proteins was at one time thought to be a member of the MFS superfamily due to similar membrane topology. However, they show no sequence homology and are now described as a separate family of transporter proteins. Proteins in this family use a sodium gradient as the energy source for effluxing drugs such as the fluoroquinolines and other dyes. 

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