Unlocking the Power of ABC Transporters: Unveiling their Functions in Cellular Homeostasis and Polypharmacological Resistance
DOI:
https://doi.org/10.31580/pjmls.v7i4.3191Keywords:
: ABC transporters, Concentration gradient, Confirmational domains, Cystic fibrosis, Multi-drug resistanceAbstract
Abstract
A major class of membrane proteins are ABC transporters which employed for various activities like the transportation of substances from exterior to intracellular environment and vice versa. These proteins requires energy in the form of ATP for the movement of substrate in the direction opposite to substrate asymmetry. These transporters are responsible for transporting materials across the plasma membrane in all organisms in both prokaryotes like bacteria and eukaryotes like humans. They have vital role in the homeostasis of various cells, nutrient balance and also involve in the multi-drug resistance . They consists of two domains for nucleotide binding and two for the material that crosses the semipermeable they also have some components like coupling helices and accessory domains also which are needed to Carry out specific functions. There is different genetic makeup for both prokaryotes and eukaryotes, like eukaryotes have a one gene responsible for the expression of partial or complete numbers of transporters . The mechanism of ABC transporters is altering the configurations like they are involve in the confirmational changes which are required for the transportation of substrate. ABC-transporters have multiple types and sub-types based on their functions and each have an important role in a specific function like in humans ABCA to ABCG linked with the transport of lipids and drug resistance. ABC transporters are clinically much important as they are involved in the multi-drug resistance during treating malignancy . Malfunctioning of chloride ion channel due to fault in the CFTR causing cystic fibrosis. It is necessary to understand the structure and functions of ATP transporters so that we can defeat health problems like cystic fibrosis and multi-drug resistance.
References
Akhtar AA, Turner DP. The role of bacterial ATP-binding cassette (ABC) transporters in pathogenesis and virulence: Therapeutic and vaccine potential. Microb Pathog. 2022;171:105734.
Vankeerberghen A, Cuppens H, Cassiman JJ. The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions. J Cyst Fibros. 2002;1(1):13–29.
Biemans-Oldehinkel E, Doeven MK, Poolman B. ABC transporter architecture and regulatory roles of accessory domains. FEBS Letters. 2006;580(4):1023–35.
Thomas C, Tampé R. Structural and Mechanistic Principles of ABC Transporters. Annu Rev Biochem. 2020;89:605–36.
Leonard GD, Fojo T, Bates SE. The role of ABC transporters in clinical practice. Oncologist. 2003;8(5):411–24.
Thomas C, Aller SG, Beis K, Carpenter EP, Chang G, Chen L. Structural and functional diversity calls for a new classification of ABC transporters. FEBS Lett. 2020;594(23):3767–75.
Jones PM, George AM. The Switch and Reciprocating Models for the Function of ABC Multidrug Exporters: Perspectives on Recent Research. Int J Mol Sci. 2023 Jan 30;24(3):2624.
Choi YH, Yu AM. ABC Transporters in Multidrug Resistance and Pharmacokinetics, and Strategies for Drug Development. Curr Pharm Des. 2014;20(5):793–807.
Moore JM, Bell EL, Hughes RO, Garfield AS. ABC transporters: human disease and pharmacotherapeutic potential. Trends in Molecular Medicine. 2023;29(2):152–72.
Guna A, Hegde RS. Transmembrane Domain Recognition during Membrane Protein Biogenesis and Quality Control. Current Biology. 2018;28(8):R498–511.
Sharpe HJ, Stevens TJ, Munro S. A Comprehensive Comparison of Transmembrane Domains Reveals Organelle-Specific Properties. Cell. 2010;142(1):158–69.
Wen PC, Tajkhorshid E. Conformational Coupling of the Nucleotide-Binding and the Transmembrane Domains in ABC Transporters. Biophys J. 2011;101(3):680–90.
Liu S, Zhou S, Tian L, Guo E, Luan Y, Zhang J, et al. Genome-wide identification and characterization of ATP-binding cassette transporters in the silkworm, Bombyx mori. BMC Genomics. 2011;12(1):491.
Furuta T, Yamaguchi T, Kato H, Sakurai M. Analysis of the Structural and Functional Roles of Coupling Helices in the ATP-Binding Cassette Transporter MsbA through Enzyme Assays and Molecular Dynamics Simulations. Biochemistry. 2014;53(26):4261–72.
Wen PC, Tajkhorshid E. Conformational Coupling of the Nucleotide-Binding and the Transmembrane Domains in ABC Transporters. Biophys J. 2011;101(3):680–90.
Srikant S, Gaudet R. Mechanics and Pharmacology of Substrate Selection and Transport by Eukaryotic ABC Exporters. Nat Struct Mol Biol. 2019;26(9):792–801.
Srikant S, Gaudet R. Mechanics and pharmacology of substrate selection and transport by eukaryotic ABC exporters. Nat Struct Mol Biol. 2019;26(9):792–801.
Do THT, Martinoia E, Lee Y, Hwang JU. 2021 update on ATP-binding cassette (ABC) transporters: how they meet the needs of plants. Plant Physiol. 2021;187(4):1876–92.
Biemans-Oldehinkel E, Doeven MK, Poolman B. ABC transporter architecture and regulatory roles of accessory domains. FEBS Letters. 2006;580(4):1023–35.
Yu J, Ge J, Heuveling J, Schneider E, Yang M. Structural basis for substrate specificity of an amino acid ABC transporter. Proceedings of the National Academy of Sciences. 2015;112(16):5243–8.
Davies JS, Currie MJ, Wright JD, Newton-Vesty MC, North RA, Mace PD, Allison JR, Dobson RC. Selective nutrient transport in bacteria: multicomponent transporter systems reign supreme. Frontiers in Molecular Biosciences. 2021;8:699222.
Choi CC, Ford RC. ATP binding cassette importers in eukaryotic organisms. Biological Reviews. 2021;96(4):1318–30.
Du D, Wang-Kan X, Neuberger A, van Veen HW, Pos KM, Piddock LJV, et al. Multidrug efflux pumps: structure, function and regulation. Nat Rev Microbiol. 2018;16(9):523–39.
Poelarends GJ, Mazurkiewicz P, Putman M, Cool RH, Veen HW van, Konings WN. An ABC-type multidrug transporter of Lactococcus lactis possesses an exceptionally broad substrate specificity. Drug Resist Updat. 2000;3(6):330–4.
Lubelski J, Konings WN, Driessen AJM. Distribution and Physiology of ABC-Type Transporters Contributing to Multidrug Resistance in Bacteria. Microbiol Mol Biol Rev. 2007 ;71(3):463–76.
Orelle C, Mathieu K, Jault JM. Multidrug ABC transporters in bacteria. Research in Microbiology. 2019;170(8):381–91.
Davidson AL, Maloney PC. ABC transporters: how small machines do a big job. Trends in Microbiology. 2007;15(10):448–55.
Da Poian AT, Castanho MA, Da Poian AT, Castanho MA. Energy conservation in metabolism: the mechanisms of ATP synthesis. Integrative Human Biochemistry: A Textbook for Medical Biochemistry. 2021:301-62.
Bittar E, editor. Cell Chemistry and Physiology: Part IV. Elsevier; 1996;4(II):1–47.
Nicolaï A, Delarue P, Senet P. Decipher the Mechanisms of Protein Conformational Changes Induced by Nucleotide Binding through Free-Energy Landscape Analysis: ATP Binding to Hsp70. PLoS Comput Biol. 2013;9(12):e1003379.
Guo J, Zhou HX. Protein Allostery and Conformational Dynamics. Chem Rev. 2016;116(11):6503–15.
Akhtar AA, Turner DPJ. The role of bacterial ATP-binding cassette (ABC) transporters in pathogenesis and virulence: Therapeutic and vaccine potential. Microbial Pathogenesis. 2022;171:105734.
Srikant S, Gaudet R. Mechanics and Pharmacology of Substrate Selection and Transport by Eukaryotic ABC Exporters. Nat Struct Mol Biol. 2019;26(9):792–801.
Dunn J, Grider MH. Physiology, Adenosine Triphosphate. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025.
Schneider E, Hunke S. ATP-binding-cassette (ABC) transport systems: functional and structural aspects of the ATP-hydrolyzing subunits/domains. FEMS Microbiol Rev. 1998;22(1):1–20.
Forrest LR, Krämer R, Ziegler C. The structural basis of secondary active transport mechanisms. Biochimica et Biophysica Acta (BBA) - Bioenergetics. 2011;1807(2):167–88.
Latorraca NR, Fastman NM, Venkatakrishnan AJ, Frommer WB, Dror RO, Feng L. Mechanism of Substrate Translocation in an Alternating Access Transporter. Cell. 2017;169(1):96-107.e12.
Ruprecht JJ, Kunji ER. Structural changes in the transport cycle of the mitochondrial ADP/ATP carrier. Current Opinion in Structural Biology. 2019;57:135–44.
Linton KJ, Higgins CF. Structure and function of ABC transporters: the ATP switch provides flexible control. Pflugers Arch - Eur J Physiol. 2007;453(5):555–67.
Lewinson O, Orelle C, Seeger MA. Structures of ABC transporters: handle with care. FEBS Lett. 2020;594(23):3799–814.
Wen PC, Tajkhorshid E. Conformational Coupling of the Nucleotide-Binding and the Transmembrane Domains in ABC Transporters. Biophys J. 2011;101(3):680–90.
Locher KP. Structure and mechanism of ATP-binding cassette transporters. Philos Trans R Soc Lond B Biol Sci. 2009;364(1514):239–45.
Locher KP. Mechanistic diversity in ATP-binding cassette (ABC) transporters. Nat Struct Mol Biol. 2016;23(6):487–93.
Thurm C, Schraven B, Kahlfuss S. ABC Transporters in T Cell-Mediated Physiological and Pathological Immune Responses. International Journal of Molecular Sciences. 2021;22(17):9186.
Vasiliou V, Vasiliou K, Nebert DW. Human ATP-binding cassette (ABC) transporter family. Hum Genomics. 2009;3(3):281–90.
Roberts AG. The Structure and Mechanism of Drug Transporters. Methods Mol Biol. 2021;2342:193–234.
Szakács G, Váradi A, Ozvegy-Laczka C, Sarkadi B. The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). Drug Discov Today. 2008;13(9–10):379–93.
Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer. 2018;18(7):452–64.
Leslie EM, Deeley RG, Cole SPC. Toxicological relevance of the multidrug resistance protein 1, MRP1 (ABCC1) and related transporters. Toxicology. 2001;167(1):3–23.
Emran TB, Shahriar A, Mahmud AR, Rahman T, Abir MH, Siddiquee MohdFR, et al. Multidrug Resistance in Cancer: Understanding Molecular Mechanisms, Immunoprevention and Therapeutic Approaches. Front Oncol. 2022;12:891652.
El-Ashmawy NE, Al-Ashmawy GM, Hamada OB, Khedr NF. The role of ABCG2 in health and disease: Linking cancer therapy resistance and other disorders. Life Sciences. 2025;360:123245.
Choi YH, Yu AM. ABC Transporters in Multidrug Resistance and Pharmacokinetics, and Strategies for Drug Development. Curr Pharm Des. 2014;20(5):793–807.
Sun YL, Patel A, Kumar P, Chen ZS. Role of ABC transporters in cancer chemotherapy. Chin J Cancer. 2012;31(2):51–7.
Begley DJ. ABC transporters and the blood-brain barrier. Curr Pharm Des. 2004;10(12):1295–312.
Kimura Y, Morita S ya, Matsuo M, Ueda K. Mechanism of multidrug recognition by MDR1/ABCB1. Cancer Sci. 2007;98(9):1303–10.
Kimura Y, Matsuo M, Takahashi K, Saeki T, Kioka N, Amachi T. ATP hydrolysis-dependent multidrug efflux transporter: MDR1/P-glycoprotein. Curr Drug Metab. 2004;5(1):1–10.
Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE. Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics. 2011;21(3):152–61.
Hanssens LS, Duchateau J, Casimir GJ. CFTR Protein: Not Just a Chloride Channel? Cells. 2021;10(11):2844.
Lukasiak A, Zajac M. The Distribution and Role of the CFTR Protein in the Intracellular Compartments. Membranes (Basel). 2021;11(11):804.
Levring J, Terry DS, Kilic Z, Fitzgerald G, Blanchard SC, Chen J. CFTR function, pathology and pharmacology at single-molecule resolution. Nature. 2023;616(7957):606–14.
Seelig A. P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers. Front Oncol. 2020;10:576559.
Downloads
Published
Issue
Section
License
Copyright (c) 2024 Pak-Euro Journal of Medical and Life Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
