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PubMed2005

The ABC of resuscitation and the Dutch (re)treat.

In 1982 the Netherlands made a unilateral decision to change the established airway-breathing-circulation (ABC) training sequence to a different approach that stressed efficiency in diagnosis and treatment. This Dutch approach became known as the CAB (circulation-airway-breathing) sequence. Twenty years later, being confronted with the new international guidelines (published 2000) that still use the ABC approach, the Netherlands Resuscitation Council (NRR) questioned again the validity of our persistence in using the "Dutch variant" of resuscitation. This resulted in revised national guidelines that conform again with the international guidelines. This article restates the main rationale and arguments behind the original decision to change to a Dutch (CAB) version of resuscitation over 20 years ago. The national decision to adopt the ABC approach once again was mainly to prevent resuscitation in the Netherlands from being isolated from the rest of the world and was not based on present knowledge of physiology and resuscitation. The authors hope that this article will open the discussion once again.

Algorithms↗

PubMed2002

Functional analysis of candidate ABC transporter proteins for sitosterol transport.

Two ATP-binding cassette (ABC) proteins, ABCG5 and ABCG8, have recently been associated with the accumulation of dietary cholesterol in the sterol storage disease sitosterolemia. These two 'half-transporters' are assumed to dimerize to form the complete sitosterol transporter which reduces the absorption of sitosterol and related molecules in the intestine by pumping them back into the lumen. Although mutations altering ABCG5 and ABCG8 are found in affected patients, no functional demonstration of sitosterol transport has been achieved. In this study, we investigated whether other ABC transporters implicated in lipid movement and expressed in tissues with a role in sterol synthesis and absorption, might also be involved in sitosterol transport. Transport by the multidrug resistance P-glycoprotein (P-gp; Abcb1), the multidrug resistance-associated protein (Mrp1; Abcc1), the breast cancer resistance protein (Bcrp; Abcg2) and the bile salt export pump (Bsep; Abcb11) was assessed using several assays. Unexpectedly, none of the candidate proteins mediated significant sitosterol transport. This has implications for the pathology of sitosterolemia. In addition, the data suggest that otherwise broad-specific ABC transporters have acquired specificity to exclude sitosterol and related sterols like cholesterol presumably because the abundance of cholesterol in the membrane would interfere with their action; in consequence, specific transporters have evolved to handle these sterols.

3T3 Cells↗

PubMed2003

ABCA10, a novel cholesterol-regulated ABCA6-like ABC transporter.

We recently identified several novel members of the A subclass of ABC transporters. In this study, we report the cloning of an additional ABC A subfamily transporter, denoted ABCA10, from macrophages. The coding sequence of ABCA10 is of 4.6 kb size and codes for a 1543-amino acid protein that bears the structural features of a full-size ABC transporter. Intriguingly, ABCA10 contains a PEST sequence downstream of the N-terminal transmembrane domain which may be potentially involved in the control of its turnover rate by proteasomal degradation. Several distinct ABCA10 transcripts are expressed in human macrophages that predict the existence of various truncated forms of the novel transporter. Moreover, we identified seven single nucleotide polymorphisms in ABCA10 transcripts. ABCA10 displays high amino acid sequence homology with ABCA6 (63%), ABCA8 (62%), and ABCA9 (63%), respectively, known members of the subgroup of ABCA6-like transporters. Like other transporters of this subfamily, ABCA10 mRNA is ubiquitously expressed and highest gene expression levels are detectable in heart, brain, and the gastrointestinal tract. Analysis of the gene structure demonstrated that the ABCA10 gene consists of 40 exons that extend across a genomic region of approximately 97kb size (Chr. 17q24.3). ABCA10 mRNA is expressed in similar quantities in monocytes and M-CSF differentiated macrophages. Importantly, ABCA10 expression is suppressed by cholesterol import into macrophages, indicating that it is a cholesterol-responsive gene. Our results identify ABCA10 as a novel member of the group of ABCA6-like transporters and suggest its involvement in macrophage lipid homeostasis.

ATP-Binding Cassette Transporters↗

PubMed1994

Structural studies on the chondroitinase ABC-resistant sulfated tetrasaccharides isolated from various chondroitin sulfate isomers.

Various commercially available chondroitin sulfates, including an A isomer from whale cartilage, C and D isomers from shark cartilage, and an E isomer from squid cartilage, were exhaustively digested with a commercial highly purified Proteus vulgaris chondroitinase ABC. Gel chromatography of all digests yielded a disaccharide and an oligosaccharide fraction which was resistant to the enzyme digestion and which accounts for 20-31 mol% of the produced total oligosaccharides. Variably sulfated tetrasaccharides were isolated from the oligosaccharide fraction of each chondroitin sulfate isomer by HPLC, then characterized chemically and enzymatically. One disulfated and three trisulfated components were also characterized by 500-MHz one- and two-dimensional 1H NMR spectroscopy. The structures of one tetrasulfated, four trisulfated, and five disulfated tetrasaccharides with the common core structure, alpha-L-delta 4,5HexpA-(1-->3)-beta-D-GalpNAc-(1-->4)-beta-D-GlcpA-(1-->3) -D-GalpNAc, were determined. All isolated tetrasaccharides were resistant to the highly purified enzyme, but susceptible to the conventional, commercial chondroitinase ABC. The former was also inactive towards alpha-L-delta 4,5HexpA-(1-->3)-beta-D-GalpNAc-(1-->4)-beta-D-GlcpA-(1-->3) -D-GalpNAc isolated from chondroitin, beta-D-GlcpA-(1-->3)-beta-D-GlcpNAc-(1-->4)-beta-D-GlcpA-(1- ->3)-D-GlcpNAc from hyaluronan, and alpha-L-delta 4,5HexpA-(1-->3)-beta-D-GalpNAc4SO3(-)-(1-->4)-alpha-L-Id opA-(1-->3)-D- GalpNAc4SO3- from dermatan sulfate. These results indicate that, unlike the conventional enzyme, highly purified chondroitinase ABC cannot degrade tetrasaccharides irrespective of their sulfation profiles. The enzymatic action is size-dependent.

Carbohydrate Sequence↗

PubMed2002

cDNA cloning and characterization of tobacco ABC transporter: NtPDR1 is a novel elicitor-responsive gene.

We isolated an INF1 elicitin-inducible cDNA encoding a pleiotropic drug resistance (PDR)-type ATP-binding cassette (ABC) transporter homolog (NtPDR1) in suspension-cultured tobacco Bright Yellow-2 (BY-2) cells by application of differential display PCR. The NtPDR1 (Nicotiana tabacum PDR protein 1) gene also encodes a 162 kDa protein that includes two putative hydrophilic domains containing the ABC signature motif and two putative hydrophobic domains. Expression of the NtPDR1 gene was rapidly and strongly activated by treatment of BY-2 cells with INF1 elicitin. Further, treatment of BY-2 cells with flagellin, a bacterial proteinaceous hypersensitive reaction elicitor, or yeast extract, a general elicitor, also induced NtPDR1 gene expression. These results indicate that NtPDR1 may be involved in the general defense response in tobacco. This is the first report that microbial elicitors induce the expression of a plant ABC transporter gene.

ATP-Binding Cassette Transporters↗

PubMed2003

Ospdr9, which encodes a PDR-type ABC transporter, is induced by heavy metals, hypoxic stress and redox perturbations in rice roots.

Little is known about the role of pleiotropic drug resistance (PDR)-type ATP-binding (ABC) proteins in plant responses to environmental stresses. We characterised ospdr9, which encodes a rice ABC protein with a reverse (ABC-TMS(6))(2) configuration. Polyethylene glycol and the heavy metals Cd (20 microM) and Zn (30 microM) rapidly and markedly induced ospdr9 in roots of rice seedlings. Hypoxic stress also induced ospdr9 in rice roots, salt stress induced ospdr9 at low levels but cold and heat shock had no effect. The plant growth regulator jasmonic acid, the auxin alpha-naphthalene acetic acid and the cytokinin 6-benzylaminopurine triggered ospdr9 expression. The antioxidants dithiothreitol and ascorbic acid rapidly and markedly induced ospdr9 in rice roots; the strong oxidant hydrogen peroxide also induced ospdr9 but at three times lower levels. The results suggested that redox changes may be involved in the abiotic stress response regulation of ospdr9 in rice roots.

ATP-Binding Cassette Transporters↗

PubMed2001

The ABC-like vacuolar transporter for rye mesophyll flavone glucuronides is not species-specific.

In many cases, the vacuolar uptake of secondary metabolites has been demonstrated to be strictly specific for a given compound and plant species. While most plants contain glycosylated secondary substances, few cases are known where flavonoids may also carry negative charges, e.g. as glucuronide conjugates. Vacuolar transport of glucosylated phenylpropanoid derivatives has been shown to occur by proton substrate antiport mechanisms (Klein, M., Weissenböck. G., Dufaud, A., Gaillard, C., Kreuz, K., Martinoia, E., 1996. Different energization mechanisms drive the vacuolar uptake of a flavonoid glucoside and a herbicide glucoside. J. Biol. Chem. 271, 29,666-29,671). In contrast, flavone glucuronides appearing specifically in rye mesophyll vacuoles are taken up by direct energisation utilising MgATP, strongly arguing for the presence of an ATP-binding cassette (ABC) transporter belonging to the subfamily of multidrug resistance-associated proteins (MRP) on the rye vacuolar membrane (Klein, M., Martinoia, E., Hoffmann-Thoma, G., Weissenböck, G., 2000. A membrane-potential dependent, ubiquitous ABC-like transporter mediates the vacuolar uptake of rye flavone glucuronides regulation of glucturonide uptake by glutathione and its conjugates. Plant Journal 21, 289-304). MRPs are known to transport negatively charged organic anions. Results presented here suggest that the vacuolar directly energised MRP-like glucuronate pump for plant-specific flavone glucuronides is ubiquitously present in diverse plant species since rye flavone glucuronides are taken up into vacuoles isolated from the barley mesophyll or from the broccoli stalk parenchyma representing two species which do not synthesise glucuronidated secondary compounds. According to the transport characteristics and inhibition profile observed we propose the existence of a high-capacity, uncoupler-insensitive vacuolar ABC transporter for flavone glucuronides and possibly other negatively charged organic compounds -- plant-born or xenobiotic -- irrespective of the plant's capability to endogenously produce glucuronidated compounds.

ATP-Binding Cassette Transporters↗

PubMed2000

Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily.

To clarify the key role of Rad50 in DNA double-strand break repair (DSBR), we biochemically and structurally characterized ATP-bound and ATP-free Rad50 catalytic domain (Rad50cd) from Pyrococcus furiosus. Rad50cd displays ATPase activity plus ATP-controlled dimerization and DNA binding activities. Rad50cd crystal structures identify probable protein and DNA interfaces and reveal an ABC-ATPase fold, linking Rad50 molecular mechanisms to ABC transporters, including P glycoprotein and cystic fibrosis transmembrane conductance regulator. Binding of ATP gamma-phosphates to conserved signature motifs in two opposing Rad50cd molecules promotes dimerization that likely couples ATP hydrolysis to dimer dissociation and DNA release. These results, validated by mutations, suggest unified molecular mechanisms for ATP-driven cooperativity and allosteric control of ABC-ATPases in DSBR, membrane transport, and chromosome condensation by SMC proteins.

Adenosine Triphosphatases↗

PubMed2002

Isolation of a genomic clone containing the promoter region of the human ATP binding cassette (ABC) transporter, ABCB6.

We previously reported on the isolation of a new rat ATP binding cassette (ABC) transporter, ABCB6. We now report the isolation of the full-length cDNA and genomic clones containing the human ABCB6 gene. ABCB6 is 100% identical to the cloned MTABC3 human ABC transporter and contains the typical ABC signature, Walker A and B motifs. We found that HuABCB6 is expressed at low levels in normal human liver. We found that ABCB6 was overexpressed in human hepatocellular carcinomas compared to paired surrounding non-malignant tissue. We found that there was no difference in ABCB6 gene copy between human liver cancer and its paired non-malignant tissue. Because HuABCB6 was overexpressed in human cancers compared to peri-tumoral tissue in the absence of gene amplification, transcriptional regulation may play an important role in its expression. Therefore, we isolated a 14 kb genomic DNA clone containing the HuABCB6 promoter and 5'-flanking region. The 5'-flanking region contains a CpG island, lacks an appropriately positioned TATA element and contains a number of putative transcription factor binding sites. Two transcription start sites were identified by S1 nuclease mapping at -274 and -296 bp from the start codon. Transient transfection of the HuABCB6 promoter constructs (HuABCB6/1.68, 1.39, 1.13, 0.90, 0.52) containing the luciferase reporter gene resulted in a 1100-2300-fold increase in luciferase activity compared to the empty vector control whereas HuABCB6/1.68 subcloned in the reverse orientation resulted in no activity. We observed a significant decrease in luciferase activity with the promoter constructs, HuABCB6/0.25, 0.15 and 0.06, which indicates that an orientation-dependent functional promoter is contained within our previously predicted promoter region of -315 bp to -565 bp as deletion of this 250 bp sequence resulted in a loss of promoter activity.

ATP-Binding Cassette Transporters↗

PubMed1997

A putative ABC-transport operon of Mycobacterium smegmatis.

We have recently described the mpr gene of Mycobacterium smegmatis whose product confers resistance to mycobacteriophages L5 and D29 when overproduced (Barsom and Hatfull (1996) Mol. Microbiol. 21, 159-170). We have determined the nt sequence of approximately 3.5 kb immediately adjacent to mpr which appears to encode components of an ATP-binding cassette (ABC) transport system. Four closely-spaced open reading frames (ORF) were identified although two of these may cooperate to produce an integral membrane component of the transport system via a programmed translational frameshift. Another putative protein is also predicted to be an integral membrane protein, while the third is an ABC-transporter protein. We propose that these three putative proteins form a mycobacterial membrane-bound complex involved in protein-dependent transport. This is the first ABC-transport system to be described in mycobacteria.

ATP-Binding Cassette Transporters↗

PubMed1997

Identification and transcriptional analysis of a Treponema pallidum operon encoding a putative ABC transport system, an iron-activated repressor protein homolog, and a glycolytic pathway enzyme homolog.

We have characterized a 5.2-kilobase (kb) putative transport related operon (tro) locus of Treponema pallidum subsp. pallidum (Nichols strain) (Tp) encoding six proteins: TroA, TroB, TroC, TroD, TroR and Phosphoglycerate mutase (Pgm). Four of these gene products (TroA-TroD) are homologous to members of the ATP-Binding Cassette (ABC) superfamily of bacterial transport proteins. TroA (previously identified as Tromp1) has significant sequence similarity to a family of Gram-negative periplasmic substrate-binding proteins and to a family of streptococcal proteins that may have dual roles as substrate binding proteins and adhesins. TroB is homologous to the ATP-binding protein component, whereas TroC and TroD are related to the hydrophobic membrane protein components of ABC transport systems. TroR is similar to Gram-positive iron-activated repressor proteins (DesR, DtxR, IdeR, and SirR). The last open reading frame (ORF) of the tro operon encodes a protein that is highly homologous to the glycolytic pathway enzyme, Pgm. Primer extension results demonstrated that the tro operon is transcribed from a sigma 70-type promoter element. Northern analysis and reverse transcriptase-polymerase chain reactions provided evidence for the presence of a primary 1-kb troA transcript and a secondary, less abundant, troA-pgm transcript. The tro operon is flanked by a Holliday structure DNA helicase homolog (upstream) and two ORFs representing a purine nucleoside phosphorylase homolog and tpp15, a previously characterized gene encoding a membrane lipoprotein (downstream). The presence of a complex operon containing a putative ABC transport system and a DtxR homolog indicates a possible linkage between transport and gene regulation in Tp.

ATP-Binding Cassette Transporters↗

PubMed1998

A fourth gene from the Candida albicans CDR family of ABC transporters.

Using primers derived from a region of the Candida albicans CDR1 (Candida drug resistance) gene that is conserved in other ABC (ATP-binding cassette) transporters, a DNA fragment from a previously unknown CDR gene was obtained by polymerase chain reaction (PCR). After screening a C. albicans genomic library with this fragment as a probe, the complete CDR4 gene was isolated and sequenced. CDR4 codes for a putative ABC transporter of 1490 amino acids with a high degree of homology to Cdr1p, Cdr2p and Cdr3p from C. albicans (62, 59 and 57% amino acid sequence identity, respectively). Cdr4p has a predicted structure typical for cluster I. 1 of yeast ABC transporters, characterized by two homologous halves, each comprising an N-terminal hydrophilic domain with consensus sequences for ATP binding and a C-terminal hydrophobic domain with six transmembrane helices. In contrast to the CDR1/CDR2 genes, the genetic structure of the CDR4 gene was conserved in 59 C. albicans isolates from six different patients. Northern hybridization analysis showed that the CDR4 gene was expressed in most isolates, but no correlation between CDR4 mRNA levels and the degree of fluconazole resistance of the isolates was found. In addition, a C. albicans mutant in which both copies of the CDR4 gene were disrupted by insertional mutagenesis was not hypersusceptible to fluconazole as compared to the parent strain. Unlike CDR1 and CDR2, CDR4 does not, therefore, seem to be involved in fluconazole resistance in C. albicans.

ATP-Binding Cassette Transporters↗

PubMedDate not supplied

ABC transporters associated with cytochrome c biogenesis.

It is generally agreed that cytochrome c biogenesis requires that the apocytochrome and heme be transported separately to their site of function and assembly. In bacteria, this is outside the cytoplasmic membrane, whereby the apocytochromes c use sec-dependent signals for their translocation. Two different hypotheses have recently emerged as to how heme is exported: one involves an helABCD-encoded ATP binding cassette (ABC) transporter complex and the second does not. The second hypothesis concludes that an (HelAB)2 heterodimeric ABC transporter does not transport heme but some other substrate for cytochrome c biogenesis. The evidence supporting each of these two hypotheses and the role of this ABC transporter is discussed.

ATP-Binding Cassette Transporters↗

PubMedDate not supplied

Mitochondrial ABC transporters.

In contrast to bacteria, mitochondria contain only a few ATP binding cassette (ABC) transporters in their inner membrane. The known mitochondrial ABC proteins fall into two major classes that, in the yeast Saccharomyces cerevisiae, are represented by the half-transporter Atm1p and the two closely homologous proteins Mdl1p and Mdl2p. In humans two Atm1p orthologues (ABC7 and MTABC3) and two proteins homologous to Mdll/2p have been localized to mitochondria. The Atm1p-like proteins perform an important function in mitochondrial iron homeostasis and in the maturation of Fe/S proteins in the cytosol. Mutations in ABC7 are causative of hereditary X-linked sideroblastic anemia and cerebellar ataxia (XLSA/A). MTABC3 may be a candidate gene for the lethal neonatal syndrome. The function of the mitochondrial Mdl1/2p-like proteins is not clear at present with the notable exception of murine ABC-me that may transport intermediates of heme biosynthesis from the matrix to the cytosol in erythroid tissues.

ATP-Binding Cassette Transporters↗

PubMed2002

Structure and mechanism of ABC transporters.

ATP-binding cassette (ABC) transporters are central to many physiological processes, including the uptake of nutrients, the non-classical secretion of signaling molecules and toxins, multidrug resistance and the development of human disease. As one might expect from this spectrum of translocation events, these ubiquitous, ATP-dependent pumps or channels are capable of transporting an enormous variety of substrates, ranging from small ions to large proteins. Recently determined structures of full-length ABC transporters and isolated ABC domains have increased our understanding of the functional mechanism of these proteins.

ATP-Binding Cassette Transporters↗

PubMed1998

The crystal structure of pneumococcal surface antigen PsaA reveals a metal-binding site and a novel structure for a putative ABC-type binding protein.

BACKGROUND: . The surface protein PsaA of the pathogenic bacterium Streptococcus pneumoniae plays an essential role in its virulence. PsaA is a putative ATP-binding cassette-type (ABC-type) binding protein involved in the uptake of Mn2+ and possibly Zn2+ and is considered to be both a potential drug target and and a candidate vaccine component. RESULTS: . The structure of PsaA has been determined to 2.0 A resolution using X-ray crystallography and is the first structure obtained for an ABC-type binding protein from a Gram-positive organism. The protein consists of two (beta/alpha)4 domains linked together by a single helix. A metal-binding site is formed in the domain interface by the sidechains of His67, His139, Glu205 and Asp280 and is occupied in the structure. CONCLUSIONS: . The structural topology of PsaA is fundamentally different from that of other ABC-type binding proteins determined thus far in that PsaA lacks the characteristic 'hinge peptides' involved in conformational change upon solute uptake and release. In our structure, the metal-binding site is probably occupied by Zn2+. The site seems to be well conserved amongst related receptors from both Gram-positive and Gram-negative bacteria.

ATP-Binding Cassette Transporters↗

PubMed2000

ABC transporters in lipid transport.

Since it was found that the P-glycoproteins encoded by the MDR3 (MDR2) gene in humans and the Mdr2 gene in mice are primarily phosphatidylcholine translocators, there has been increasing interest in the possibility that other ATP binding cassette (ABC) transporters are involved in lipid transport. The evidence reviewed here shows that the MDR1 P-glycoprotein and the multidrug resistance (-associated) transporter 1 (MRP1) are able to transport lipid analogues, but probably not major natural membrane lipids. Both transporters can transport a wide range of hydrophobic drugs and may see lipid analogues as just another drug. The MDR3 gene probably arose in evolution from a drug-transporting P-glycoprotein gene. Recent work has shown that the phosphatidylcholine translocator has retained significant drug transport activity and that this transport is inhibited by inhibitors of drug-transporting P-glycoproteins. Whether the phosphatidylcholine translocator also functions as a transporter of some drugs in vivo remains to be seen. Three other ABC transporters were recently shown to be involved in lipid transport: ABCR, also called Rim protein, was shown to be defective in Stargardt's macular dystrophy; this protein probably transports a complex of retinaldehyde and phosphatidylethanolamine in the retina of the eye. ABC1 was shown to be essential for the exit of cholesterol from cells and is probably a cholesterol transporter. A third example, the ABC transporter involved in the import of long-chain fatty acids into peroxisomes, is discussed in the chapter by Hettema and Tabak in this volume.

ATP Binding Cassette Transporter 1↗

PubMed2000

Prenyl-flavonoids as potent inhibitors of the Pdr5p multidrug ABC transporter from Saccharomyces cerevisiae.

The Pdr5p multidrug ABC ("ATP-binding cassette) transporter was highly overexpressed in plasma membranes from a yeast strain exhibiting both pdr1-3 gain-of-function mutation in the transcription factor-encoding gene PDR1 and disruption of genes encoding other plasma membrane ABC transporters. Solubilized and purified Pdr5p displayed a tryptophan-characteristic intrinsic fluorescence, whose quenching was used to monitor interactions with substrates and effectors. The transporter exhibited a magnesium-dependent binding affinity for ATP and its fluorescent analogue 2'(3')-N-methylanthraniloyl-ATP, producing a marked fluorescence resonance-energy transfer. It also bound a series of known drug substrates and modulators. Interestingly, yeast Pdr5p interacted with flavonoids recently found to bind to cancer cell P-glycoprotein and to the protozoan parasite multidrug transporter. The extent of high-affinity binding of prenyl-flavonoids to purified Pdr5p was correlated to their efficiency to inhibit energy-dependent quenching of rhodamine 6G fluorescence catalyzed by Pdr5p-enriched plasma membranes. The hydrophobic flavonoid derivative 6-(3, 3-dimethylallyl)galangin was the most efficient, with a K(i) of 0.18 microM for competitive inhibition of the MgATP-dependent quenching of rhodamine 6G fluorescence. In contrast, inhibition of either ATP or UTP hydrolysis occurred at much higher concentrations and appeared to be noncompetitive. Prenyl-flavonoids therefore behave as potent inhibitors of drug binding to the yeast Pdr5p ABC transporter.

ATP-Binding Cassette Transporters↗