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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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diseases associated with abc transporters november 4 2013

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
What are ABC transporters?

ATP- Binding Cassette Transporter

  • Superfamily of transmembrane proteins (7 classes) that use ATP hydrolysis for import and export of molecules across the plasma membrane, ER, mitochondria, etc.

Substrates: Sugars, amino acids, ions, peptides, hormones, etc.

Main functions functions:

  • Cell division
  • Nutrient uptake
  • Antigen processing
  • Pathogenesis
abc transporter
ABC Transporter

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

normal function abc transporters
Normal Function ABC Transporters

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

mls antibiotic resistance
MLS Antibiotic Resistance
  • NBD2 Transporters: ABC transporters involved in MLS (macrolide, lincosamide and streptogramin) antibiotic resistance and consisting of two NBDs
  • Antibiotic site of action is in ribosomal polypeptide exit tunnel
  • Two proposed mechanisms of NBD2
mechanism of antibiotic resistance
Mechanism of Antibiotic Resistance

Ribosomal protection: reduction of accessibility of ribosomal target site of MLS drugs

OR

NBD2 binds a membrane spanning protein causing it to efflux MLS antibiotic

(Kerr, Reynolds, & Covet, 2005)

abc transporters and anticancer resistance
ABC Transporters and Anticancer Resistance
  • Tumors are associated with overexpression of certain subfamilies of ABC transporters
  • Results in increase production of MDR and MRP transporters

ABCB (MDR1/P-glycoprotein)

  • first to describe multidrug resistance (MDR) in cancer cells
  • perfect anti-cancer drug efflux transporter due to broad transport specificity

ABCC1/MRP1 (multi-drug resistance associated protein)

  • Non- P-glycoprotein associated resistance
  • organic anion transporter and hydrophobic drugs
abc transporters and anticancer resistance1
ABC Transporters and Anticancer Resistance

MRP4

  • Confers resistance to 9-(2-phosphonylmethoxyethyl) guanine (PMEG)
  • PMEG has antineoplastic activity

MRP5

  • Transports drugs involved in treatment of acute lymphoblastic or myeloid leukemia

ABCG2

  • Half transporters- only one TBD and one NBD
  • Multidrug resistance of in breast cancer
  • Resistance to Mitoxantrone, Topotecan and Methotrexate
overcoming anticancer resistance
Overcoming Anticancer Resistance
  • Goal is to develop anticancer agents that do not interacts with multidrug resistance transporters
  • Activity of all ABC transporters have been inhibited by Vanadate

Vanadate replaces phosphate during ATP hydrolysis, stabilizing transition state conformation

  • MDR modifying agents: inhibit function of MDR protein competitively or noncompetitively

e.g.Small hydrophobic peptide derivatives (Reversins) interact with PGP with high affinity and selectivity

genetic disorders abc transporters
Genetic Disorders & ABC Transporters

-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
Cystic Fibrosis

-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

signs symptoms
Signs & Symptoms

-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

mutation of cftr
Mutation of CFTR

-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

pathophysiology
Pathophysiology

-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 transporters at the blood brain barrier
ABC Transporters at the Blood- Brain Barrier

-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

targeting abc efflux transporters to improve cns pharmacology
Targeting ABC Efflux Transporters to Improve CNS Pharmacology

-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.

overcoming abc transporter efflux
Overcoming ABC Transporter Efflux

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.

citations
Citations

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

summary
Summary
  • ATP Binding Cassette Transporters are used for import and export of molecules (ex. sugars, ions, amino acids, etc.) for cell functions like cell division and nutrient uptake
  • Binding of 2 ATP molecules allows for conformational change to deliver molecule from one side of the membrane to the other
  • NBD2 Transporters: ABC transporters involved in MLS (macrolide, lincosamide and streptogramin) antibiotic resistance and consisting of two NBDs
  • MLS target ribosomal polypeptide exit tunnels
  • Mechanisms of NBD2: Ribosomal Protection and association with membrane spanning proteins
  • Tumors overexpress subfamilies of efflux ABC transporters (e.g. MDR1, MRP1, MRP4, MRP5, ABCG2)
  • Overexpression of ABC transporters results in anticancer resistance
  • MDR modifying agents: inhibit function of MDR protein competitively or noncompetitively
  • 13 genetic disorders associated with defects in ABC transporters including; cystic fibrosis, Stargardt disease, age-related macular degeneration, adrenoleukodystrophy, Tangier disease, Dubin-Johnson syndrome and progressive familial intrahepatic cholestasis
  • cystic fibrosis linked to the CFTR mutation responsible for chloride ion channels in epithelial cell membranes, blocking the flow of ions out of the cells
  • formation of thick mucus in passageways and increased salt levels in sweat; issues with respiratory system, biliary secretion, digestion, reproduction
  • ABC efflux transporters at the BBB restrict delivery of drugs into the brain, which severely impairs pharmacotherapy of CNS disorders.