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1
Daugherty, Robin M., Nicole Linka, Jonathon P. Audia, Claude Urbany, H. Ekkehard Neuhaus, and Herbert H. Winkler. "The Nucleotide Transporter of Caedibacter caryophilus Exhibits an Extended Substrate Spectrum Compared to the Analogous ATP/ADP Translocase of Rickettsia prowazekii." Journal of Bacteriology 186, no. 10 (May 15, 2004): 3262–65. http://dx.doi.org/10.1128/jb.186.10.3262-3265.2004.
Повний текст джерелаАнотація:
ABSTRACT The two obligate intracellular alphaproteobacteria Rickettsia prowazekii and Caedibacter caryophilus, a human pathogen and a paramecium endosymbiont, respectively, possess transport systems to facilitate ATP uptake from the host cell cytosol. These transport proteins, which have 65% identity at the amino acid level, were heterologously expressed in Escherichia coli, and their properties were compared. The results presented here demonstrate that the caedibacter transporter had a broader substrate than the more selective rickettsial transporter. ATP analogs with modified sugar moieties, dATP and ddATP, inhibited the transport of ATP by the caedibacter transporter but not by the rickettsial transporter. Both transporters were specific for di- and trinucleotides with an adenine base in that adenosine tetraphosphate, AMP, UTP, CTP, and GTP were not competitive inhibitors. Furthermore, the antiporter nature of both transport systems was shown by the dependence of the efflux of [α-32P]ATP on the influx of substrate (ATP but not dATP for rickettsiae, ATP or dATP for caedibacter).
2
Tjaden, J., H. H. Winkler, C. Schwöppe, M. Van Der Laan, T. Möhlmann, and H. E. Neuhaus. "Two Nucleotide Transport Proteins in Chlamydia trachomatis, One for Net Nucleoside Triphosphate Uptake and the Other for Transport of Energy." Journal of Bacteriology 181, no. 4 (February 15, 1999): 1196–202. http://dx.doi.org/10.1128/jb.181.4.1196-1202.1999.
Повний текст джерелаАнотація:
ABSTRACT The genome of Chlamydia trachomatis, one of the most prominent human pathogens, contains two structural genes coding for proteins, herein called Npt1Ct and Npt2Ct(nucleoside phosphate transporters 1 and 2 of C. trachomatis), exhibiting 68 and 61% similarity, respectively, to the ATP/ADP transporter from the intracellular bacteriumRickettsia prowazekii at the deduced amino acid level. Hydropathy analysis and sequence alignments suggested that both proteins have 12 transmembrane domains. The putative transporters were expressed as histidine-tagged proteins in Escherichia colito study their biochemical properties. His10-Npt1Ct catalyzed ATP and ADP transport in an exchange mode. The apparent Km values were 48 (ATP) and 39 (ADP) μM. ATP and ADP transport was specific since AMP, GTP, CTP, UTP, dATP, dCTP, dGTP, and dTTP did not inhibit uptake. In contrast, His10-Npt2Ct transported all four ribonucleoside triphosphates with apparent Kmvalues of 31 μM (GTP), 302 μM (UTP), 528 μM (CTP), and 1,158 μM (ATP). Ribonucleoside di- and monophosphates and deoxyribonucleotides were not substrates. The protonophore m -chlorocarbonylcyanide phenylhydrazone abolished uptake of all nucleoside triphosphates by Npt2Ct. This observation indicated that His10-Npt2Ctacts as a nucleosidetriphosphate/H+ symporter energized by the proton motive force across the Escherichia colicytoplasmic membrane. We conclude that Npt1Ct provides chlamydiae with energy whereas Npt2Ct catalyzes the net uptake of ribonucleoside triphosphates required for anabolic reactions.
3
Schwiebert, Erik M. "ABC transporter-facilitated ATP conductive transport." American Journal of Physiology-Cell Physiology 276, no. 1 (January 1, 1999): C1—C8. http://dx.doi.org/10.1152/ajpcell.1999.276.1.c1.
Повний текст джерелаАнотація:
The concept that the cystic fibrosis (CF) transmembrane conductance regulator, the protein product of the CF gene, can conduct larger multivalent anions such as ATP as well as Cl− is controversial. In this review, I examine briefly past findings that resulted in controversy. It is not the goal of this review to revisit these disparate findings in detail. Rather, I focus intently on more recent studies, current studies in progress, and possible future directions that arose from the controversy and that may reconcile this issue. Important questions and hypotheses are raised as to the physiological roles that ATP-binding cassette (ABC) transporter-facilitated ATP transport and signaling may play in the control of epithelial cell function. Perhaps the identification of key biological paradigms for ABC transporter-mediated extracellular nucleotide signaling may unify and guide the CF research community and other research groups interested in ABC transporters toward understanding why ABC transporters facilitate ATP transport.
4
Agboh, Kelvin, Calvin H. F. Lau, Yvonne S. K. Khoo, Himansha Singh, Sagar Raturi, Asha V. Nair, Julie Howard, et al. "Powering the ABC multidrug exporter LmrA: How nucleotides embrace the ion-motive force." Science Advances 4, no. 9 (September 2018): eaas9365. http://dx.doi.org/10.1126/sciadv.aas9365.
Повний текст джерелаАнотація:
LmrA is a bacterial ATP-binding cassette (ABC) multidrug exporter that uses metabolic energy to transport ions, cytotoxic drugs, and lipids. Voltage clamping in a Port-a-Patch was used to monitor electrical currents associated with the transport of monovalent cationic HEPES+by single-LmrA transporters and ensembles of transporters. In these experiments, one proton and one chloride ion are effluxed together with each HEPES+ion out of the inner compartment, whereas two sodium ions are transported into this compartment. Consequently, the sodium-motive force (interior negative and low) can drive this electrogenic ion exchange mechanism in cells under physiological conditions. The same mechanism is also relevant for the efflux of monovalent cationic ethidium, a typical multidrug transporter substrate. Studies in the presence of Mg-ATP (adenosine 5′-triphosphate) show that ion-coupled HEPES+transport is associated with ATP-bound LmrA, whereas ion-coupled ethidium transport requires ATP binding and hydrolysis. HEPES+is highly soluble in a water-based environment, whereas ethidium has a strong preference for residence in the water-repelling plasma membrane. We conclude that the mechanism of the ABC transporter LmrA is fundamentally related to that of an ion antiporter that uses extra steps (ATP binding and hydrolysis) to retrieve and transport membrane-soluble substrates from the phospholipid bilayer.
5
Jang, Jun Young, and Se Won Suh. "Structure of STM3169, a tripartite ATP-independent periplasmic transporter." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1653. http://dx.doi.org/10.1107/s2053273314083466.
Повний текст джерелаАнотація:
Substrate-binding proteins (SBPs) form a group of proteins that are commonly related to membrane protein complexes for transport or cell signal transduction. SBPs are comprised of prokaryotic ATP-binding cassette (ABC)-transporters, prokaryotic tripartite ATP-independent periplasmic (TRAP)-transporters, prokaryotic two-component regulatory systems, eukaryotic guanylatecyclase-atrial natriuretic peptide receptors, G-protein coupled receptors (GPCRs) and ligand-gated ion channels (Berntsson et al., 2010).The TRAP transporters are less known as compared with ABC transporters but are ubiquitous in prokaryotes. The TRAP transporters are important elements of solute uptake systems in prokaryotes. These transporters contain two membrane protein components, predicted to have four and twelve transmembrane helices, respectively. In the TRAP transporters of DctP-type, substrate recognition is mediated through a well-conserved and specific arginine/carboxylate interaction in the SBP (Mulligan et al., 2011). Here we have determined the crystal structure of the TRAP transporter from Salmonella entericaserovarTyphimurium. Unexpectedly, this structure shows that various ligands can bind to the TRAP transporters. It provides insights into substrate binding mechanism in the TRAP transporter system.
6
PASCOLO, Lorella, Enrique J. BAYON, Felicia CUPELLI, J. Donald OSTROW, and Claudio TIRIBELLI. "ATP-dependent transport of unconjugated bilirubin by rat liver canalicular plasma membrane vesicles." Biochemical Journal 331, no. 1 (April 1, 1998): 99–103. http://dx.doi.org/10.1042/bj3310099.
Повний текст джерелаАнотація:
The transport of highly purified 3H-labelled unconjugated bilirubin (UCB) was investigated in rat liver plasma membrane vesicles enriched in the canalicular domain and found to be stimulated (more than 5-fold) by the addition of ATP. Other nucleotides, such as AMP, ADP, GTP and a non-hydrolysable ATP analogue (adenosine 5´-[α,β-methylene] triphosphate), did not stimulate [3H]UCB transport, indicating that ATP hydrolysis was necessary for the stimulatory effect. [3H]UCB uptake occurred into an osmotically sensitive space. At an unbound bilirubin concentration ([Bf]) below saturation of the aqueous phase (no more than 70 nM UCB), the ATP-dependent transport followed saturation kinetics with respect to [Bf], with a Km of 26±8 nM and a Vmax of 117±11 pmol per 15 s per mg of protein. Unlabelled UCB inhibited the uptake of [3H]UCB, indicating that UCB was the transported species. Inhibitors of ATPase activity such as vanadate or diethyl pyrocarbonate decreased the ATP effect (59±11% and 100% respectively). Daunomycin, a known substrate for multidrug resistance protein-1, and taurocholate did not inhibit the ATP-dependent [3H]UCB transport, suggesting that neither mdr-1 nor the canalicular bile acid transporter is involved in the canalicular transport of UCB. [3H]UCB uptake (both with and without ATP) in canalicular vesicles obtained from TR- rats was comparable to that in vesicles obtained from Wistar rats, indicating that the canalicular multispecific organic anion transporter, cMOAT, does not account for UCB transport. These results indicate that UCB is transported across the canalicular membrane of the liver cell by an ATP-dependent mechanism involving an as yet unidentified transporter.
7
Webb, Alexander J., and Arthur H. F. Hosie. "A Member of the Second Carbohydrate Uptake Subfamily of ATP-Binding Cassette Transporters Is Responsible for Ribonucleoside Uptake in Streptococcus mutans." Journal of Bacteriology 188, no. 23 (September 22, 2006): 8005–12. http://dx.doi.org/10.1128/jb.01101-06.
Повний текст джерелаАнотація:
ABSTRACT Streptococcus mutans has a significant number of transporters of the ATP-binding cassette (ABC) superfamily. Members of this superfamily are involved in the translocation of a diverse range of molecules across membranes. However, the functions of many of these members remain unknown. We have investigated the role of the single S. mutans representative of the second subfamily of carbohydrate uptake transporters (CUT2) of the ABC superfamily. The genetic context of genes encoding this transporter indicates that it may have a role in ribonucleoside scavenging. Inactivation of rnsA (ATPase) or rnsB (solute binding protein) resulted in strains resistant to 5-fluorocytidine and 5-fluorouridine (toxic ribonucleoside analogues). As other ribonucleosides including cytidine, uridine, adenosine, 2-deoxyuridine, and 2-deoxycytidine protected S. mutans from 5-fluorocytidine and 5-fluorouridine toxicity, it is likely that this transporter is involved in the uptake of these molecules. Indeed, the rnsA and rnsB mutants were unable to transport [2-14C]cytidine or [2-14C]uridine and had significantly reduced [8-14C]adenosine uptake rates. Characterization of this transporter in wild-type S. mutans indicates that it is a high-affinity (Km = 1 to 2 μM) transporter of cytidine, uridine, and adenosine. The inhibition of [14C]cytidine uptake by a range of structurally related molecules indicates that the CUT2 transporter is involved in the uptake of most ribonucleosides, including 2-deoxyribonucleosides, but not ribose or nucleobases. The characterization of this permease has directly shown for the first time that an ABC transporter is involved in the uptake of ribonucleosides and extends the range of substrates known to be transported by members of the ABC transporter superfamily.
8
Jedlitschky, Gabriele, Andreas Greinacher, and Heyo K. Kroemer. "Transporters in human platelets: physiologic function and impact for pharmacotherapy." Blood 119, no. 15 (April 12, 2012): 3394–402. http://dx.doi.org/10.1182/blood-2011-09-336933.
Повний текст джерелаАнотація:
Platelets store signaling molecules (eg, serotonin and ADP) within their granules. Transporters mediate accumulation of these molecules in platelet granules and, on platelet activation, their translocation across the plasma membrane. The balance between transporter-mediated uptake and elimination of signaling molecules and drugs in platelets determines their intracellular concentrations and effects. Several members of the 2 major transporter families, ATP-binding cassette (ABC) transporters and solute carriers (SLCs), have been identified in platelets. An example of an ABC transporter is MRP4 (ABCC4), which facilitates ADP accumulation in dense granules. MRP4 is a versatile transporter, and various additional functions have been proposed, notably lipid mediator release and a role in aspirin resistance. Several other ABC proteins have been detected in platelets with functions in glutathione and lipid homeostasis. The serotonin transporter (SERT, SLC6A4) in the platelet plasma membrane represents a well-characterized example of the SLC family. Moreover, recent experiments indicate expression of OATP2B1 (SLCO2B1), a high affinity transporter for certain statins, in platelets. Changes in transporter localization and expression can affect platelet function and drug sensitivity. This review summarizes available data on the physiologic and pharmacologic role of transporters in platelets.
9
Mendum, Mary Lou, and Linda Tombras Smith. "Characterization of Glycine Betaine Porter I from Listeria monocytogenes and Its Roles in Salt and Chill Tolerance." Applied and Environmental Microbiology 68, no. 2 (February 2002): 813–19. http://dx.doi.org/10.1128/aem.68.2.813-819.2002.
Повний текст джерелаАнотація:
ABSTRACT Listeria monocytogenes is a pathogenic bacterium that can grow at low temperatures and elevated osmolarity. The organism survives these stresses by the intracellular accumulation of osmolytes: low-molecular-weight organic compounds which exert a counterbalancing force. The primary osmolyte in L. monocytogenes is glycine betaine, which is accumulated from the environment via two transport systems: glycine betaine porter I, an Na+-glycine betaine symporter; and glycine betaine porter II, an ATP-dependent transporter. The biochemical characteristics of glycine betaine porter I were investigated in a mutant strain (LTG59) lacking the ATP-dependent transporter. At 4% NaCl, glycine betaine uptake in LTG59 was about fivefold lower than in strain DP-L1044, which has both transporters, indicating that the ATP-dependent transporter is the primary means by which glycine betaine enters the cell. In the absence of osmotic stress, cold-activated uptake by both transporters was most rapid between 7 and 12�C, but a larger fraction of the total uptake was via the ATP-dependent transporter than was observed under salt-stressed conditions. Twelve glycine betaine analogs were tested for their ability to inhibit glycine betaine uptake and growth of stressed cultures. Carnitine, dimethylglycine, and γ-butyrobetaine appear to inhibit the ATP-dependent transporter, while trigonelline and triethylglycine primarily inhibit glycine betaine porter I. Triethylglycine was also able to retard the growth of osmotically stressed L. monocytogenes grown in the presence of glycine betaine.
10
Sims, Gregory E., та In-Geol Choi. "인간 ATP 결합카세트 수퍼페미리 단백질 분류를 위한 서브페미리 특이적인 모티프 프로화일링". Institute of Life Science and Natural Resources 30 (31 грудня 2022): 41–51. http://dx.doi.org/10.33147/lsnrr.2022.30.1.41.
Повний текст джерелаАнотація:
The ATP binding cassette (ABC) transporter superfamily is ubiquitous in all three domains of life. The cellular and molecular functions of ABC transporters are diverse and essential to all living organisms. In human, mutations associated with ABC transporters are known to cause many genetic diseases. Although the members of ABC transporter superfamily share common sequential feature, the subfamily recognition is not a trivial task because of its domain complexity. The functional annotation begins with subfamily recognition. Here, we showed that a motif profiling provides simple and intuitive approach to recognize the subfamily level. Along with relation to the structural feature, the motif profiling approach will be a guide to annotate and understand molecular functions of subfamilies with a big superfamily
11
Wu, Chao, Swapan Chakrabarty, Minghui Jin, Kaiyu Liu, and Yutao Xiao. "Insect ATP-Binding Cassette (ABC) Transporters: Roles in Xenobiotic Detoxification and Bt Insecticidal Activity." International Journal of Molecular Sciences 20, no. 11 (June 10, 2019): 2829. http://dx.doi.org/10.3390/ijms20112829.
Повний текст джерелаАнотація:
ATP-binding cassette (ABC) transporters, a large class of transmembrane proteins, are widely found in organisms and play an important role in the transport of xenobiotics. Insect ABC transporters are involved in insecticide detoxification and Bacillus thuringiensis (Bt) toxin perforation. The complete ABC transporter is composed of two hydrophobic transmembrane domains (TMDs) and two nucleotide binding domains (NBDs). Conformational changes that are needed for their action are mediated by ATP hydrolysis. According to the similarity among their sequences and organization of conserved ATP-binding cassette domains, insect ABC transporters have been divided into eight subfamilies (ABCA–ABCH). This review describes the functions and mechanisms of ABC transporters in insecticide detoxification, plant toxic secondary metabolites transport and insecticidal activity of Bt toxin. With improved understanding of the role and mechanisms of ABC transporter in resistance to insecticides and Bt toxins, we can identify valuable target sites for developing new strategies to control pests and manage resistance and achieve green pest control.
12
Sharma, Parul, Navneet Singh, and Siddharth Sharma. "ATP binding cassette transporters and cancer: revisiting their controversial role." Pharmacogenomics 22, no. 18 (December 2021): 1211–35. http://dx.doi.org/10.2217/pgs-2021-0116.
Повний текст джерелаАнотація:
The expression of ATP-binding cassette transporter (ABC transporters) has been reported in various tissues such as the lung, liver, kidney, brain and intestine. These proteins account for the efflux of different compounds and metabolites across the membrane, thus decreasing the concentration of the toxic compounds. ABC transporter genes play a vital role in the development of multidrug resistance, which is the main obstacle that hinders the success of chemotherapy. Preclinical and clinical trials have investigated the probability of overcoming drug-associated resistance and substantial toxicities. The focus has been put on several strategies to overcome multidrug resistance. These strategies include the development of modulators that can modulate ABC transporters. This knowledge can be translated for clinical oncology treatment in the future.
13
Golin, John, and Suresh V. Ambudkar. "The multidrug transporter Pdr5 on the 25th anniversary of its discovery: an important model for the study of asymmetric ABC transporters." Biochemical Journal 467, no. 3 (April 17, 2015): 353–63. http://dx.doi.org/10.1042/bj20150042.
Повний текст джерелаАнотація:
Asymmetric ABC (ATP-binding cassette) transporters make up a significant proportion of this important superfamily of integral membrane proteins. These proteins contain one canonical (catalytic) ATP-binding site and a second atypical site with little enzymatic capability. The baker's yeast (Saccharomyces cerevisiae) Pdr5 multidrug transporter is the founding member of the Pdr subfamily of asymmetric ABC transporters, which exist only in fungi and slime moulds. Because these organisms are of considerable medical and agricultural significance, Pdr5 has been studied extensively, as has its medically important homologue Cdr1 from Candida albicans. Genetic and biochemical analyses of Pdr5 have contributed important observations that are likely to be applicable to mammalian asymmetric ABC multidrug transporter proteins, including the basis of transporter promiscuity, the function of the non-catalytic deviant ATP-binding site, the most complete description of an in vivo transmission interface, and the recent discovery that Pdr5 is a molecular diode (one-way gate). In the present review, we discuss the observations made with Pdr5 and compare them with findings from clinically important asymmetric ABC transporters, such as CFTR (cystic fibrosis transmembrane conductance regulator), Cdr1 and Tap1/Tap2.
14
Venter, H., S. Shahi, L. Balakrishnan, S. Velamakanni, A. Bapna, B. Woebking, and H. W. van Veen. "Similarities between ATP-dependent and ion-coupled multidrug transporters." Biochemical Society Transactions 33, no. 5 (October 26, 2005): 1008–11. http://dx.doi.org/10.1042/bst0331008.
Повний текст джерелаАнотація:
The movement of drugs across biological membranes is mediated by two major classes of membrane transporters. Primary-active, ABC (ATP-binding cassette) multidrug transporters are dependent on ATP-binding/hydrolysis, whereas secondary-active multidrug transporters are coupled to the proton (or sodium)-motive force that exists across the plasma membrane. Recent work on LmrA, an ABC multidrug transporter in Lactococcus lactis, suggests that primary- and secondary-active multidrug transporters share functional and structural features. Some of these similarities and their implications for the mechanism of transport by ABC multidrug transporters will be discussed.
15
Barbieri, Alessandro, Nopnithi Thonghin, Talha Shafi, Stephen M. Prince, Richard F. Collins, and Robert C. Ford. "Structure of ABCB1/P-Glycoprotein in the Presence of the CFTR Potentiator Ivacaftor." Membranes 11, no. 12 (November 25, 2021): 923. http://dx.doi.org/10.3390/membranes11120923.
Повний текст джерелаАнотація:
ABCB1/P-glycoprotein is an ATP binding cassette transporter that is involved in the clearance of xenobiotics, and it affects the disposition of many drugs in the body. Conformational flexibility of the protein within the membrane is an intrinsic part of its mechanism of action, but this has made structural studies challenging. Here, we have studied different conformations of P-glycoprotein simultaneously in the presence of ivacaftor, a known competitive inhibitor. In order to conduct this, we used high contrast cryo-electron microscopy imaging with a Volta phase plate. We associate the presence of ivacaftor with the appearance of an additional density in one of the conformational states detected. The additional density is in the central aqueous cavity and is associated with a wider separation of the two halves of the transporter in the inward-facing state. Conformational changes to the nucleotide-binding domains are also observed and may help to explain the stimulation of ATPase activity that occurs when transported substrate is bound in many ATP binding cassette transporters.
16
Ho, Maria, Donna E. Hogge, and Victor Ling. "Expression of the Human ATP-Binding Cassette Transporter Superfamily in Acute Myeloid Leukemia." Blood 104, no. 11 (November 16, 2004): 1179. http://dx.doi.org/10.1182/blood.v104.11.1179.1179.
Повний текст джерелаАнотація:
Abstract Members of the ATP-Binding-Cassette (ABC) transporter superfamily of proteins are involved in resistance to multiple chemotherapeutic drugs ( Multidrug Resistance or MDR) in a variety of malignant cells including leukemic blasts. Overexpression of some ABC transporters has been demonstrated in acute myeloid leukemia (AML) and is associated with clinical MDR and failure of conventional chemotherapy, which occurs frequently in this leukemia. Recent studies have also demonstrated ABC transporter expression in primitive normal hematopoietic cells, including progenitors which may give rise to AML after malignant transformation. In this study we used quantitative Real-Time PCR to assess and compare the expression level of all 47 known human ABC transporters in AML blasts and normal peripheral blood. Peripheral blood blasts from 17 patients with newly-diagnosed AML who subsequently received conventional remission induction therapy with cytosine arabinoside and daunorubicin were studied; 11 of these subsequently achieved complete remission of their leukemia while the remaining 6 had chemotherapy refractory disease. Contrary to expectations, no consistent difference in mRNA levels was found between the chemotherapy responsive and refractory groups of patient samples for any ABC transporter, including known MDR-related members such as MDR-1 and BCRP. Profiling of the 47 ABC transporters in 12 normal peripheral blood samples (6 mobilized with G-CSF, 6 non-mobilized) showed that TAP1 and MRP3 were 3.3-fold (P = 0.032) and 24-fold (P = 0.012), respectively, higher in normal donors as compared to AML patients. ABCA7, ABCB8, MRP3, MRP7, ALDP, PMP70 and PMP69 were greater than 3-fold higher (P < 0.05) in G-CSF-mobilized as compared to steady state normal blood. These results suggest that levels of ABC transporter mRNA expression in AML blasts prior to chemotherapy are not predictive of treatment response. This raises questions regarding the role of ABC transporters in intrinsic as opposed to induced or acquired chemotherapy drug resistance, which in turn has important implications in clinical usage of ABC-reversal agents. In addition, we identified expression of a variety of ABC transporters in both AML blasts and normal blood cells suggesting that this class of transporter proteins may have importance in both normal and malignant hematopoiesis.
17
Zhang, Wandong, Qing Yan Liu, Arsalan S. Haqqani, Ziying Liu, Caroline Sodja, Sonia Leclerc, Ewa Baumann, Christie E. Delaney, Eric Brunette, and Danica B. Stanimirovic. "Differential Expression of ABC Transporter Genes in Brain Vessels vs. Peripheral Tissues and Vessels from Human, Mouse and Rat." Pharmaceutics 15, no. 5 (May 22, 2023): 1563. http://dx.doi.org/10.3390/pharmaceutics15051563.
Повний текст джерелаАнотація:
Background: ATP-binding cassette (ABC) transporters comprise a superfamily of genes encoding membrane proteins with nucleotide-binding domains (NBD). These transporters, including drug efflux across the blood–brain barrier (BBB), carry a variety of substrates through plasma membranes against substrate gradients, fueled by hydrolyzing ATP. The expression patterns/enrichment of ABC transporter genes in brain microvessels compared to peripheral vessels and tissues are largely uncharacterized. Methods: In this study, the expression patterns of ABC transporter genes in brain microvessels, peripheral tissues (lung, liver and spleen) and lung vessels were investigated using RNA-seq and WesTM analyses in three species: human, mouse and rat. Results: The study demonstrated that ABC drug efflux transporter genes (including ABCB1, ABCG2, ABCC4 and ABCC5) were highly expressed in isolated brain microvessels in all three species studied; the expression of ABCB1, ABCG2, ABCC1, ABCC4 and ABCC5 was generally higher in rodent brain microvessels compared to those of humans. In contrast, ABCC2 and ABCC3 expression was low in brain microvessels, but high in rodent liver and lung vessels. Overall, most ABC transporters (with the exception of drug efflux transporters) were enriched in peripheral tissues compared to brain microvessels in humans, while in rodent species, additional ABC transporters were found to be enriched in brain microvessels. Conclusions: This study furthers the understanding of species similarities and differences in the expression patterns of ABC transporter genes; this is important for translational studies in drug development. In particular, CNS drug delivery and toxicity may vary among species depending on their unique profiles of ABC transporter expression in brain microvessels and BBB.
18
Sato, Ryoichi, Satomi Adegawa, Xiaoyi Li, Shiho Tanaka, and Haruka Endo. "Function and Role of ATP-Binding Cassette Transporters as Receptors for 3D-Cry Toxins." Toxins 11, no. 2 (February 19, 2019): 124. http://dx.doi.org/10.3390/toxins11020124.
Повний текст джерелаАнотація:
When ABC transporter family C2 (ABCC2) and ABC transporter family B1 (ABCB1) were heterologously expressed in non-susceptible cultured cells, the cells swelled in response to Cry1A and Cry3 toxins, respectively. Consistent with the notion that 3D-Cry toxins form cation-permeable pores, Bombyx mori ABCC2 (BmABCC2) facilitated cation-permeable pore formation by Cry1A when expressed in Xenopus oocytes. Furthermore, BmABCC2 had a high binding affinity (KD) to Cry1Aa of 3.1 × 10−10 M. These findings suggest that ABC transporters, including ABCC2 and ABCB1, are functional receptors for 3D-Cry toxins. In addition, the Cry2 toxins most distant from Cry1A toxins on the phylogenetic tree used ABC transporter A2 as a receptor. These data suggest that 3D-Cry toxins use ABC transporters as receptors. In terms of inducing cell swelling, ABCC2 has greater activity than cadherin-like receptor. The pore opening of ABC transporters was hypothesized to be linked to their receptor function, but this was repudiated by experiments using mutants deficient in export activity. The synergistic relationship between ABCC2 and cadherin-like receptor explains their ability to cause resistance in one species of insect.
19
Johnson, Eric T., Rebecca Lyon, David Zaitlin, Abdul Burhan Khan, and Mohammad Aman Jairajpuri. "A comparison of transporter gene expression in three species of Peronospora plant pathogens during host infection." PLOS ONE 18, no. 6 (June 1, 2023): e0285685. http://dx.doi.org/10.1371/journal.pone.0285685.
Повний текст джерелаАнотація:
Protein transporters move essential metabolites across membranes in all living organisms. Downy mildew causing plant pathogens are biotrophic oomycetes that transport essential nutrients from their hosts to grow. Little is known about the functions and gene expression levels of membrane transporters produced by downy mildew causing pathogens during infection of their hosts. Approximately 170–190 nonredundant transporter genes were identified in the genomes of Peronospora belbahrii, Peronospora effusa, and Peronospora tabacina, which are specialized pathogens of basil, spinach, and tobacco, respectively. The largest groups of transporter genes in each species belonged to the major facilitator superfamily, mitochondrial carriers (MC), and the drug/metabolite transporter group. Gene expression of putative Peronospora transporters was measured using RNA sequencing data at two time points following inoculation onto leaves of their hosts. There were 16 transporter genes, seven of which were MCs, expressed in each Peronospora species that were among the top 45 most highly expressed transporter genes 5–7 days after inoculation. Gene transcripts encoding the ADP/ATP translocase and the mitochondrial phosphate carrier protein were the most abundant mRNAs detected in each Peronospora species. This study found a number of Peronospora genes that are likely critical for pathogenesis and which might serve as future targets for control of these devastating plant pathogens.
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Langmann, Thomas, Richard Mauerer, and Gerd Schmitz. "Human ATP-Binding Cassette Transporter TaqMan Low-Density Array: Analysis of Macrophage Differentiation and Foam Cell Formation." Clinical Chemistry 52, no. 2 (February 1, 2006): 310–13. http://dx.doi.org/10.1373/clinchem.2005.059774.
Повний текст джерелаАнотація:
Abstract Background: ATP-binding cassette (ABC) transporters cause various diseases and regulate many physiologic processes, such as lipid homeostasis, iron transport, and immune mechanisms. Several ABC transporters are involved in bile acid, phospholipid, and sterol transport, and their expression is itself controlled by lipids. In addition, ABC proteins mediate drug export in tumor cells and promote the development of multidrug resistance. Methods: We created an ABC Transporter TaqMan Low-Density Array based on an Applied Biosystems 7900HT Micro Fluidic Card. We used a 2-μL reaction well with 2 ng of sample. To evaluate this method for lipidomic research and to characterize expression patterns of ABC transporters in cells relevant for atherosclerosis research, we monitored mRNA expression in human primary monocytes, in vitro–differentiated macrophages, and cells stimulated with the liver-X-receptor and retinoid-X-receptor agonists T0901317 and 9-cis retinoic acid, mimicking sterol loading. Results: The method enabled simultaneous analysis of 47 human ABC transporters and the reference gene 18S rRNA in 2 replicates of 4 samples per run. Conclusions: The new system uses only 2 ng of sample and small volumes of reagent, and the precaptured primers and probes avoided labor-intensive pipetting steps. The ABC Transporter TaqMan Low-Density Array may be a useful tool to monitor dysregulated ABC transporter mRNA profiles in human lipid disorders and cancer-related multidrug resistance and to analyze the pharmacologic and metabolic regulation of ABC transporter expression important for drug development in large-scale screening approaches.
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Li, Senyang, Jiahui Qian, Ming Xu, Jing Yang, Zhengming He, Tongjie Zhao, Junlong Zhao, and Rui Fang. "A new adenine nucleotide transporter located in the ER is essential for maintaining the growth of Toxoplasma gondii." PLOS Pathogens 18, no. 7 (July 5, 2022): e1010665. http://dx.doi.org/10.1371/journal.ppat.1010665.
Повний текст джерелаАнотація:
The lumen of the endoplasmic reticulum (ER) is the subcellular site where secretory protein folding, glycosylation and sulfation of membrane-bound proteins, proteoglycans, and lipids occur. The protein folding and degradation in the lumen of the ER require high levels of energy in the form of ATP. Biochemical and genetic approaches show that ATP must first be translocated across ER membrane by particular transporters before serving as substrates and energy sources in the lumenal reactions. Here we describe an ATP/ADP transporter residing in the ER membranes of T.gondii. Immunofluorescence (IFA) assay in transgenic TgANT1-HA tag revealed that TgANT1 is a protein specifically expressed in the ER. In vitro assays, functional integration of TgANT in the cytoplasmic membrane of intact E. coli cells reveals high specificity for an ATP/ADP antiport. The depletion of TgANT leads to fatal growth defects in T.gondii, including a significant slowdown in replication, no visible plaque formation, and reduced ability to invade. We also found that the amino acid mutations in two domains of TgANT lead to the complete loss of its function. Since these two domains are conserved in multiple species, they may share the same transport mechanism. Our results indicate that TgANT is the only ATP/ADP transporter in the ER of T. gondii, and the lack of ATP in the ER is the cause of the death of T. gondii.
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Hui, David Y., Eric D. Labonté, and Philip N. Howles. "Development and Physiological Regulation of Intestinal Lipid Absorption. III. Intestinal transporters and cholesterol absorption." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 4 (April 2008): G839—G843. http://dx.doi.org/10.1152/ajpgi.00061.2008.
Повний текст джерелаАнотація:
Intestinal cholesterol absorption is modulated by transport proteins in enterocytes. Cholesterol uptake from intestinal lumen requires several proteins on apical brush-border membranes, including Niemann-Pick C1-like 1 (NPC1L1), scavenger receptor B-I, and CD36, whereas two ATP-binding cassette half transporters, ABCG5 and ABCG8, on apical membranes work together for cholesterol efflux back to the intestinal lumen to limit cholesterol absorption. NPC1L1 is essential for cholesterol absorption, but its function as a cell surface transporter or an intracellular cholesterol transport protein needs clarification. Another ATP transporter, ABCA1, is present in the basolateral membrane to mediate HDL secretion from enterocytes.
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Paul, Sanjoy, Daniel Diekema, and W. Scott Moye-Rowley. "Contributions of Aspergillus fumigatus ATP-Binding Cassette Transporter Proteins to Drug Resistance and Virulence." Eukaryotic Cell 12, no. 12 (October 11, 2013): 1619–28. http://dx.doi.org/10.1128/ec.00171-13.
Повний текст джерелаАнотація:
ABSTRACTIn yeast cells such as those ofSaccharomyces cerevisiae, expression of ATP-binding cassette (ABC) transporter proteins has been found to be increased and correlates with a concomitant elevation in azole drug resistance. In this study, we investigated the roles of twoAspergillus fumigatusproteins that share high sequence similarity withS. cerevisiaePdr5, an ABC transporter protein that is commonly overproduced in azole-resistant isolates in this yeast. The twoA. fumigatusgenes encoding the ABC transporters sharing the highest sequence similarity toS. cerevisiaePdr5 are calledabcAandabcBhere. We constructed deletion alleles of these two different ABC transporter-encoding genes in three different strains ofA. fumigatus. Loss ofabcBinvariably elicited increased azole susceptibility, whileabcAdisruption alleles had variable phenotypes. Specific antibodies were raised to both AbcA and AbcB proteins. These antisera allowed detection of AbcB in wild-type cells, while AbcA could be visualized only when overproduced from thehspApromoter inA. fumigatus. Overproduction of AbcA also yielded increased azole resistance. Green fluorescent protein fusions were used to provide evidence that both AbcA and AbcB are localized to the plasma membrane inA. fumigatus. Promoter fusions to firefly luciferase suggested that expression of both ABC transporter-encoding genes is inducible by azole challenge. Virulence assays implicated AbcB as a possible factor required for normal pathogenesis. This work provides important new insights into the physiological roles of ABC transporters in this major fungal pathogen.
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Van Eck, Miranda. "ATP-binding cassette transporter A1." Current Opinion in Lipidology 25, no. 4 (August 2014): 297–303. http://dx.doi.org/10.1097/mol.0000000000000088.
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Van Aubel, Rémon A. M. H., Janny G. P. Peters, Rosalinde Masereeuw, Carel H. Van Os, and Frans G. M. Russel. "Multidrug resistance protein Mrp2 mediates ATP-dependent transport of classic renal organic anion p-aminohippurate." American Journal of Physiology-Renal Physiology 279, no. 4 (October 1, 2000): F713—F717. http://dx.doi.org/10.1152/ajprenal.2000.279.4.f713.
Повний текст джерелаАнотація:
p-Aminohippurate (PAH) is widely used as a model substrate to characterize organic anion transport in kidney proximal tubules. The carrier responsible for uptake of PAH across the basolateral membrane has been cloned and well characterized, whereas transporters mediating PAH excretion across the brush-border (apical) membrane are yet unknown. In this study we investigated whether PAH is a substrate for the apical multidrug resistance protein 2 (Mrp2). Overexpression of recombinant rabbit Mrp2 in Sf9 cells significantly increased ATP-dependent [14C]PAH uptake into isolated membrane vesicles compared with endogenous ATP-dependent uptake. The Michaelis-Menten constant and maximal velocity for Mrp2-mediated ATP-dependent [14C]PAH transport were 1.9 ± 0.8 mM and 187 ± 29 pmol · mg−1 · min−1, respectively. On the basis of the inhibitory profile, the endogenous ATP-dependent PAH transporter does not appear to be an ortholog of Mrp2. Together, our results show that Mrp2 is a low-affinity ATP-dependent PAH transporter, indicating that Mrp2 might contribute to urinary PAH excretion.
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Kim, Seon Hwa, and Vladimir Vujanovic. "ATP-Binding Cassette (ABC) Transporters in Fusarium Specific Mycoparasite Sphaerodes mycoparasitica during Biotrophic Mycoparasitism." Applied Sciences 12, no. 15 (July 29, 2022): 7641. http://dx.doi.org/10.3390/app12157641.
Повний текст джерелаАнотація:
Recent transcriptomic profiling has revealed importance membrane transporters such as ATP-binding cassette (ABC) transporters in fungal necrotrophic mycoparasites. In this study, RNA-Seq allowed rapid detection of ABC transcripts involved in biotrophic mycoparasitism of Sphaerodes mycoparasitica against the phytopathogenic and mycotoxigenic Fusarium graminearum host, the causal agent of Fusarium head blight (FHB). Transcriptomic analyses of highly expressed S. mycoparasitica genes, and their phylogenetic relationships with other eukaryotic fungi, portrayed the ABC transporters’ evolutionary paths towards biotrophic mycoparasitism. Prior to the in silico phylogenetic analyses, transmission electron microscopy (TEM) was used to confirm the formation of appressorium/haustorium infection structures in S. mycoparasitica during early (1.5 d and 3.5 d) stages of mycoparasitism. Transcripts encoding biotrophy-associated secreted proteins did uncover the enrolment of ABC transporter genes in this specific biocontrol mode of action, while tandem ABC and BUB2 (non-ABC) transcripts seemed to be proper for appressorium development. The next-generation HiSeq transcriptomic profiling of the mycoparasitic hypha samples, revealed 81 transcripts annotated to ABC transporters consisting of a variety of ABC-B (14%), ABC-C (22%), and ABC-G (23%), and to ABC-A, ABC-F, aliphatic sulfonates importer (TC 3.A.1.17.2), BtuF, ribose importer (TC 3.A.1.2.1), and unknown families. The most abundant transcripts belonged to the multidrug resistance exporter (TC 3.A.1.201) subfamily of the ABC-B family, the conjugate transporter (TC 3.A.1.208) subfamily of the ABC-C family, and the pleiotropic drug resistance (PDR) (TC 3.A.1.205) subfamily of the ABC-G family. These findings highlight the significance of ABC transporter genes that control cellular detoxification against toxic substances (e.g., chemical pesticides and mycotoxins) in sustaining a virulence of S. mycoparasitica for effective biotrophic mycoparasitism on the F. graminearum host. The findings of this study provide clues to better understand the biotrophic mycoparasitism of S. mycoparasitica interacting with the Fusarium host, which implies that the ABC transporter group of key proteins is involved in the mycoparasite’s virulence and multidrug resistance to toxic substances including cellular detoxification.
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Pinos, Daniel, María Martínez-Solís, Salvador Herrero, Juan Ferré, and Patricia Hernández-Martínez. "The Spodoptera exigua ABCC2 Acts as a Cry1A Receptor Independently of its Nucleotide Binding Domain II." Toxins 11, no. 3 (March 22, 2019): 172. http://dx.doi.org/10.3390/toxins11030172.
Повний текст джерелаАнотація:
ABC proteins are primary-active transporters that require the binding and hydrolysis of ATP to transport substrates across the membrane. Since the first report of an ABCC2 transporter as receptor of Cry1A toxins, the number of ABC transporters known to be involved in the mode of action of Cry toxins has increased. In Spodoptera exigua, a mutation in the SeABCC2 gene is described as genetically linked to resistance to the Bt-product XentariTM. This mutation affects an intracellular domain involved in ATP binding, but not the extracellular loops. We analyzed whether this mutation affects the role of the SeABCC2 as a functional receptor to Cry1A toxins. The results show that Sf21 cells expressing the truncated form of the transporter were susceptible to Cry1A toxins. Moreover, specific Cry1Ac binding was observed in those cells expressing the truncated SeABCC2. Additionally, no differences in the irreversible Cry1Ac binding component (associated with the toxin insertion into the membrane) were observed when tested in Sf21 cells expressing either the full-length or the truncated form of the SeABCC2 transporter. Therefore, our results point out that the partial lack of the nucleotide binding domain II in the truncated transporter does not affect its functionality as a Cry1A receptor.
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Lee, Yu Ran, Hee Kyoung Joo, Eun Ok Lee, Hyun Sil Cho, Sunga Choi, Cuk-Seong Kim, and Byeong Hwa Jeon. "ATP Binding Cassette Transporter A1 is Involved in Extracellular Secretion of Acetylated APE1/Ref-1." International Journal of Molecular Sciences 20, no. 13 (June 28, 2019): 3178. http://dx.doi.org/10.3390/ijms20133178.
Повний текст джерелаАнотація:
Acetylation of nuclear apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) is associated with its extracellular secretion, despite the lack of an N-terminal protein secretion signal. In this study, we investigated plasma membrane targeting and translocation of APE1/Ref-1 in HEK293T cells with enhanced acetylation. While APE1/Ref-1 targeting was not affected by inhibition of the endoplasmic reticulum/Golgi-dependent secretion, its secretion was reduced by inhibitors of ATP-binding cassette (ABC) transporters, and siRNA-mediated down-regulation of ABC transporter A1. The association between APE1/Ref-1 and ABCA1 transporter was confirmed by proximal ligation assay and immunoprecipitation experiments. An APE1/Ref-1 construct with mutated acetylation sites (K6/K7R) showed reduced co-localization with ABC transporter A1. Exposure of trichostatin A (TSA) induced the acetylation of APE1/Ref-1, which translocated into membrane fraction. Taken together, acetylation of APE1/Ref-1 is considered to be necessary for its extracellular targeting via non-classical secretory pathway using the ABCA1 transporter.
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Eckardt, Nancy A. "Identification of an Endoplasmic Reticulum ATP/ADP Transporter." Plant Cell 20, no. 2 (February 2008): 245. http://dx.doi.org/10.1105/tpc.108.200211.
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Chapman, Lee P., Matthew J. Epton, Julia C. Buckingham, John F. Morris, and Helen C. Christian. "Evidence for a Role of the Adenosine 5′-Triphosphate-Binding Cassette Transporter A1 in the Externalization of Annexin I from Pituitary Folliculo-Stellate Cells." Endocrinology 144, no. 3 (March 1, 2003): 1062–73. http://dx.doi.org/10.1210/en.2002-220650.
Повний текст джерелаАнотація:
Annexin 1 (ANXA1) has a well-demonstrated role in early delayed inhibitory feedback of glucocorticoids in the pituitary. ANXA1 is located in folliculo-stellate (FS) cells, and glucocorticoids act on these cells to externalize and stimulate the synthesis of ANXA1. However, ANXA1 lacks a signal sequence so the mechanism by which ANXA1 is externalized from FS cells was unknown and has been investigated. The ATP-binding cassette (ABC) transporters are a large group of transporters with varied roles that include the externalization of proteins. Glucocorticoid-induced externalization of ANXA1 from an FS cell line (TtT/GF) and rat anterior pituitary was blocked by glyburide, which inhibits ABC transporters. Glyburide also blocked the glucocorticoid inhibition of forskolin-stimulated ACTH release from pituitary tissue in vitro. RT-PCR revealed mRNA and Western blotting demonstrated protein for the ATP binding cassette A1 (ABCA1) transporter in mouse FS, TtT/GF, and A549 lung adenocarcinoma cells from which glucocorticoids also induce externalization of ANXA1. In TtT/GF cells, immunofluorescence labeling revealed a near total colocalization of cell surface ANXA1 and ABCA1. We conclude that ANXA1, which mediates the early delayed feedback of glucocorticoids in the anterior pituitary, is externalized from FS cells by an ABC transporter and that the ABCA1 transporter is a likely candidate.
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Tamaki, Akina, Caterina Ierano, Gergely Szakacs, Robert W. Robey, and Susan E. Bates. "The controversial role of ABC transporters in clinical oncology." Essays in Biochemistry 50 (September 7, 2011): 209–32. http://dx.doi.org/10.1042/bse0500209.
Повний текст джерелаАнотація:
The phenomenon of multidrug resistance in cancer is often associated with the overexpression of the ABC (ATP-binding cassette) transporters Pgp (P-glycoprotein) (ABCB1), MRP1 (multidrug resistance-associated protein 1) (ABCC1) and ABCG2 [BCRP (breast cancer resistance protein)]. Since the discovery of Pgp over 35 years ago, studies have convincingly linked ABC transporter expression to poor outcome in several cancer types, leading to the development of transporter inhibitors. Three generations of inhibitors later, we are still no closer to validating the ‘Pgp hypothesis’, the idea that increased chemotherapy efficacy can be achieved by inhibition of transporter-mediated efflux. In this chapter, we highlight the difficulties and past failures encountered in the development of clinical inhibitors of ABC transporters. We discuss the challenges that remain in our effort to exploit decades of work on ABC transporters in oncology. In learning from past mistakes, it is hoped that ABC transporters can be developed as targets for clinical intervention.
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Pinos, Daniel, Anabel Millán-Leiva, Juan Ferré, and Patricia Hernández-Martínez. "New Paralogs of the Heliothis virescens ABCC2 Transporter as Potential Receptors for Bt Cry1A Proteins." Biomolecules 14, no. 4 (March 26, 2024): 397. http://dx.doi.org/10.3390/biom14040397.
Повний текст джерелаАнотація:
The ATP-binding cassette (ABC) transporters are a superfamily of membrane proteins. These active transporters are involved in the export of different substances such as xenobiotics. ABC transporters from subfamily C (ABCC) have also been described as functional receptors for different insecticidal proteins from Bacillus thuringiensis (Bt) in several lepidopteran species. Numerous studies have characterized the relationship between the ABCC2 transporter and Bt Cry1 proteins. Although other ABCC transporters sharing structural and functional similarities have been described, little is known of their role in the mode of action of Bt proteins. For Heliothis virescens, only the ABCC2 transporter and its interaction with Cry1A proteins have been studied to date. Here, we have searched for paralogs to the ABCC2 gene in H. virescens, and identified two new ABC transporter genes: HvABCC3 and HvABCC4. Furthermore, we have characterized their gene expression in the midgut and their protein topology, and compared them with that of ABCC2. Finally, we discuss their possible interaction with Bt proteins by performing protein docking analysis.
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Ostuni, Angela, Monica Carmosino, Rocchina Miglionico, Vittorio Abruzzese, Fabio Martinelli, Daniela Russo, Ilaria Laurenzana, Agata Petillo, and Faustino Bisaccia. "Inhibition of ABCC6 Transporter Modifies Cytoskeleton and Reduces Motility of HepG2 Cells via Purinergic Pathway." Cells 9, no. 6 (June 5, 2020): 1410. http://dx.doi.org/10.3390/cells9061410.
Повний текст джерелаАнотація:
ABCC6, belonging to sub-family C of ATP-binding cassette transporter, is an ATP-dependent transporter mainly present in the basolateral plasma membrane of hepatic and kidney cells. Although the substrates transported are still uncertain, ABCC6 has been shown to promote ATP release. The extracellular ATP and its derivatives di- and mono-nucleotides and adenosine by acting on specific receptors activate the so-called purinergic pathway, which in turn controls relevant cellular functions such as cell immunity, inflammation, and cancer. Here, we analyzed the effect of Abcc6 knockdown and probenecid-induced ABCC6 inhibition on cell cycle, cytoskeleton, and motility of HepG2 cells. Gene and protein expression were evaluated by quantitative Reverse Transcription PCR (RT-qPCR) and western blot, respectively. Cellular cycle analysis was evaluated by flow cytometry. Actin cytoskeleton dynamics was evaluated by laser confocal microscopy using fluorophore-conjugated phalloidin. Cell motility was analyzed by in vitro wound-healing migration assay. Cell migration is reduced both in Abcc6 knockdown HepG2 cells and in probenecid treated HepG2 cells by interfering with the extracellular reserve of ATP. Therefore, ABCC6 could contribute to cytoskeleton rearrangements and cell motility through purinergic signaling. Altogether, our findings shed light on a new role of the ABCC6 transporter in HepG2 cells and suggest that its inhibitor/s could be considered potential anti-metastatic drugs.
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Bingham, M. J., T. J. Ong, W. J. Ingledew, and H. J. McArdle. "ATP-dependent copper transporter, in the Golgi apparatus of rat hepatocytes, transports Cu(II) not Cu(I)." American Journal of Physiology-Gastrointestinal and Liver Physiology 271, no. 5 (November 1, 1996): G741—G746. http://dx.doi.org/10.1152/ajpgi.1996.271.5.g741.
Повний текст джерелаАнотація:
The Wilson disease adenosinetriphosphatase (ATPase; ATP7B) is believed to bind copper as Cu(I). We provide evidence to suggest that the ATPase actually transports Cu as Cu(II). When the copper is presented to rat liver microsomes as Cu(I), virtually all uptake is ATP independent. If the copper is presented as copper oxalate [Cu(II)], total uptake is reduced to approximately 10% of Cu(I) levels, but ATP-dependent uptake rises, both as a proportion of total uptake and in absolute terms. The reducing agent vitamin C and the Cu(I) chelator bathocuproine both override the effect of oxalate. The data indicate that there are two transporters in the microsomes, an ATP-independent Cu(I) transporter and an ATP-dependent Cu(II) pump. The activity of the Cu(I) transporter correlates most strongly with alkaline phosphatase, suggesting that it is derived from plasma membrane contamination. Cu(II) ATP-dependent transport correlates only with beta-1, 4-galactosyltransferase, which indicates that it is located in the Golgi apparatus.
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Ford, Robert C., and Konstantinos Beis. "Learning the ABCs one at a time: structure and mechanism of ABC transporters." Biochemical Society Transactions 47, no. 1 (January 9, 2019): 23–36. http://dx.doi.org/10.1042/bst20180147.
Повний текст джерелаАнотація:
Abstract ATP-binding cassette (ABC) transporters are essential proteins that are found across all kingdoms of life. ABC transporters harness the energy of ATP hydrolysis to drive the import of nutrients inside bacterial cells or the export of toxic compounds or essential lipids across bacteria and eukaryotic membranes. Typically, ABC transporters consist of transmembrane domains (TMDs) and nucleotide-binding domains (NBDs) to bind their substrate and ATP, respectively. The TMDs dictate what ligands can be recognised, whereas the NBDs are the power engine of the ABC transporter, carrying out ATP binding and hydrolysis. It has been proposed that they utilise the alternating access mechanism, inward- to outward-facing conformation, to transport their substrates. Here, we will review the recent progress on the structure determination of eukaryotic and bacterial ABC transporters as well as the novel mechanisms that have also been proposed, that fall out of the alternating access mechanism model.
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Sofue, M., Y. Yoshimura, M. Nishida, and J. Kawada. "ADP modifies the function of the glucose transporter: studies with reconstituted liposomes." Biochemical Journal 292, no. 3 (June 15, 1993): 877–81. http://dx.doi.org/10.1042/bj2920877.
Повний текст джерелаАнотація:
Modification of function of the glucose transporter by nucleotides was studied by using liposomes reconstituted with the human erythrocyte glucose transporter. ADP enclosed in the liposomes inhibited the uptake of D-glucose and nicotinamide in a dose-dependent manner, but other enclosed nucleotides (ATP, AMP, CDP, GDP, UDP) showed no effect on the uptake of both. Only intraliposomal ADP was effective, and extra-liposomal ADP was not, under our experimental conditions. Intraliposomal ADP did not change Km, but decreased Vmax to approximately one-third of control for uptake of both D-glucose and nicotinamide. However, the binding and the affinity of cytochalasin B to the reconstituted liposomes were not affected by intraliposomal ADP. The uptake of uridine was not changed in the presence of ADP, indicating that the nucleoside transporter co-existing in the liposomal membranes is not regulated by ADP. Human erythrocytes whose intracellular ATP was decreased by Ca2+ ionophore A23187 also showed decreased uptake of 2-deoxy-D-glucose and nicotinamide. This phenomenon was very similar to that found in the liposomes. These findings suggest the possibility that the function of the glucose transporter is directly and negatively modified by an increased concentration of intracellular ADP.
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Sugimoto, Hiroshi, Youichi Naoe, Nozomi Nakamura, Akihiro Doi, and Yoshitsugu Shiro. "Inward-facing conformation of the bacterial heme transporter." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1500. http://dx.doi.org/10.1107/s205327331408499x.
Повний текст джерелаАнотація:
Iron is an essential element for almost all organisms, since iron serves as a catalytic center for redox reactions in many enzymes. Bacterial pathogens need to acquire iron from tissues of host to survive. Heme transport by ATP-binding cassette (ABC) transporter plays a key role in pathological processes. In gram-negative bacteria, the heme or heme protein binds to specific outer membrane receptors on the bacterial surface. The heme is then transported into the cell via ABC transporters. Here, we present the crystal structure of the heme transporter complex BhuUV-T from Burkholderia cenocepacia at 3.5 Å resolution in nucleotide-free state. The permeation pathway created by transmembrane helices of two BhuU subunit exhibits an inward-facing conformation. Comparison with the outward-facing conformation previously reported for the heme transporter HmuUV from Yersinia pestis and homologous vitamin B12 transporter BtuCD-F from E. coli indicates the structural mechanism involving the translational shift of nucleotide binding subunit and repositioning of the helices of permease subunits for substrate translocation. Structure of interface between BhuUV and periplasmic heme-binding protein BhuT suggests that the acidic residues of BhuU at the periplasmic interface may have an important role in releasing the heme from BhuT. We also determined the BhuT in apo and two types of holo form, providing the structural basis for transient and ambiguous heme recognition.
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Manjula, Mallappa, Kudigana J. Pampa, Shankar Madan Kumar, Naoki Kunishima, and Neratur K. Lokanath. "Purification, crystallization and preliminary X-ray diffraction studies of the ATP-binding subunit of an ABC transporter fromGeobacillus kaustophilus." Acta Crystallographica Section F Structural Biology and Crystallization Communications 68, no. 11 (October 30, 2012): 1406–8. http://dx.doi.org/10.1107/s1744309112037918.
Повний текст джерелаАнотація:
ATP-binding cassette (ABC) transporters, also known as traffic ATPases, form a large family of integral membrane proteins responsible for the translocation of a variety of chemically diverse substrates across the lipid bilayers of cellular membranes of both prokaryotes and eukaryotes by the hydrolysis of ATP. The ATP-binding subunit of an ABC transporter fromGeobacillus kaustophilus, a homodimeric enzyme, was overexpressed inEscherichia coliand purified. Crystals were obtained using the microbatch-under-oil method at 291 K. X-ray diffraction data to 1.6 Å resolution were collected on SPring-8 beamline BL26B1. The crystals belonged to the orthorhombic space groupI222, with unit-cell parametersa= 54.94,b = 78.63,c= 112.96 Å. Assuming the presence of a dimer in the asymmetric unit gave a crystal volume per protein weight (VM) of 2.32 Å3 Da−1and a solvent content of 47%; this was consistent with the results of a dynamic light-scattering experiment, which showed a dimeric state of the protein in solution. Molecular-replacement trials using the crystal structure of HisP from theSalmonella typhimuriumATP-binding subunit of an ABC transporter as a search model did not provide a satisfactory solution, indicating that the two ATP-binding subunits of ABC transporters have substantially different structures.
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Geisler, Markus. "Regulation von ABC-Transportern durch FKBPs." BIOspektrum 27, no. 2 (March 2021): 131–34. http://dx.doi.org/10.1007/s12268-021-1548-x.
Повний текст джерелаАнотація:
AbstractThe plant hormone auxin is distributed in the plant by a sophisticated network of importers and exporters, including members of the ABCB subclass of ATP-binding cassette (ABC) transporters. ABCB-mediated auxin transport is controlled by Twisted Dwarf1, a member of the FK506-binding protein (FKBP) family. Here, we summarize current knowledge on ABC transporter regulation by FKBPs, which seems to be conserved over kingdoms and ABC subfamilies arguing for conserved mechanism of plant and mammalian post-translational transporter regulation.
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Gottschalk, Birgit, Gerd Bröker, Melanie Kuhn, Simone Aymanns, Ute Gleich-Theurer, and Barbara Spellerberg. "Transport of Multidrug Resistance Substrates by the Streptococcus agalactiae Hemolysin Transporter." Journal of Bacteriology 188, no. 16 (August 15, 2006): 5984–92. http://dx.doi.org/10.1128/jb.00768-05.
Повний текст джерелаАнотація:
ABSTRACT Streptococcus agalactiae (group B streptococcus [GBS]) causes neonatal sepsis, pneumonia, and meningitis, as well as infections of the bovine udder. The S. agalactiae hemolysin is regarded as an important virulence factor, and hemolysin expression is dependent on the cyl gene cluster. cylA and cylB encode the ATP binding and transmembrane domains of a typical ATP binding cassette (ABC) transporter. The deduced proteins contain the signature sequence of a multidrug resistance (MDR) transporter, and mutation of the genes results in a nonhemolytic and nonpigmented phenotype. To further elucidate the function of the putative transporter, nonpolar deletion mutants of cylA were constructed. These mutants are nonhemolytic and can be complemented by the transporter genes. Wild-type strain and nonhemolytic cylA and cylK deletion mutants were exposed to known substrates of MDR transporters. Mutation of cylA significantly impaired growth in the presence of daunorubicin, doxorubicin, and rhodamine 6G and resulted in a decreased export of doxorubicin from the cells. The mutation of cylK, a gene of unknown function located downstream from cylA, caused a loss of hemolysis but had no effect on the transport of MDR substrates. Furthermore, the hemolytic activity of the wild-type strain was inhibited by reserpine in a dose-dependent manner. We conclude that CylAB closely resembles an ABC-type MDR transporter and propose that the GBS hemolysin molecule represents a natural substrate of the transporter.
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Ahmad, Ashfaq, Sidra Majaz, and Faisal Nouroz. "Two-component systems regulate ABC transporters in antimicrobial peptide production, immunity and resistance." Microbiology 166, no. 1 (January 1, 2020): 4–20. http://dx.doi.org/10.1099/mic.0.000823.
Повний текст джерелаАнотація:
Bacteria offer resistance to a broad range of antibiotics by activating their export channels of ATP-binding cassette transporters. These transporters perform a central role in vital processes of self-immunity, antibiotic transport and resistance. The majority of ATP-binding cassette transporters are capable of detecting the presence of antibiotics in an external vicinity and are tightly regulated by two-component systems. The presence of an extracellular loop and an adjacent location of both the transporter and two-component system offers serious assistance to induce a quick and specific response against antibiotics. Both systems have demonstrated their ability of sensing such agents, however, the exact mechanism is not yet fully established. This review highlighted the three key functions of antibiotic resistance, transport and self-immunity of ATP-binding cassette transporters and an adjacent two-component regulatory system.
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He, Qiyi, Zhentian Yan, Fengling Si, Yong Zhou, Wenbo Fu, and Bin Chen. "ATP-Binding Cassette (ABC) Transporter Genes Involved in Pyrethroid Resistance in the Malaria Vector Anopheles sinensis: Genome-Wide Identification, Characteristics, Phylogenetics, and Expression Profile." International Journal of Molecular Sciences 20, no. 6 (March 20, 2019): 1409. http://dx.doi.org/10.3390/ijms20061409.
Повний текст джерелаАнотація:
background: The ATP-binding cassette (ABC) transporters family is one of the largest families of membrane proteins existing in all living organisms. Pyrethroid resistance has become the largest unique obstacle for mosquito control worldwide. ABC transporters are thought to be associated with pyrethroid resistance in some agricultural pests, but little information is known for mosquitoes. Herein, we investigated the diversity, location, characteristics, phylogenetics, and evolution of ABC transporter family of genes in the Anopheles sinensis genome, and identified the ABC transporter genes associated with pyrethroid resistance through expression profiles using RNA-seq and qPCR. Results: 61 ABC transporter genes are identified and divided into eight subfamilies (ABCA-H), located on 22 different scaffolds. Phylogenetic and evolution analyses with ABC transporters of A. gambiae, Drosophila melanogaster, and Homo sapiens suggest that the ABCD, ABCG, and ABCH subfamilies are monophyly, and that the ABCC and ABCG subfamilies have experienced a gene duplication event. Both RNA-seq and qPCR analyses show that the AsABCG28 gene is uniquely significantly upregulated gene in all three field pyrethroid-resistant populations (Anhui, Chongqing, and Yunnan provinces) in comparison with a laboratory-susceptible strain from Jiangsu province. The AsABCG28 is significantly upregulated at 12-h and 24-h after deltamethrin exposure in three-day-old female adults. Conclusion: This study provides the information frame for ABC transporter subfamily of genes, and lays an important basis for the better understanding and further research of ABC transporter function in insecticide toxification. The AsABCG28 gene is associated with pyrethroid detoxification, and it functions at later period in the detoxification process for xenobiotics transportation.
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Hui, Wu, Yuan Yongliang, Chen Yongde, Lu Guo, Lan Li, Yang Zhonglin, Ji Hui, and Hu Qinghua. "Hypouricemic and Nephroprotective Effects of Emodinol in Oxonate-Induced Hyperuricemic Mice are Mediated by Organic Ion Transporters and OIT3." Planta Medica 82, no. 04 (November 19, 2015): 289–97. http://dx.doi.org/10.1055/s-0035-1558212.
Повний текст джерелаАнотація:
AbstractEmodinol, 1β,3β,23-trihydroxyolean-12-en-28-acid, as the main active ingredient firstly extracted from the rhizomes of Elaeagus pungens by our research group, has been demonstrated to exhibit uricosuric activity by our previous study. The aim of this study was to evaluate the uricosuric and nephroprotective effects of emodinol and explore its possible mechanisms in potassium oxonate-induced hyperuricemic mice with renal dysfunction. Mice were orally administrated 250 mg/kg of potassium oxonate once daily for 7 consecutive days to induce hyperuricemia with renal dysfunction. Emodinol was given at doses of 25, 50, and 100 mg/kg on the same day 1 h after oxonate treatment, and allopurinol (10 mg/kg) was given as a positive control. After 1 week, serum uric acid, serum creatinine, urine uric acid, urine creatinine, blood urea nitrogen, and hepatic xanthine oxidase activity were determined. The mRNA and protein levels of urate transporter 1, glucose transporter 9, ATP-binding cassette subfamily G member 2, organic anion transporter 1, oncoprotein-induced transcript 3, and organic cation/carnitine transporters in the kidney were detected by real-time polymerase chain reaction and Western blot analysis. In addition, urinary and renal Tamm-Horsfall glycoprotein concentrations were examined by ELISA assays. Emodinol significantly reduced serum urate levels, increased urinary urate levels and fractional excretion of uric acid, and inhibited hepatic xanthine oxidase activity in hyperuricemic mice. Moreover, potassium oxonate administration led to dys expressions of renal urate transporter 1, glucose transporter 9, ATP-binding cassette subfamily G member 2, organic anion transporter 1, and oncoprotein-induced transcript 3 as well as alternations of uromodulin concentrations, which could be reversed by emodinol. On the other hand, treatment of emodinol caused upregulated expressions of organic cation/carnitine transporters, resulting in an improvement of renal function characterized by decreased serum creatinine and blood urea nitrogen levels. Emodinol exhibited hypouricemic and nephroprotective actions by inhibiting xanthine oxidase activity and regulating renal ion transporters and oncoprotein-induced transcript 3, which may be a potential therapeutic agent in hyperuricemia and renal dysfunction.
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Chen, Chiliang, та Gwyn A. Beattie. "Characterization of the Osmoprotectant Transporter OpuC from Pseudomonas syringae and Demonstration that Cystathionine-β-Synthase Domains Are Required for Its Osmoregulatory Function". Journal of Bacteriology 189, № 19 (27 липня 2007): 6901–12. http://dx.doi.org/10.1128/jb.00763-07.
Повний текст джерелаАнотація:
ABSTRACT The plant pathogen Pseudomonas syringae may cope with osmotic stress on plants, in part, by importing osmoprotective compounds. In this study, we found that P. syringae pv. tomato strain DC3000 was distinct from most bacterial species in deriving greater osmoprotection from exogenous choline than from glycine betaine. This superior osmoprotection was correlated with a higher capacity for uptake of choline than for uptake of glycine betaine. Of four putative osmoregulatory ABC transporters in DC3000, one, designated OpuC, functioned as the primary or sole transporter for glycine betaine and as one of multiple transporters for choline under high osmolarity. Surprisingly, the homolog of the well-characterized ProU transporter from Escherichia coli and Salmonella enterica serovar Typhimurium did not function in osmoprotection. The P. syringae pv. tomato OpuC transporter was more closely related to the Bacillus subtilis and Listeria monocytogenes OpuC transporters than to known osmoprotectant transporters in gram-negative bacteria based on sequence similarity and genetic arrangement. The P. syringae pv. tomato OpuC transporter had a high affinity for glycine betaine, a low affinity for choline, and a broad substrate specificity that included acetylcholine, carnitine, and proline betaine. Tandem cystathionine-β-synthase (CBS) domains in the ATP-binding component of OpuC were required for transporter function. The presence of these CBS domains was correlated with osmoregulatory function among the putative transporters examined in DC3000 and was found to be predictive of functional osmoregulatory transporters in other pseudomonads. These results provide the first functional evaluation of an osmoprotectant transporter in a Pseudomonas species and demonstrate the usefulness of the CBS domains as predictors of osmoregulatory activity.
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Luckenbach, Till, and David Epel. "ABCB- and ABCC-type transporters confer multixenobiotic resistance and form an environment-tissue barrier in bivalve gills." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 294, no. 6 (June 2008): R1919—R1929. http://dx.doi.org/10.1152/ajpregu.00563.2007.
Повний текст джерелаАнотація:
Aquatic organisms and, in particular, filter feeders, such as mussels, are continuously exposed to toxicants dissolved in the water and, presumably, require adaptations to avoid the detrimental effects from such chemicals. Previous work indicates that activity of ATP-binding cassette (ABC) transporters protects mussels against toxicants, but the nature of these transporters and the structural basis of protection are not known. Here we meld studies on transporter function, gene expression, and localization of transporter protein in mussel gill tissue and show activity and expression of two xenobiotic transporter types in the gills, where they provide an effective structural barrier against chemicals. Activity of ABCB/MDR/P-glycoprotein and ABCC/MRP-type transporters was indicated by sensitivity of efflux of the test substrate calcein-AM to the ABCB inhibitor PSC-833 and the ABCC inhibitor MK-571. This activity profile is supported by our cloning of the complete sequence of two ABC transporter types from RNA in mussel tissue with a high degree of identity to transporters from the ABCB and ABCC subfamilies. Overall identity of the amino acid sequences with corresponding homologs from other organisms was 38–50% (ABCB) and 27–44% (ABCC). C219 antibody staining specific for ABCB revealed that this transporter was restricted to cells in the gill filaments with direct exposure to water flow. Taken together, our data demonstrate that ABC transporters form an active, physiological barrier at the tissue-environment interface in mussel gills, providing protection against environmental xenotoxicants.
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Van Bibber, Michael, Clive Bradbeer, Nica Clark, and John R. Roth. "A New Class of Cobalamin Transport Mutants (btuF) Provides Genetic Evidence for a Periplasmic Binding Protein in Salmonella typhimurium." Journal of Bacteriology 181, no. 17 (September 1, 1999): 5539–41. http://dx.doi.org/10.1128/jb.181.17.5539-5541.1999.
Повний текст джерелаАнотація:
ABSTRACT No periplasmic binding protein has been demonstrated for the ATP-binding cassette (ABC)-type cobalamin transporter BtuCD. New mutations (btuF) are described that affect inner-membrane transport. The BtuF protein has a signal sequence and resembles the periplasmic binding proteins of several other ABC transporters.
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Seelig, Anna, and Xiaochun Li-Blatter. "P-glycoprotein (ABCB1) - weak dipolar interactions provide the key to understanding allocrite recognition, binding, and transport." Cancer Drug Resistance 6, no. 1 (2022): 1–29. http://dx.doi.org/10.20517/cdr.2022.59.
Повний текст джерелаАнотація:
P-glycoprotein (ABCB1) is the first discovered mammalian member of the large family of ATP binding cassette (ABC) transporters. It facilitates the movement of compounds (called allocrites) across membranes, using the energy of ATP binding and hydrolysis. Here, we review the thermodynamics of allocrite binding and the kinetics of ATP hydrolysis by ABCB1. In combination with our previous molecular dynamics simulations, these data lead to a new model for allocrite transport by ABCB1. In contrast to previous models, we take into account that the transporter was evolutionarily optimized to operate within a membrane, which dictates the nature of interactions. Hydrophobic interactions drive lipid-water partitioning of allocrites, the transport process’s first step. Weak dipolar interactions (including hydrogen bonding, π-π stacking, and π-cation interactions) drive allocrite recognition, binding, and transport by ABCB1 within the membrane. Increasing the lateral membrane packing density reduces allocrite partitioning but enhances dipolar interactions between allocrites and ABCB1. Allocrite flopping (or reorientation of the polar part towards the extracellular aqueous phase) occurs after hydrolysis of one ATP molecule and opening of ABCB1 at the extracellular side. Rebinding of ATP re-closes the transporter at the extracellular side and expels the potentially remaining allocrite into the membrane. The high sensitivity of the steady-state ATP hydrolysis rate to the nature and number of dipolar interactions, as well as to the dielectric constant of the membrane, points to a flopping process, which occurs to a large extent at the membrane-transporter interface. The proposed unidirectional ABCB1 transport cycle, driven by weak dipolar interactions, is consistent with membrane biophysics.
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Mishra, Awdhesh Kumar, Jinhee Choi, Muhammad Fazle Rabbee, and Kwang-Hyun Baek. "In Silico Genome-Wide Analysis of the ATP-Binding Cassette Transporter Gene Family in Soybean (Glycine max L.) and Their Expression Profiling." BioMed Research International 2019 (January 10, 2019): 1–14. http://dx.doi.org/10.1155/2019/8150523.
Повний текст джерелаАнотація:
ATP-binding cassette (ABC) transporters constitute one of the largest gene families in all living organisms, most of which mediate transport across biological membranes by hydrolyzing ATP. However, detailed studies of ABC transporter genes in the important oil crop, soybean, are still lacking. In the present study, we carried out genome-wide identification and phylogenetic and transcriptional analyses of the ABC gene family in G. max. A total of 261 G. max ABC (GmABCs) genes were identified and unevenly localized onto 20 chromosomes. Referring to protein-domain orientation and phylogeny, the GmABC family could be classified into eight (ABCA-ABCG and ABCI) subfamilies and ABCG were the most abundantly present. Further, investigation of whole genome duplication (WGD) signifies the role of segmental duplication in the expansion of the ABC transporter gene family in soybean. The Ka/Ks ratio indicates that several duplicated genes are governed by intense purifying selection during evolution. In addition, in silico expression analysis based on RNA-sequence using publicly available database revealed that ABC transporters are differentially expressed in tissues and developmental stages and in dehydration. Overall, we provide an extensive overview of the GmABC transporter gene family and it promises the primary basis for the study in development and response to dehydration tolerance.
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García-Lino, Álvarez-Fernández, Blanco-Paniagua, Merino, and Álvarez. "Transporters in the Mammary Gland—Contribution to Presence of Nutrients and Drugs into Milk." Nutrients 11, no. 10 (October 5, 2019): 2372. http://dx.doi.org/10.3390/nu11102372.
Повний текст джерелаАнотація:
A large number of nutrients and bioactive ingredients found in milk play an important role in the nourishment of breast-fed infants and dairy consumers. Some of these ingredients include physiologically relevant compounds such as vitamins, peptides, neuroactive compounds and hormones. Conversely, milk may contain substances—drugs, pesticides, carcinogens, environmental pollutants—which have undesirable effects on health. The transfer of these compounds into milk is unavoidably linked to the function of transport proteins. Expression of transporters belonging to the ATP-binding cassette (ABC-) and Solute Carrier (SLC-) superfamilies varies with the lactation stages of the mammary gland. In particular, Organic Anion Transporting Polypeptides 1A2 (OATP1A2) and 2B1 (OATP2B1), Organic Cation Transporter 1 (OCT1), Novel Organic Cation Transporter 1 (OCTN1), Concentrative Nucleoside Transporters 1, 2 and 3 (CNT1, CNT2 and CNT3), Peptide Transporter 2 (PEPT2), Sodium-dependent Vitamin C Transporter 2 (SVCT2), Multidrug Resistance-associated Protein 5 (ABCC5) and Breast Cancer Resistance Protein (ABCG2) are highly induced during lactation. This review will focus on these transporters overexpressed during lactation and their role in the transfer of products into the milk, including both beneficial and harmful compounds. Furthermore, additional factors, such as regulation, polymorphisms or drug-drug interactions will be described.
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Rigalli, Juan Pablo, Anna Gagliardi, Klara Diester, Gzona Bajraktari-Sylejmani, Antje Blank, Jürgen Burhenne, Alexander Lenard, et al. "Extracellular Vesicles as Surrogates for the Regulation of the Drug Transporters ABCC2 (MRP2) and ABCG2 (BCRP)." International Journal of Molecular Sciences 25, no. 7 (April 8, 2024): 4118. http://dx.doi.org/10.3390/ijms25074118.
Повний текст джерелаАнотація:
Drug efflux transporters of the ATP-binding-cassette superfamily play a major role in the availability and concentration of drugs at their site of action. ABCC2 (MRP2) and ABCG2 (BCRP) are among the most important drug transporters that determine the pharmacokinetics of many drugs and whose overexpression is associated with cancer chemoresistance. ABCC2 and ABCG2 expression is frequently altered during treatment, thus influencing efficacy and toxicity. Currently, there are no routine approaches available to closely monitor transporter expression. Here, we developed and validated a UPLC-MS/MS method to quantify ABCC2 and ABCG2 in extracellular vesicles (EVs) from cell culture and plasma. In this way, an association between ABCC2 protein levels and transporter activity in HepG2 cells treated with rifampicin and hypericin and their derived EVs was observed. Although ABCG2 was detected in MCF7 cell-derived EVs, the transporter levels in the vesicles did not reflect the expression in the cells. An analysis of plasma EVs from healthy volunteers confirmed, for the first time at the protein level, the presence of both transporters in more than half of the samples. Our findings support the potential of analyzing ABC transporters, and especially ABCC2, in EVs to estimate the transporter expression in HepG2 cells.