Call us
301-363-4651 (Available 9 a.m. to 5 p.m. CST from Monday to Friday)
ATP-binding cassette (ABC) transporters are the largest known transmembrane protein superfamily, widely distributed in eukaryotes and prokaryotes. ABC proteins bind and hydrolyze ATP and use energy to drive various molecules across the plasma membrane as well as the endoplasmic reticulum (ER), peroxisome and mitochondrial inner membrane [1][2]. It is involved in the transport of specific molecules on the lipid membrane and the resistance in all organisms.
Figure 1. The Structure of ATP-binding cassette
The picture is from wikipedia
Figure 2. Three basic organization forms of ABC transporters
ABC protein has a typical modular structure, consisting of four protein domains or subunits: two hydrophobic transmembrane domains (TMD) are considered to constitute transmembrane transport pathways or channels (usually composed of six transmembrane alpha helix); two hydrophilic nucleotide binding domains (NBDs) (ATP binding domains, known as nucleotide binding folding (NBF)) provide energy for active transport [2]. NBF contains three conserved domains: Walker A and B domains, and C motif [3]. The C domain is unique to the ABC transporter.
In addition to the complete transporters, there are also half transporters that contain one of each domain.
Figure 2. The structure and transport process of ABC
The ATP-binding cassette (ABC) transporter superfamily transfers a variety of substrates, including sugars, amino acids, metal ions, peptides and proteins, as well as a large number of hydrophobic compounds and metabolites across the extracellular and intracellular membranes.
ABC transporters are one of the largest known protein superfamily: there are 49 ABC transporters in humans and 80 in gram-negative E. coli bacteria.
The ABC gene in the human genome is divided into 7 subfamilies (ABCA~ABCG) based on amino acid sequence similarity and phylogeny. The following table is a list of human ABC genes.
Table 1 List of human ABC genes and function
| Subfamily | Member | Function |
|---|---|---|
| ABCA | ABCA1 | Cholesterol efflux onto HDL |
| ABCA2 | Drug resistance | |
| ABCA3 | Phosphatidyl choline efflux | |
| ABCA4 | N-retinylidiene-PE efflux | |
| ABCA5; ABCA6; ABCA7;ABCA8; ABCA9; ABCA10; ABCA11; ABCA12; ABCA13. | / | |
| ABCB | ABCB1 | Multidrug resistance |
| ABCB3 | Peptide transport | |
| ABCB4 | PC transport | |
| ABCB5 | Iron transport | |
| ABCB6 | Fe/S cluster transport | |
| ABCB11 | Bile salt transport | |
| ABCB2; ABCB7; ABCB8; ABCB9; ABCB10. | / | |
| ABCC | ABCC1 | Drug resistance |
| ABCC2 | Organic anion efflux | |
| ABCC3 | Drug resistance | |
| ABCC4 | Nucleoside transport | |
| ABCC5 | Nucleoside transport | |
| CFTR (ABCC7) | Chloride ion channel | |
| ABCC8 | Sulfonylurea receptor | |
| ABCC9 | Potassium channel regulation | |
| ABCC6; ABCC10; ABCC11; ABCC12. | / | |
| ABCD | ABCD1 | VLCFA transport regulation |
| ABCD2; ABCD3; ABCD4. | / | |
| ABCE | ABCE1 | Elongation factor complex |
| ABCF | ABCF1; ABCF2; ABCF3. | / |
| ABCG | ABCG1 | Cholesterol transport |
| ABCG2 | Toxin efflux, drug resistance | |
| ABCG4 | Cholesterol transport | |
| ABCG5 | Sterol transport | |
| ABCG8 | Sterol transport |
The ATP-binding cassette (ABC) superfamily gene plays an important role in transporting compounds between the intestinal tract, the blood-brain barrier, and the placenta. It also plays an important role in the body's core function of resisting foreign bodies and detoxification [4]. Different subtypes have different functions and can act as drug efflux transporters (ABCB1, ABCC subfamily and ABCG2) or sterol transporters (ABCA1, ABCA7, ABCG1, ABCG5 and ABCG8).
In eukaryotes, most ABC genes move compounds from the cytoplasm to the extracellular or extracellular compartment (endoplasmic reticulum, mitochondria, peroxisomes). Its importance in eukaryotic systems has been fully demonstrated, characterized by its association with genetic diseases and its role in multidrug resistance to cancer.
In bacteria, the ABC gene is mainly involved in the import of essential compounds that cannot pass through cells through diffusion (eg, sugars, vitamins, metal ions, etc.). These genes play a role in nutrient absorption, toxin secretion and antibacterial drugs. The role of ABC transporters is mainly in the pathogenicity and toxicity of bacteria. In pathogenic bacteria, these functions are usually to evade or resist the host's defense. Therefore, many cell surfaces or secreted factors can be useful targets for antibacterial therapy or vaccine development.
ATP-binding cassette (ABC) transporter in plant is an important membrane protein used to transport a variety of compounds, including heavy metals, antibiotics, phytohormones and secondary metabolites [5]. The number of ABC family members in the plant genome has more than doubled compared to animals and insects.
In plants, ATP-binding cassette transporters have important physiological functions such as cell detoxification, cuticle formation, stomatal regulation, seed germination, and resistance to pathogenic bacteria.
In rice, several ATP-binding cassette transporters of the ABCG family are essential for cuticle formation [6].
In tomato, the ATP-binding cassette transporter is involved in the transport of tomato fruit auxin. As a member of the subfamily ABCB, SlABCB4 plays an important role in the transport of auxin during tomato fruit development.
In Arabidopsis, some members of the ABC transporter ABCB subfamily also are involved in auxin transport [7].
ABC transporters also play an important role in the detoxification of pesticides.
The ATP-binding cassette (ABC) transporter [8] was identified as an important detoxifying enzyme in Plutella xylostella.
Epis et al. [9] demonstrated the role of ABC transporters in insecticide defense.
The ATP-binding cassette (ABC) superfamily genes encode membrane proteins that transport different substrates on the cell membrane. The genetic variation of the ATP-binding cassette (ABC) transporter superfamily gene is the cause or contributing factor of various Mendelian diseases and complex genetic diseases in humans. The heterozygous variation in ABC gene mutations is related to the susceptibility of specific complex diseases.
Currently, there are 17 ABC genes related to Mendelian inheritance. These include adrenoleukodystrophy, cystic fibrosis, retinal degeneration, hypercholesterolemia and cholestasis, neurological diseases, anemia and drug reactions. Many of the ABC genes that cause disease lead to many different clinical phenotypes. For example, cystic fibrosis associated with specific CFTR genotypes includes pancreatic sufficiency and pancreatic insufficiency.
ABCA1 mediates the transport of intracellular free cholesterol and phospholipids through the cell membrane to poor apoA1 to form HDL [10]. It plays a key role in reverse cholesterol transport and cellular lipid efflux, is the initial rate-limiting step of reverted cholesterol transport (RCT) in macrophages [11], and is the most critical determinant of plasma high density lipoprotein (HDL) levels in hepatic cells.
Mutations in the ABCA1 gene may induce Tangier disease [12] and familial hypolipoproteinemia [13] and may also result in loss of cellular cholesterol homeostasis in prostate cancer. In the general population, some common single-nucleotide polymorphisms of ABCA1 also affect blood lipid levels, atherosclerosis generation and the severity of coronary heart disease [14].
In recent years, a large amount of evidence indicates that abnormal cholesterol metabolism may play an important role in the development of Alzheimer's disease AD (ABCA2/ABCA7), and apoE gene is also closely related to the metabolism of cholesterol in the brain [15].
Regulatory Factors of ABC1
The expression of the ABCA1 gene is mainly regulated by the liver X receptor (LXR)/retinoid X receptor (RXR).In addition, interferon- γ (IFN- γ ) inhibits liver X receptor α (LXR α ) through the JAK/STAT signaling pathway, which can down-regulate ABCA1 expression and intracellular cholesterol outflow [16].
Mutations in the ABCA4 gene lead to retinitis pigmentosa, recessive pyramidal malnutrition, and Stargardt disease [17]. All of these diseases are characterized by retinal degeneration, the severity of which is roughly related to the predicted severity of ABCA4 mutation. Patients with heterozygous mutation of ABCA4 gene are more likely to suffer from late-onset macular degeneration - age-related macular degeneration (AMD) [18]. Women with heterozygous mutations of liver transporters that lead to cholestasis may have a higher risk of cholestasis during pregnancy [19].
Members of the ABCG subfamily, ABCG5 and G8 are involved in the development of glutathione, a genetic disorder of lipid metabolism. ABCG1 mainly mediates the transport of intracellular free cholesterol to mature HDL. It works synergistically with ABCA1 to promote extracellular lipids out of the cell and complete reverse cholesterol transport in the body [20]. ABCG1 deficiency can also participate in foam cell formation, endothelial cell dysfunction and inflammatory response, and thus affects the formation and development of atherosclerosis.
Table 2 Diseases and phenotyes caused by ABC genes
| Gene | Mendelian disorder | Complex disease | Animal model |
|---|---|---|---|
| ABCA1 | Tangier disease, FHDLD | HDL levels | Mouse, chicken |
| ABCA3 | Surfactant deficiency | / | / |
| ABCA4 | Stargardt/FFM, RP, CRD | AMD | Mouse |
| ABCA12 | Lamellar ichthyosis | / | / |
| ABCB1 | Ivermectin sensitivitya | Digoxin uptake | Mouse, dog |
| ABCB2 | Immune deficiency | / | Mouse |
| ABCB3 | Immune deficiency | / | Mouse |
| ABCB4 | PFIC-3 | ICP | / |
| ABCB7 | XLSA/A | / | / |
| ABCB11 | PFIC-2 | / | / |
| ABCC2 | Dubin-Johnson Syndrome | / | Rat, sheep, monkey |
| ABCC6 | Pseudoxanthoma elasticum | / | Mouse |
| ABCC7 | Cystic Fibrosis, CBAVD | Pancreatitis, bronchiectasis | Mouse |
| ABCC8 | FPHHI | Mouse | |
| ABCC9 | DCVT | ||
| ABCD1 | ALD | Mouse | |
| ABCG5 | Sitosterolemia | Mouse | |
| ABCG8 | Sitosterolemia | Mouse |
This table derived from literature "Evolution of the ATP-binding cassette (ABC) transporter superfamily in vertebrates" [21]
Currently, chemotherapy is one of the approaches to cancer treatment, and multidrug resistance (MDR) is a major obstacle to successful chemotherapy [22]. MDR refers to the phenomenon that tumor cells are cross-resistant to a variety of structurally unrelated chemotherapeutic drugs. Clinically, drug resistance is caused by multiple factors. The efflux of cytotoxic drugs mediated by ATP-binding cassette transporters is the "classical MDR" pathway [23]. ABC transporters pump drugs out of cells and reduce the concentration of intracellular chemotherapy drugs. Overexpression of ABC transporters in tumor cells is the main mechanism of tumor MDR.
ATP binding cassette transporters (ABC transporters) can transport chemotherapy drugs to the extracellular environment and reduce intracellular drug concentration. There are four main types ATP binding cassette multidrug transporter: P-glycoprotein (P-gp, MDR1, ABCB1), Multidrug resistance-associated protein (MDR-related protein /MRP, ABCC), lung resistance-related protein (LRP) and breast cancer resistance protein (BCRP, ABCG2) [24].
Breast cancer resistance protein (BCRP, ABCG2) belongs to the ABCG gene family. The gene is located on chromosome 4 and is a recently discovered ABC drug efflux transporter. In structure, BCRP is "half transporter" [25].
Acquired MDR of hepatocellular carcinoma may be related to the expression of MRP1, MRP3 and MRP5 genes, and MRP2 is the main target of endogenous drug resistance, BCRP is a new drug efflux pump related to tumor MDR. Liver cancer MDR mediated by ATP-binding cassette transporter severely limits chemotherapy efficacy and prognosis.
Pancreatic cancer is resistant to a variety of chemotherapeutic drugs, and resistance is associated with the ATP-binding cassette (ABC) transport vector superfamily [26].
For MDR induced by ATP-binding cassette transporters, inhibition of ATP-binding cassette transporter-mediated drug efflux is the easiest and direct route.
Inhibitors of ABC transporters include competitive and non-competitive inhibitors. Currently, there are 3 generations of chemical reversals, most of which are competitive inhibitors of MDR1.
First-generation drugs: (including verapamil, tamoxifen, cyclosporine A, quinine).Calcium channel blocker verapamil inhibits MDR1 synthesis and its activity at mRNA level while competing for MDR1 binding sites, thereby reversing drug resistance [27].
Second-generation drugs: (including biricodar, elacridar and valspodar) failed to show overall efficacy improvements in multiple randomized clinical trials due to poor efficacy and increased toxicity.
Third-generation drugs: have high transporter affinity and low pharmacokinetics, including Tariquidar, Zosuquidar and Laniquidar.
Strategies for circumvention of MDR also include small interfering RNA (siRNA) [28] and microRNA (miRNA) to down-regulate the expression of ABC transporters.
Plant Anti-Tumor Drugs: Plant anti-tumor drugs provide new ideas for the development of MDR reversal agents due to their small side effects, natural sources and low cost.
It has been found that artemisinin, quercetin, magnolia officinalis phenol, emodin, zhejiang fritillaria alkaloid, osmanthus cnidii, ginsenoside, total saponin of panax notoginseng, root of mahonia mahogany, ganoderma lucidum and other traditional Chinese medicines or their effective components can reverse the drug resistance of tumor cells by down-regulating the expression of MDR1.
Psoralen, tetramethylpyrazine, tetrandrine, and paeonol are calcium antagonists, which can inhibit the function of pumping drugs out of cells by binding to P-gp, increase the concentration of intracellular chemotherapeutic drugs, and then reverse Resistance.
Studies have found that diosgenin can reverse the resistance of leukemia cells by inhibiting NF-κB down-regulation of MDR1 [29].
In addition, immunotherapy reversion, gene reversion, somatostatin and its analogues reversion and Chinese herbal reversion were also used to reverse MDR.
The increased oxidative stress and the activated NF-κB transcription factor may be involved in the inhibition of ABCG1 expression by high glucose.
References
[1] Momburg F, Roelse J, Howard J C, et al. Selectivity of MHC-encoded peptide transporters from human, mouse and rat [J]. Nature (London), 1994, 367(6464): 648-651.
[2] Higgins C F. ABC transporters: from microorganisms to man [J]. Annu Rev Cell Biol, 1991, 8(1): 67-113.
[3] Hyde S C, Emsley P, Hartshorn M J, et al. Structural model of ATP-binding proteing associated with cystic fibrosis, multidrug resistance and bacterial transport [J]. Nature, 1990, 346(6282): 362-365.
[4] Fletcher J I, Haber M, Henderson M J, et al. ABC transporters in cancer: more than just drug efflux pumps [J]. Nature Reviews Cancer, 2010, 10(2): 147.
[5] Yazaki K, Shitan N, Sugiyama A, et al. Cell and molecular biology of ATP-binding cassette proteins in plants [J]. Int Rev Cell Mol Biol, 2009, 276: 263-299.
[6] Bessire M, Borel S, Fabre G, et al. A Member of the PLEIOTROPIC DRUG RESISTANCE Family of ATP Binding Cassette Transporters Is Required for the Formation of a Functional Cuticle in Arabidopsis [J]. Plant Cell, 2011, 23(5): 1958-1970.
[7] Cho M, Cho H T. The function of ABCB transporters in auxin transport [J]. Plant Signaling & Behavior, 2013, 8(2): e22990.
[8] He W, You M, Vasseur L, et al. Developmental and insecticide-resistant insights from the de novo assembled transcriptome of the diamondback moth, Plutella xylostella [J]. Genomics, 2012, 99(3): 169-177.
[9] Epis S D, Porretta V, Mastrantonio S, et al. Temporal dynamics of the ABC transporter response to insecticide treatment: insights from the malaria vector Anopheles stephensi [J]. Sci Rep, 2014, 4: 7435-7435.
[10] Oram J F, Heinecke J W. ATP-Binding Cassette Transporter A1: A Cell Cholesterol Exporter That Protects Against Cardiovascular Disease [J]. Physiological Reviews, 2005, 85(4): 1343.
[11] Jiang Z, Zhou R, Xu C, et al. Genetic variation of the ATP-binding cassette transporter A1 and susceptibility to coronary heart disease [J]. Molecular Genetics and Metabolism, 2011, 103(1): 0-88.
[12] Santamarina-Fojo S, Remaley A T, Neufeld E B, et al. Regulation and intracellular trafficking of the ABCA1 transporter [J]. Journal of Lipid Research, 2001, 42(9): 1339-1345.
[13] Brookswilson A, Marcil M, Clee S M, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency [J]. Nature Genetics, 1999, 22(4): 336-345.
[14] Cenarro A, Artieda M, Castillo S, et al. A common variant in the ABCA1 gene is associated with a lower risk for premature coronary heart disease in familial hypercholesterolaemia [J]. Journal of Medical Genetics, 2003, 40(3): 163-168.
[15] Lahiri D. Apolipoprotein e as a target for developing new therapeutics for Alzheimer's disease based on studies from protein, RNA, and regulatory region of the gene [J]. Journal of Molecular Neuroscience, 2004, 23(3): 225-234.
[16] Hao X, Cao D, Hu Y, et al. IFN-γ down-regulates ABCA1 expression by inhibiting LXRα in a JAK/STAT signaling pathway-dependent manner [J]. Atherosclerosis, 2009, 203(2): 417-428.
[17] Amalia MartínezMir, Paloma E, Allikmets R, et al. Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR [J]. Nature Genetics, 1998, 18(1): 11.
[18] Allikmets R. Simple and Complex ABCR: Genetic Predisposition to Retinal Disease [J]. American Journal of Human Genetics, 2000, 67(4): 793-799.
[19] Pauli-Magnus C, Lang T, Meier Y, et al. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy [J]. Pharmacogenetics, 2004, 14(2): 91-102.
[20] Gelissen I C, Harris M, Rye K A, et al. ABCA1 and ABCG1 Synergize to Mediate Cholesterol Export to ApoA-I [J]. Arteriosclerosis Thrombosis & Vascular Biology, 2006, 7(3): 541-541.
[21] Dean M, Annilo T. EVOLUTION OF THE ATP-BINDING CASSETTE (ABC) TRANSPORTER SUPERFAMILY IN VERTEBRATES*[J]. Annu Rev Genomics Hum Genet, 2005, 6(1): 123-142.
[22] Binkhathlan Z, Lavasanifar A. P-glycoprotein Inhibition as a Therapeutic Approach for Overcoming Multidrug Resistance in Cancer: Current Status and Future Perspectives [J]. Curr Cancer Drug Targets, 2013, 13(3):-.
[23] Borst P, Elferink R O. Mammalian ABC transporters in health and disease [J]. Ann Rev Biochem, 2003, 71(1): 537.
[24] Igarashi A, Konno H, Tanaka T, et al. Liposomal photofrin enhances therapeutic efficacy of photodynamic therapy against the human gastric cancer [J]. Toxicology Letters, 2003, 145(2): 133-141.
[25] Chang G, Roth C B. Structure of MsbA from E. coli: a homolog of the multidrug resistance ATP binding cassette (ABC) transporters [J]. Science, 2001, 293(5536): 1793-800.
[26] Nieth C, Priebsch A, Stege A, et al. Modulation of the classical multidrug resistance (MDR) phenotype by RNA interference (RNAi) [J]. Febs Letters, 2003, 545(2): 144-150.
[27] Kohno M, Pouyssegur J. Targeting the ERK signaling pathway in cancer therapy [J]. Annals of Medicine, 2006, 38(3): 200-211.
[28] Abbasi M, Lavasanifar A, Uludag H. Recent attempts at RNAi-mediated P-glycoprotein downregulation for reversal of multidrug resistance in cancer [J]. Medicinal Research Reviews, 2013, 33(1): 33-53.
[29] Wang L, Meng Q, Wang C, et al. Dioscin restores the activity of the anticancer agent adriamycin in multidrug-resistant human leukemia K562/adriamycin cells by down-regulating MDR1 via a mechanism involving NF-κB signaling inhibition [J]. Journal of Natural Products, 2013, 76(5): 909-914.
Aquaporin
Ion Channels
G protein-Coupled Receptor
ATP-binding Cassette
Human Leukocyte Antigen
