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Diseases Associated with ABC Transporters November 4, 2013. By: Mariam Sardar, Neha Ramani, Kristina Vranjesevic, Nneka Nwaogu. PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson. What are ABC transporters?. ATP- Binding Cassette Transporter
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ATP- Binding Cassette Transporter
Substrates: Sugars, amino acids, ions, peptides, hormones, etc.
Main functions functions:
2 Nucleotide Binding Domains (NBD) in the cytoplasmic side - ATP binding domains
2 Transmembrane Domains (TMD)
Uses 2 molecules of ATP per transport cycle
Many theories on mechanism
1)Substrate binds to high affinity site on transmembrane domain
2) Allows for 2 ADP to be exchanged for 2 ATP at the ATPase site in NBD
3) The 2 NBD dimerize when bound to ATP
4) Dimerizations allows substrate in cavity in transmembrane domain to be released to other side
5) Hydrolysis of ATP restores transporter back to initial conformation
Ribosomal protection: reduction of accessibility of ribosomal target site of MLS drugs
NBD2 binds a membrane spanning protein causing it to efflux MLS antibiotic
(Kerr, Reynolds, & Covet, 2005)
ABCC1/MRP1 (multi-drug resistance associated protein)
Vanadate replaces phosphate during ATP hydrolysis, stabilizing transition state conformation
e.g.Small hydrophobic peptide derivatives (Reversins) interact with PGP with high affinity and selectivity
-there are approximately 13 known genetic disorders linked to defects of ABC transporters (50) in humans
-some of these genetic diseases include; cystic fibrosis, Stargardt disease, age-related macular degeneration, adrenoleukodystrophy, Tangier disease, Dubin-Johnson syndrome and progressive familial intrahepatic cholestasis.
-these genetic disorders and the associated transporter are illustrated in the next slide
-Cystic Fibrosis (CF), also known as mucoviscidosis, is an autosomal recessive genetic disorder
-most common among Caucasians, where 4% of people of European descent are carriers for CF
-associated with a mutation of the gene that encodes for cystic fibrosis conductance regulator (CFTR) protein gene located on chromosome 7 in the human genome
-production of large amounts of thick mucus;
issues in all of the bodys exocrine glands
-mucus lining organs of lungs, pancreas and other organs thicker and stickier
-releasing abnormal amounts of salt from sweat glands --> characteristic sign of salty skin in children (sweat test)
-blockages leading to difficulty breathing, digestive issues and infertility
-chronic infections as bacteria become trapped in mucus
-over 1,700 types of mutation associated with CFTR protein
-most common one implicated in CF is called ΔF508 ( ~ 70 % of cases worldwide)
-caused by the deletion of phenylalanine at position 508 within the CFTR protein
-as a result protein does not fold properly and is subsequently degraded by the cell
-CFTR protein channel normally involved in regulating the flow of water and chloride ions across an epithelial membrane (lungs, pancreas, sweat glands etc)
-mutation of the CFTR protein leads to a blockage of the transporter, disallowing the movement of ions out of the cells
-leads to high salt formation in sweat glands and formation of thick, dehydrated mucus in passageways
-ABC efflux transporters represent the molecular basis of selective, active BBB function. They actively clear the brain of metabolic wastes and prevent xenobiotics, including harmful toxicants and a vast number of therapeutic drugs, from entering the brain.
-The importance of P-glycoprotein, BCRP, and the MRPs for the BBB are due to four critical characteristics these transporters share:
1) substantial amount
2) localization in the luminal plasma membrane of brain capillary endothelial cells, at the interface between blood and CNS
3) efflux transport against a concentration gradient
4) broad substrate spectrum that covers a wide range of structurally diverse therapeutic drugs such as morphine and cyclosporine A
-These characteristics allow ABC drug efflux transporters at the BBB to protect the brain from toxicants but also restrict therapeutic drugs from entering the brain, and thus, impairing effective CNS pharmacotherapy
-Understanding intracellular signaling pathways and networks, and identifying molecular switches that regulate ABC transporters at the BBB, will provide new molecular targets for CNS therapy.
Two strategies have been introduced to overcome efflux transporter-mediated barrier:
1) Transporter Inhibition to Improve Brain Drug Delivery- However humans transporter inhibitors seem to have low potency, weak effectiveness, and poor selectivity, and would have to be given chronically at high doses to block transporter function effectively.
2) Targeting ABC Transporter Regulation- finding the molecular switches of these transporters will allow selective modulation of transporter function and/or expression for therapeutic purposes.
Cuthbert, A. W., (1992). “The biochemical defect in cystic fibrosis”. Journal of the Royal Society of Medicine, 19(85), 1-5. Web. 31 Oct. 2013.
Dean, Michael, Yannick Hamon, and Giovanna Chimini. "The human ATP-binding cassette (ABC) transporter superfamily." Journal of Lipid Research. N.p., n.d. Web. 30 Oct. 2013. <http://www.jlr.org/content/42/7/1007.long>.
Glavinas, H., Kracjsci, P., Cserepes, J., & Sarkadi, B. (2004). “The Role of ABC Transporters in Drug Resistance, Metabolism and Toxicity”. Current Drug Delivery, 1(1), 27-42. Web. 31 Oct. 2013
Kerr, I., Reynolds, E., & Covet, J. (2005). “ABC Proteins and Antibiotic Drug Resistance: is it all about transport?”. Biochemistry Society Transactions, 33(5), 1000-1002. Web. 31 Oct. 2013
Stefkova, J., Poledne, R., & Hubacek, J.A. (2004). “ATP- Binding Cassette (ABC) Transporters in Human Metabolism and Diseases”. Physiological Research, 53, 235-243. Web. 31 Oct. 2013
Hartz, A . and Bauer, B. (2010). “Regulation of ABC Transporters at the Blood-Brain Barrier: New Targets for CNS therapy”. Mol. Interventions, 10(5), 293-304. Fri. 1 Nov 2013