scholarly journals Structural basis for the mechanism of ABC transporters

2015 ◽  
Vol 43 (5) ◽  
pp. 889-893 ◽  
Author(s):  
Konstantinos Beis
Keyword(s):  
Drug Resistance ◽  
Binding Site ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Eukaryotic Cells ◽  
Structural Basis ◽  
Multi Drug Resistance ◽  
Hydrolysis Of ◽  
Transport Molecules ◽  
Alternating Access

The ATP-binding cassette (ABC) transporters are primary transporters that couple the energy stored in adenosine triphosphate (ATP) to the movement of molecules across the membrane. ABC transporters can be divided into exporters and importers; importers mediate the uptake of essential nutrients into cells and are found predominantly in prokaryotes whereas exporters transport molecules out of cells or into organelles and are found in all organisms. ABC exporters have been linked with multi-drug resistance in both bacterial and eukaryotic cells. ABC transporters are powered by the hydrolysis of ATP and transport their substrate via the alternating access mechanism, whereby the protein alternates between a conformation in which the substrate-binding site is accessible from the outside of the membrane, outward-facing and one in which it is inward-facing. In this mini-review, the structures of different ABC transporter types in different conformations are presented within the context of the alternating access mechanism and how they have shaped our current understanding of the mechanism of ABC transporters.

scholarly journals Identification of the PA1113 Gene Product as an ABC Transporter Involved in the Uptake of Carbenicillin in Pseudomonas aeruginosa PAO1

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 596
Author(s):  
Christian Hulen ◽  
Pierre-jean Racine ◽  
Sylvie Chevalier ◽  
Marc Feuilloley ◽  
Nour-Eddine LOMRI
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Cell Wall ◽  
Gene Product ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Inhibitory Effect ◽  
Eukaryotic Cells ◽  
Amino Acid Sequence Homology ◽  
Protein Targets ◽  
Bacterial Cytoplasm

The resistance of Pseudomonas aeruginosa to antibiotics is multi factorial and complex. Whereas efflux pumps such as MexAB-OprM have been thought to predominate, here we show that a novel ATP Binding Cassette (ABC) transporter that mediates influx of carbenicillin from the periplasm to the cytoplasm and away from its cell wall target plays an important role in the resistance of P. aeruginosa to this antibiotic. Treatment of P. aeruginosa with verapamil, an inhibitor of ABC transporters in eukaryotic cells, increases its sensitivity to carbenicillin. Using amino acid sequence homology with known verapamil protein targets as a probe, we determined that the PA1113 gene product, an ABC transporter, mediates carbenicillin uptake into the bacterial cytoplasm. Docking and pharmacological analyses showed that verapamil and carbenicillin compete for the same site on the PA1113 gene protein, explaining the inhibitory effect of verapamil on carbenicillin uptake, and furthermore suggest that the PA1113 ABC transporter accounts for about 30% of P. aeruginosa carbenicillin resistance. Our findings demonstrate that the PA1113 gene product helps mediate carbenicillin resistance by transporting it away from its cell wall target and represents a promising new therapeutic target.

Inhibition of Hexokinase II Inactivates ABC Transporters and Restores Drug Sensitivity in Myeloma Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 135-135
Author(s):  
Ayako Nakano ◽  
Masahiro Abe ◽  
Daisuke Tsuji ◽  
Hirokazu Miki ◽  
Akishige Ikegame ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Malignant Cells ◽  
Cancer Resistance ◽  
Hexokinase Ii ◽  
Atp Production ◽  
Rpmi 8226

Abstract Abstract 135 Malignant cells aberrantly up-regulate ATP-binding cassette (ABC) transporters and ATP-dependent drug efflux pumps, which causes drug resistance. Because the activity of TCA cycle in mitochondria is suppressed through oncogenic alterations including the mutation of p53, ATP is largely produced by aerobic glycolytic metabolism enhanced in malignant cells (the Warburg effect). Hexokinase II (HKII), a key enzyme of glycolysis, is widely over-expressed in cancer cells. However, HKII levels and its roles in ATP production and ATP-dependent cellular process have not been elucidated in hematopoietic malignant cells including myeloma (MM) cells. In the present study, we therefore explored the expression levels of HKII and the effect of HKII inhibition on ABC transporter activity as well as the susceptibility to chemotherapeutic agents in MM cells. HKII protein was constitutively expressed at higher level in MM cells than in normal peripheral blood mononuclear cells (PBMCs). The expression level of HKII in MM cells was further up-regulated when cocultured with osteoclasts. 3-bromopyruvate (3BrPA), an inhibitor of HKII promptly inhibited glycolysis and substantially suppressed ATP production in MM cells but not in normal PBMCs. 3BrPA preferentially induced cell death in MM cells but not in normal hematopoietic cells in bone marrow samples from patients with MM, suggesting that HKII is a potential target for treatment of MM cells. We next examined the effects of 3BrPA on ABC transporter activity in RPMI 8226 (MM) and KG-1 (acute myeloid leukemia) cells which are aberrantly over-expressed breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1), respectively. After passive incorporation of auto-fluorescence emitting daunorubicin, these cells were washed and incubated for 2 hours without daunorubicin in the absence or presence of 3BrPA, and then the intracellular daunorubicin levels were measured by flow cytometry. Treatment with 3BrPA markedly enhanced the accumulation and retention of daunorubicin in both cells. Therefore, inhibition of HKII by 3BrPA appears to be able to effectively deplete intracellular ATP production and suppress ABC transporter activity. Importantly, 3BrPA restored cytotoxic effects of doxorubicin and daunorubicin on RPMI 8226 and KG-1 cells. We next focused on “Side population (SP)” which is regarded as a highly drug-resistant fraction with enhanced ABC transporter activity, and contains clonogenic or tumor-initiating cells. SP cells isolated from RPMI 8226 cells exhibited higher levels of glycolysis with an increased expression of genes involved in the glycolytic pathway. Treatment with 3BrPA abolished Hoechst 33342 exclusion in the SP cells, and clonogenic capacity in RPMI 8226 and KG-1 cells. Furthermore, 3BrPA cooperatively suppressed subcutaneous tumor growth in combination with doxorubicin in RPMI 8226-implanted mice. These results demonstrate that HKII is a tumor specific target for treatment of MM and that inhibition of HKII effectively depletes ATP and inactivate ABC transporters to overcome drug resistance. ABC transporter-expressing SP cells with enhanced glycolysis and clonogenic cells with high proliferative potential are suggested to be a good target of the inhibition of glycolysis. These findings highlight a novel role of enhanced glycolysis in malignant cells in tumor growth and drug resistance, and relevance to anti-cancer strategies attempting to target unique metabolic pathway of cancer cells. Disclosures: No relevant conflicts of interest to declare.

Mutations of the multi-drug resistance-associated protein ABC transporter gene 5 result in reduction of phytic acid in rice seeds

2009 ◽  
Vol 119 (1) ◽  
pp. 75-83 ◽  
Author(s):  
Xiu-Hong Xu ◽  
Hai-Jun Zhao ◽  
Qing-Long Liu ◽  
Thomas Frank ◽  
Karl-Heinz Engel ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Phytic Acid ◽  
Abc Transporter ◽  
Multi Drug Resistance ◽  
Transporter Gene ◽  
Rice Seeds

scholarly journals Contributions of Aspergillus fumigatus ATP-Binding Cassette Transporter Proteins to Drug Resistance and Virulence

2013 ◽  
Vol 12 (12) ◽  
pp. 1619-1628 ◽  
Author(s):  
Sanjoy Paul ◽  
Daniel Diekema ◽  
W. Scott Moye-Rowley
Keyword(s):  
Drug Resistance ◽  
Aspergillus Fumigatus ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Sequence Similarity ◽  
Atp Binding ◽  
Content Type ◽  
Transporter Proteins ◽  
Encoding Genes ◽  
Atp Binding Cassette

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.

scholarly journals Transcriptional study of the ABC transporter-encoding genes in response to fungicide treatment and during plant infection in the phytopathogenic fungusBotrytis cinerea

2016 ◽  
Author(s):  
Elise Loisel ◽  
Isabelle R. Goncalves ◽  
Nathalie Poussereau ◽  
Marie-Claire Grosjean-Cournoyer ◽  
François Villalba ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Abc Transporters ◽  
Grey Mould ◽  
Multi Drug Resistance ◽  
Drug Efflux ◽  
Mould Fungus ◽  
Over Expression ◽  
Plant Infection ◽  
Commercially Important ◽  
Encoding Genes

AbstractThe grey mould fungusBotrytis cinereacauses worldwide losses of commercially important fruits, vegetables and ornamentals. Various fungicides, with different modes of action, are effective against this pathogen, but isolates with multiple fungicide-resistance phenotypes (Multi Drug Resistance, MDR) have been observed with increasing frequency. In fungi, ATP binding cassette (ABC) transporters participate in drug efflux and we report here on the parallel transcriptional study of the predicted ABC transporter-encoding genes inB. cinerea.During plant infection, transcription of all of these genes was activated and over-expression was observed for a few of these genes if the plants were treated with a fungicide prior to infection. In the absence of plant, most of the genes were transcriptionally activated in response to two different fungicides. Both common and specific transcriptional signatures were observed.

scholarly journals Computational design of molecular motors as nanocircuits in Leishmaniasis

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 94
Author(s):  
Dipali Kosey ◽  
Shailza Singh
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Time Delay ◽  
Response Time ◽  
Abc Transporters ◽  
Leishmania Major ◽  
Genetic Regulatory Networks ◽  
Multi Drug Resistance ◽  
Bistable Switch ◽  
Gene Expression Response

Cutaneous leishmaniasis is the most common form of leishmaniasis, caused by Leishmania major and is spread by the bite of a sandfly.This species infects the macrophages and dendritic cells Due to multi-drug resistance, there is a need for a new therapeutic technique. Recently, a novel molecular motor of Leishmania, Myosin XXI, was classified and characterized. In addition, the drug resistance in this organism has been linked with the overexpression of ABC transporters. Systems biology aims to study the simulation and modeling of natural biological systems whereas synthetic biology deals with building novel and artificial biological parts and devices  Together they have contributed enormously to drug discovery, vaccine design and development, infectious disease detection and diagnostics. Synthetic genetic regulatory networks with desired properties, like toggling and oscillation have been proposed to be useful for gene therapy. In this work, a nanocircuit with coupled bistable switch – repressilator  has been designed, simulated in the presence and absence of inducer, in silico, using Tinker Cell. When inducer is added, the circuit has been shown to produce reporter at high levels, which will impair the activity of Myosin XXI and ABC transporters. Validation of the circuit was also performed using GRENITS and BoolNet. The influence of inducer on the working of the circuit, i.e., the type of gene expression, response time delay, the steady states formed by the circuit and the quasipotential landscape of the circuit were performed. It was found that the addition of inducer reduced the response time delay in the graded type of gene expression and removed the multiple intermediate attractors of the circuit. Thus, the inducer increased the probability of the circuit to be present in the dominant stable state with high reporter concentration and hence the designed nanocircuit may be used for the treatment of leishmaniasis.

scholarly journals Structural basis of trehalose recycling by the ABC transporter LpqY-SugABC

2020 ◽  
Vol 6 (44) ◽  
pp. eabb9833
Author(s):  
Fengjiang Liu ◽  
Jingxi Liang ◽  
Bing Zhang ◽  
Yan Gao ◽  
Xiuna Yang ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Unique Feature ◽  
Structural Basis ◽  
Human Pathogens ◽  
Gram Positive Bacteria ◽  
Cryo Electron Microscopy ◽  
Uptake Of Nutrients ◽  
Initial Mode

In bacteria, adenosine 5′-triphosphate (ATP)–binding cassette (ABC) importers are essential for the uptake of nutrients including the nonreducing disaccharide trehalose, a metabolite that is crucial for the survival and virulence of several human pathogens including Mycobacterium tuberculosis. SugABC is an ABC transporter that translocates trehalose from the periplasmic lipoprotein LpqY into the cytoplasm of mycobacteria. Here, we report four high-resolution cryo–electron microscopy structures of the mycobacterial LpqY-SugABC complex to reveal how it binds and passes trehalose through the membrane to the cytoplasm. A unique feature observed in this system is the initial mode of capture of the trehalose at the LpqY interface. Uptake is achieved by a pivotal rotation of LpqY relative to SugABC, moving from an open and accessible conformation to a clamped conformation upon trehalose binding. These findings enrich our understanding as to how ABC transporters facilitate substrate transport across the membrane in Gram-positive bacteria.

scholarly journals Computational design of molecular motors as nanocircuits in Leishmaniasis

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 94 ◽  
Author(s):  
Dipali Kosey ◽  
Shailza Singh
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Time Delay ◽  
Response Time ◽  
Abc Transporters ◽  
Leishmania Major ◽  
Genetic Regulatory Networks ◽  
Multi Drug Resistance ◽  
Bistable Switch ◽  
Gene Expression Response

Cutaneous leishmaniasis is the most common form of lesihmaniasis, caused by Leishmania major and is spread by the bite of a sandfly.This species infects the macrophages and dendritic cells Due to multi-drug resistance, there is a need for a new therapeutic technique. Recently, a novel molecular motor of Leishmania, Myosin XXI, was classified and characterized. In addition, the drug resistance in this organism has been linked with the overexpression of ABC transporters. Systems biology aims to study the simulation and modeling of natural biological systems whereas synthetic biology deals with building novel and artificial biological parts and devices  Together they have contributed enormously to drug discovery, vaccine design and development, infectious disease detection and diagnostics. Synthetic genetic regulatory networks with desired properties, like toggling and oscillation have been proposed to be useful for gene therapy. In this work, a nanocircuit with coupled bistable switch – repressilator  has been designed, simulated in the presence and absence of inducer, in silico, using Tinker Cell. When inducer is added, the circuit has been shown to produce reporter at high levels, which will impair the activity of Myosin XXI and ABC transporters. Validation of the circuit was also performed using GRENITS and BoolNet. The influence of inducer on the working of the circuit, i.e., the type of gene expression, response time delay, the steady states formed by the circuit and the quasipotential landscape of the circuit were performed. It was found that the addition of inducer reduced the response time delay in the graded type of gene expression and removed the multiple intermediate attractors of the circuit. Thus, the inducer increased the probability of the circuit to be present in the dominant stable state with high reporter concentration and hence the designed nanocircuit may be used for the treatment of leishmaniasis.

Mouse ATP-Binding Cassette (ABC) Transporters Conferring Multi-Drug Resistance

2015 ◽  
Vol 15 (4) ◽  
pp. 423-432 ◽  
Author(s):  
Shuaizhang Li ◽  
Wen Zhang ◽  
Xuejiao Yin ◽  
Shilai Xing ◽  
Heidi Xie ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Abc Transporters ◽  
Multi Drug Resistance ◽  
Atp Binding ◽  
Atp Binding Cassette

scholarly journals Multi-Drug Resistance ABC Transporter Inhibition Enhances Murine Ventral Prostate Stem/Progenitor Cell Differentiation

2015 ◽  
Vol 24 (10) ◽  
pp. 1236-1251 ◽  
Author(s):  
Mugdha D. Samant ◽  
Courtney M. Jackson ◽  
Carina L. Felix ◽  
Anthony J. Jones ◽  
David W. Goodrich ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Differentiation ◽  
Abc Transporter ◽  
Progenitor Cell ◽  
Ventral Prostate ◽  
Multi Drug Resistance
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