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PubMed2005

Multidrug resistance in parasites: ABC transporters, P-glycoproteins and molecular modelling.

Parasitic diseases, caused by protozoa, helminths and arthropods, rank among the most important problems in human and veterinary medicine, and in agriculture, leading to debilitating sicknesses and loss of life. In the absence of vaccines and with the general failure of vector eradication programs, drugs are the main line of defence, but the newest drugs are being tracked by the emergence of resistance in parasites, sharing ominous parallels with multidrug resistance in bacterial pathogens. Any of a number of mechanisms will elicit a drug resistance phenotype in parasites, including: active efflux, reduced uptake, target modification, drug modification, drug sequestration, by-pass shunting, or substrate competition. The role of ABC transporters in parasitic multidrug resistance mechanisms is being subjected to more scrutiny, due in part to the established roles of certain ABC transporters in human diseases, and also to an increasing portfolio of ABC transporters from parasite genome sequencing projects. For example, over 100 ABC transporters have been identified in the Escherichia coli genome, but to date only about 65 in all parasitic genomes. Long established laboratory investigations are now being assisted by molecular biology, bioinformatics, and computational modelling, and it is in these areas that the role of ABC transporters in parasitic multidrug resistance mechanisms may be defined and put in perspective with that of other proteins. We discuss ABC transporters in parasites, and conclude with an example of molecular modelling that identifies a new interaction between the structural domains of a parasite P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Structure of MsbA from E. coli: a homolog of the multidrug resistance ATP binding cassette (ABC) transporters.

Multidrug resistance (MDR) is a serious medical problem and presents a major challenge to the treatment of disease and the development of novel therapeutics. ABC transporters that are associated with multidrug resistance (MDR-ABC transporters) translocate hydrophobic drugs and lipids from the inner to the outer leaflet of the cell membrane. To better elucidate the structural basis for the "flip-flop" mechanism of substrate movement across the lipid bilayer, we have determined the structure of the lipid flippase MsbA from Escherichia coli by x-ray crystallography to a resolution of 4.5 angstroms. MsbA is organized as a homodimer with each subunit containing six transmembrane alpha-helices and a nucleotide-binding domain. The asymmetric distribution of charged residues lining a central chamber suggests a general mechanism for the translocation of substrate by MsbA and other MDR-ABC transporters. The structure of MsbA can serve as a model for the MDR-ABC transporters that confer multidrug resistance to cancer cells and infectious microorganisms.

ATP-Binding Cassette Transporters↗
PubMed2000

The role of ABC transporters from Aspergillus nidulans in protection against cytotoxic agents and in antibiotic production.

This paper describes the characterization of atrC and atrD (ABC transporters C and D), two novel ABC transporter-encoding genes from the filamentous fungus Aspergillus nidulans, and provides evidence for the involvement of atrD in multidrug transport and antibiotic production. BLAST analysis of the deduced amino acid sequences of AtrCp and AtrDp reveals high homology to ABC transporter proteins of the P-glycoprotein cluster. AtrDp shows a particularly high degree of identity to the amino acid sequence of Afu Mdr1p, a previously characterized ABC transporter from the human pathogen A. fumigatus. Northern analysis demonstrates an increase in transcript levels of atrC and atrD in fungal germlings upon treatment with natural toxic compounds and xenobiotics. The atrC gene has a high constitutive level of expression relative to attrD, which suggests its involvement in a metabolic function. Single knock-out mutants for atrC and atrD were generated by gene replacement using pyrG from A. oryzae as a selectable marker. DeltatrD mutants display a hypersensitive phenotype to compounds such as cycloheximide, the cyclosporin derivative PSC 833, nigericin and valinomycin, indicating that AtrDp is involved in protection against cytotoxic compounds. Energy-dependent efflux of the azole-related fungicide fenarimol is inhibited by substrates of AtrDp (e.g. PSC 833, nigericin and valinomycin), suggesting that AtrDp plays a role in efflux of this fungicide. Most interestingly, (delta)atrD mutants display a decrease in penicillin production, measured indirectly as antimicrobial activity against Micrococcus luteus. These results suggest that ABC transporters may be involved in secretion of penicillin from fungal cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice.

BACKGROUND & AIMS: Cholestasis induces changes in hepatic adenosine triphosphate-binding cassette (ABC) transporter expression. We aimed to investigate the role of the nuclear bile acid receptor (farnesoid X receptor [FXR]) in mediating changes in ABC transporter expression and in determining liver injury. METHODS: Hepatic ABC transporter (multidrug resistance-associated proteins [Mrp] 2-4 and bile salt export pump [Bsep]) expression and localization were studied in common bile duct-ligated (CBDL) FXR knockout (FXR(-/-)), wild-type (FXR(+/+)), and sham-operated mice. Serum alanine aminotransferase, alkaline phosphatase, bilirubin and bile acid levels, hepatic bile acid composition, and liver histology were investigated. Cholangiomanometry and bile duct morphometry were performed. RESULTS: CBDL induced expression of Mrp 3 and Mrp 4 in FXR(+/+) and even more in FXR(-/-), whereas Mrp 2 expression remained unchanged. Bsep expression was maintained in CBDL FXR(+/+) but remained undetectable in CBDL FXR(-/-). Alanine aminotransferase levels and mortality rates did not differ between CBDL FXR(+/+) and FXR(-/-). CBDL increased biliary pressure and induced bile ductular proliferation and bile infarcts in FXR(+/+), whereas FXR(-/-) had lower biliary pressures, less ductular proliferation, and developed disseminated liver cell necroses. CONCLUSIONS: Overexpression of Mrp 3 and Mrp 4 in CBDL mice is FXR independent and could play an important role in the adaptive hepatic ABC transporter response to cholestasis. Maintenance of Bsep expression strictly depends on FXR and is a critical determinant of the cholestatic phenotype. Lack of bile infarcts in CBDL FXR(-/-) suggests that development of bile infarcts is related to bile acid-dependent bile flow and biliary pressure. This information is relevant for the potential use of FXR modulators in the treatment of cholestatic liver diseases.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Identification of the tliDEF ABC transporter specific for lipase in Pseudomonas fluorescens SIK W1.

Pseudomonas fluorescens, a gram-negative psychrotrophic bacterium, secretes a thermostable lipase into the extracellular medium. In our previous study, the lipase of P. fluorescens SIK W1 was cloned and expressed in Escherichia coli, but it accumulated as inactive inclusion bodies. Amino acid sequence analysis of the lipase revealed a potential C-terminal targeting sequence recognized by the ATP-binding cassette (ABC) transporter. The genetic loci around the lipase gene were searched, and a secretory gene was identified. Nucleotide sequencing of an 8.5-kb DNA fragment revealed three components of the ABC transporter, tliD, tliE, and tliF, upstream of the lipase gene, tliA. In addition, genes encoding a protease and a protease inhibitor were located upstream of tliDEF. tliDEF showed high similarity to ABC transporters of Pseudomonas aeruginosa alkaline protease, Erwinia chrysanthemi protease, Serratia marcescens lipase, and Pseudomonas fluorescens CY091 protease. tliDEF and the lipase structural gene in a single operon were sufficient for E. coli cells to secrete the lipase. In addition, E. coli harboring the lipase gene secreted the lipase by complementation of tliDEF in a different plasmid. The ABC transporter of P. fluorescens was optimally functional at 20 and 25 degrees C, while the ABC transporter, aprD, aprE, and aprF, of P. aeruginosa secreted the lipase irrespective of temperature between 20 and 37 degrees C. These results demonstrated that the lipase is secreted by the P. fluorescens SIK W1 ABC transporter, which is organized as an operon with tliA, and that its secretory function is temperature dependent.

ATP-Binding Cassette Transporters↗
PubMed2002

Regulatory relationship of two-component and ABC transport systems and clustering of their genes in the Bacillus/Clostridium group, suggest a functional link between them.

On the Bacillus subtilis chromosome there are five examples of genes encoding two-component systems with response regulators of the OmpR family adjacent to genes encoding sub-family 9 ABC transport systems. Three of these (yts, yvc, yxd) are very similar in gene organization and in sequence. We demonstrate that the TCS and ABC transporter genes do not belong to the same transcriptional unit. The ABC transport and TCS systems are functionally linked, each response regulator controlling the expression of its cognate ABC transporter genes but not its own. Analysis of 48 bacterial genomes revealed that such family clusters only exist in the Bacillus/Clostridium group. Evolutionary analyses indicated that almost all clustered OmpR response regulators constitute two groups ("GI" and "GIIl") whereas almost all clustered sub-family 9 nucleotide-binding domains belong to two other groups ("9A" and "9B"). Interestingly, there is a mutually exclusive clustering between genes encoding "GI" or a "GII" response regulators and genes encoding "9A" or a "9B" nucleotide binding proteins. We propose that a two-component system and its cognate ABC transporter genes have evolved as a unit in Bacillus/Clostridium, both systems participating in a common physiological process.

ATP-Binding Cassette Transporters↗
PubMed2004

[Drug resistance mediated by ABC transporters].

Remarkable advances have been made in cancer chemotherapy by developing new anticancer drugs and pharmacogenomics strategies. However, multidrug resistance in human cancers is the major obstacle to long-term, sustained patient response to chemotherapy. Several ATP-binding cassette (ABC) transporters cause multidrug resistance in cancer cells by actively extruding the clinically administered chemotherapeutic drugs. P-glycoprotein (ABCB1/MDR1/P-gp) and MRP1 (ABCC1/GS-X pump) have been well characterized in terms of their molecular structure and function. In addition, ABCG2/breast cancer resistance protein (BCRP) is the most recently identified/ABC transporter, and is also reportedly associated with cellular resistance against chemotherapeutic agents, such as DNA topoisomerase I, II inhibitor. It is important to note that these ABC transporters are expressed not only in cancer cells but also in normal tissues to play a pivotal role in the absorption, distribution, and excretion of endogenous substances as well as xenobiotics. ABC transporters are key factors that can affect the pharmacokinetic profiles of drugs. Recent studies have revealed that many single nucleotide polymorphisms (SNPs) reside in these ABC transporter genes. Functional analysis of the genetic polymorphism of ABC transporters would greatly contribute to our understanding of individual differences in the drug response and also to the development of personalized medicine in the near future.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Membrane topology distinguishes a subfamily of the ATP-binding cassette (ABC) transporters.

A group of ATP-binding cassette (ABC) transporters, including the yeast cadmium transporter (YCF1), the mammalian multidrug resistance-associated protein (MRP), the multispecific organic anion transporter and its congener (MOAT and EBCR), as well as the sulfonylurea receptor (SUR), group into a subfamily by sequence comparison. We suggest that these MRP-related proteins are also characterized by a special, common membrane topology pattern. The most studied ABC transporters, the cystic fibrosis transmembrane conductance regulator (CFTR) and the multidrug resistance (MDR) proteins, were shown to contain a tandem repeat of six transmembrane helices, each set followed by an ATP-binding domain. According to the present study, in contrast to various membrane topology predictions proposed for the different MRP-related proteins, they all seem to have a CFTR/MDR-like core structure, and an additional, large, N-terminal hydrophobic region. This latter domain is predicted to contain 4-6 (most probably 5) transmembrane helices, and is occasionally glycosylated on the cell surface. Since all the MRP-related transporters were shown to interact with anionic compounds, the N-terminal membrane-bound domain may have a key role in these interactions.

ATP-Binding Cassette Transporters↗
PubMed2006

ABCdb: an online resource for ABC transporter repertories from sequenced archaeal and bacterial genomes.

The ATP-binding cassette (ABC) transporters are one of the major classes of active transporters. They are widespread in archaea, bacteria, and eukaryota, indicating that they have arisen early in evolution. They are involved in many essential physiological processes, but the majority import or export a wide variety of compounds across cellular membranes. These systems share a common architecture composed of four (exporters) or five (importers) domains. To identify and reconstruct functional ABC transporters encoded by archaeal and bacterial genomes, we have developed a bioinformatic strategy. Cross-reference to the transport classification system is used to predict the type of compound transported. A high quality of annotation is achieved by manual verification of the predictions. However, in order to face the rapid increase in the number of published genomes, we also include analyses of genomes issuing directly from the automated strategy. Querying the database (http://www-abcdb.biotoul.fr) allows to easily retrieve ABC transporter repertories and related data. Additional query tools have been developed for the analysis of the ABC family from both functional and evolutionary perspectives.

ATP-Binding Cassette Transporters↗
PubMed2004

Molecular evolution of the ATPase subunit of three archaeal sugar ABC transporters.

The sequence of genes encoding extracellular amylopullulanase and putative maltodextrin ATP binding cassette (ABC) transporter of a hyperthermophilic archaeon, Thermococcus litoralis, was determined. The mdxK gene, which encodes an ATPase subunit of the putative maltodextrin ABC transporter, has extraordinarily high similarity with the malK gene, which encodes an ATPase subunit of trehalose/maltose ABC transporter of the same organism. DNA sequence comparison revealed that the malK gene was generated through the duplication of the mdxK gene before lateral gene transfer of the mal gene cluster from T. litoralis to Pyrococcus furiosus.

ATP-Binding Cassette Transporters↗
PubMed2006

[Plant ABC transporters--the family with tradition].

ATP binding cassette (ABC) transporters, which are found in all species, are known mainly for their ability to confer drug resistance. They have been thoroughly studied in mammals, where they became the center of interest for clinical reasons related to the resistance of tumor cells to chemotherapy treatment. Less is known about plant members of the ABC family, however, growing number of reports on their role in different physiological processes attract attention. The vacuolar ABC transporters in plants characterized to date are involved in the intracellular sequestration of cytotoxins (e.g. herbicides), as well as the products of endogenous metabolism like chlorophyll catabolites. Others localized within plasma membrane are active in the transport of secondary metabolites or phytohormones. Finally certain transporters are present in cell organelles and play a role in such processes as P oxidation. Here, we briefly introduce these proteins, and describe structural characteristic and physiological aspect of their activity in a plant cell.

ATP-Binding Cassette Transporters↗
PubMed2005

[ABC transporters of pathogenic fungi: recent advances in functional analyses].

ABC (ATP binding cassette) transporters consist of transmembrane domains which confer specificity, and structurally conserved nucleotide binding domains that contain highly conserved amino acid motifs. They act not only as transporters but also as receptors or channels that use energy generated by ATP hydrolysis. ABC transporters are widely dispersed in nature. They are found in cells ranging from prokaryotes (bacteria) to eukaryotes (including humans) and several are considered to play crucial roles in cellular homeostasis. Defects in ABC transporters in humans are associated with severe diseases such as type 2 diabetes and cystic fibrosis. Some ABC transporters extrude xenobiotics and confer resistance to chemotherapeutics on microbial pathogens and cancer cells. Thus ABC transporters are of considerable medical importance. Structure-function analysis of ABC transporters has begun to elucidate their mechanisms of substrate recognition, the functional regulation of ATP-binding and hydrolysis and to identify intrinsic physiological functions. In pathogenic fungi, ABC transporters contribute to the clinical problem of drug resistance. The application of new technologies to the examination of fungal ABC transporter function is providing new insights into the use of antifungal drugs in medical mycology and contributing to a better understanding of these important membrane proteins.

ATP-Binding Cassette Transporters↗
PubMed2003

ABC transporters of the wheat pathogen Mycosphaerella graminicola function as protectants against biotic and xenobiotic toxic compounds.

We have studied the role of five ABC transporter genes (MgAtr to MgAtr5) from the wheat pathogen Mycosphaerella graminicola in multidrug resistance (MDR). Complementation of Saccharomyces cerevisiae mutants with the ABC transporter genes from M. graminicola showed that all the genes tested encode proteins that provide protection against chemically unrelated compounds, indicating that their products function as multidrug transporters with distinct but overlapping substrate specificities. Their substrate range in yeast includes fungicides, plant metabolites, antibiotics, and a mycotoxin derived from Fusarium graminearum (diacetoxyscirpenol). Transformants of M. graminicola in which individual ABC transporter genes were deleted or disrupted did not exhibit clear-cut phenotypes, probably due to the functional redundancy of transporters with overlapping substrate specificity. Independently generated MgAtr5 deletion mutants of M. graminicola showed an increase in sensitivity to the putative wheat defence compound resorcinol and to the grape phytoalexin resveratrol, suggesting a role for this transporter in protecting the fungus against plant defence compounds. Bioassays with antagonistic bacteria indicated that MgAtr2 provides protection against metabolites produced by Pseudomonas fluorescens and Burkholderia cepacia. In summary, our results show that ABC transporters from M. graminicola play a role in protection against toxic compounds of natural and artificial origin.

ATP-Binding Cassette Transporters↗
PubMedDate not supplied

Trypanosoma brucei glycosomal ABC transporters: identification and membrane targeting.

Trypanosomes contain unique peroxisome-like organelles designated glycosomes which sequester enzymes involved in a variety of metabolic processes including glycolysis. We identified three ABC transporters associated with the glycosomal membrane of Trypanosoma brucei. They were designated GAT1-3 for Glycosomal ABC Transporters. These polypeptides are so-called half-ABC transporters containing only one transmembrane domain and a single nucleotide-binding domain, like their homologues of mammalian and yeast peroxisomes. The glycosomal localization was shown by immunofluorescence microscopy of trypanosomes expressing fusion constructs of the transporters with Green Fluorescent Protein. By expression of fluorescent deletion constructs, the glycosome-targeting determinant of two transporters was mapped to different fragments of their respective primary structures. Interestingly, these fragments share a short sequence motif and contain adjacent to it one--but not the same--of the predicted six transmembrane segments of the transmembrane domain. We also identified the T. brucei homologue of peroxin PEX19, which is considered to act as a chaperonin and/or receptor for cytosolically synthesized proteins destined for insertion into the peroxisomal membrane. By using a bacterial two-hybrid system, it was shown that glycosomal ABC transporter fragments containing an organelle-targeting determinant can interact with both the trypanosomatid and human PEX19, despite their low overall sequence identity. Mutated forms of human PEX19 that lost interaction with human peroxisomal membrane proteins also did not bind anymore to the T. brucei glycosomal transporter. Moreover, fragments of the glycosomal transporter were targeted to the peroxisomal membrane when expressed in mammalian cells. Together these results indicate evolutionary conservation of the glycosomal/peroxisomal membrane protein import mechanism.

ATP-Binding Cassette Transporters↗
PubMed2002

[Functional activity of ABC transporters (markers of multidrug resistance) in human colon adenocarcinoma and normal colonic mucosa].

Functional activity of multidrug resistance (MDR) markers (total activity of ABC-transporters, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) activities) in human colon adenocarcinoma and normal mucosa was examined. Functional activity of ABC-transporters was revealed in all colon tumors and in 70% of normal mucosa samples investigated. Expression of Pgp and MRP functional activity was determined in about 50% and 70% of colon tumors respectively. Pgp+MRP+ phenotype was determined in 36% of normal mucosa and adenocarcinoma samples. Expression of Pgp+MRP- phenotype was practically the same in normal mucosa and tumors (in 10 and 18% of samples respectively). Pgp-MRP+ phenotype was revealed two times more often in tumors than in mucosa--in 36 and 18% respectively. On the contrary, Pgp-MRP- phenotype was detected more rarely in tumors than in mucosa (in 10 and 36% of samples respectively). Transporters different from Pgp and MRP were also determined in some tumors and normal mucosa. At the patients with expression of Pgp function in normal mucosa the activity of the transporter was revealed in 25% of tumor samples only. On the contrary, at the patients with expression of MRP function in normal mucosa the activity of the transporter was revealed in 70% of tumor samples. At the patients with no expression of Pgp or MRP activity in normal mucosa the function of the transporters in tumors was determined in 60% and 70% of samples respectively. It is concluded that functional activity of various ABC-transporters (Pgp, MRP and other different from Pgp and MRP) is expressed in human colon adenocarcinoma; expression of ABC-transporters functional activity in normal mucosa does not predict MDR phenotype of the tumor.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Heterologous expression of a mammalian ABC transporter in plant and its application to phytoremediation.

Mammalian ATP-binding cassette (ABC) transporters involved in the multidrug-resistance of cancer cells can efflux cytotoxic compounds that show a wide variety of chemical structures and biological activities. Human multidrug resistance-associated protein (hMRP1) is one of the most intensively studied ABC transporters and many substrates have been identified, including both organic and inorganic compounds. In an attempt at novel 'transport engineering' using hMRP1 as a molecular pump, we established transgenic tobacco plants that showed clear resistance to cadmium and daunorubicin, although they were not resistant to etoposide, another known substrate of hMRP1. When expressed in tobacco cells, hMRP1 protein was localized at vacuolar membrane, while members of the MRP family are localized at plasma membrane in mammalian cells to reduce the cellular accumulation of various drugs. Thus, the hMRP1-expressing tobacco cells were able to take up these substrates across the tonoplast and sequestrate them in the vacuolar matrix. These results suggest that it may be possible to use the transgenic tobacco in phytoremediation, where a single transformation with an ABC transporter with broad substrate specificity should be effective for extracting various environmental pollutants including both organic and inorganic compounds, and accumulate them in the plant body. This should be advantageous for the remediation of a complex polluted environment, which is commonly found in the real world.

Antibiotics, Antineoplastic↗
PubMed2006

ABC transporter expression profiling after ischemic reperfusion injury in mouse kidney.

Renal ATP binding cassette (ABC) transporters have an important role in the elimination of metabolic waste products and compounds foreign to the body. The kidney has the ability to tightly control the expression of these efflux transporters to maintain homeostasis, and as a major mechanism of adaptation to environmental stress. In the present study, we investigated the expression of 45 ABC transporter genes in the mouse kidney under basal conditions, after induction of ischemia and after regeneration. Two days after clamping, mice showed a 76% decrease in renal creatinine clearance, which improved clearly within 7 days. This was confirmed by histological examinations. Seven days after ischemia, real-time quantitative Polymerase chain reaction data showed that transcript abundance of abcb1, abcb11, and abcc4 was increased, and that of abca3, abcc2, and abcg2 decreased. Expression of all transporters returned to baseline after 14 days, except for abcb11, which was reduced. Abcb11 is the major liver canalicular bile salt export pump. Here we show for the first time expression in the kidney and localization of the transporter to the apical membrane of proximal tubules. The presence of another novel renal transporter, abca3, was confirmed by Western blotting. Immunohistochemistry showed that abca3 is localized to the peritubular capillaries and apical membrane of proximal tubules. In conclusion, after inducing ischemic reperfusion injury in the kidney, ABC transporters appear to be differentially regulated, which might be associated with the renal regeneration process. Furthermore, we showed for the first time expression and subcellular localization of abcb11 and abca3 in mouse kidney.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2004

Nucleotide-dependent conformational changes in HisP: molecular dynamics simulations of an ABC transporter nucleotide-binding domain.

ATP-binding cassette (ABC) transporters mediate the movement of molecules across cell membranes in both prokaryotes and eukaryotes. In ABC transporters, solute translocation occurs after ATP is either bound or hydrolyzed at the intracellular nucleotide-binding domains (NBDs). Molecular dynamics (MD) simulations have been employed to study the interactions of nucleotide with NBD. The results of extended (approximately 20 ns) MD simulations of HisP (total simulation time approximately 80 ns), the NBD of the histidine transporter HisQMP2J from Salmonella typhimurium, are presented. Analysis of the MD trajectories reveals conformational changes within HisP that are dependent on the presence of ATP in the binding pocket of the protein, and are sensitive to the presence/absence of Mg ions bound to the ATP. These changes are predominantly confined to the alpha-helical subdomain of HisP. Specifically there is a rotation of three alpha-helices within the subdomain, and a movement of the signature sequence toward the bound nucleotide. In addition, there is considerable conformational flexibility in a conserved glutamine-containing loop, which is situated at the interface between the alpha-helical subdomain and the F1-like subdomain. These results support the mechanism for ATP-induced conformational transitions derived from the crystal structures of other NBDs.

ATP-Binding Cassette Transporters↗