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Journal ArticleDOI

Complete inventory of ABC proteins in human pathogenic yeast, Candida albicans.

TL;DR: It is hoped that the inventory of Candida ABC transporters created will provide new insights into the role of ABC proteins in antifungal resistance as well as help in the functional characterization of the superfamily of these proteins.
Abstract: The recent completion of the sequencing project of the opportunistic human pathogenic yeast, Candida albicans (http://www.ncbi.nlm.nih.gov/), led us to analyze and classify its ATP-binding cassette (ABC) proteins, which constitute one of the largest superfamilies of proteins. Some of its members are multidrug transporters responsible for the commonly encountered problem of antifungal resistance. TBLASTN searches together with domain analysis identified 81 nucleotide-binding domains, which belong to 51 different putative open reading frames. Considering that each allelic pair represents a single ABC protein of the Candida genome, the total number of putative members of this superfamily is 28. Domain organization, sequence-based analysis and self-organizing map-based clustering led to the classification of Candida ABC proteins into 6 distinct subfamilies. Each subfamily from C. albicans has an equivalent in Saccharomyces cerevisiae suggesting a close evolutionary relationship between the two yeasts. Our searches also led to the identification of a new motif to each subfamily in Candida that could be used to identify sequences from the corresponding subfamily in other organisms. It is hoped that the inventory of Candida ABC transporters thus created will provide new insights into the role of ABC proteins in antifungal resistance as well as help in the functional characterization of the superfamily of these proteins.
Citations
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Journal ArticleDOI
TL;DR: Phylogenetic analysis of the ABC pleiotropic drug resistance family has provided a new view of the evolution of this important class of efflux pumps, and potential therapeutic approaches that could overcome azole resistance are proposed.
Abstract: Fungi cause serious infections in the immunocompromised and debilitated, and the incidence of invasive mycoses has increased significantly over the last 3 decades. Slow diagnosis and the relatively few classes of antifungal drugs result in high attributable mortality for systemic fungal infections. Azole antifungals are commonly used for fungal infections, but azole resistance can be a problem for some patient groups. High-level, clinically significant azole resistance usually involves overexpression of plasma membrane efflux pumps belonging to the ATP-binding cassette (ABC) or the major facilitator superfamily class of transporters. The heterologous expression of efflux pumps in model systems, such Saccharomyces cerevisiae, has enabled the functional analysis of efflux pumps from a variety of fungi. Phylogenetic analysis of the ABC pleiotropic drug resistance family has provided a new view of the evolution of this important class of efflux pumps. There are several ways in which the clinical significance of efflux-mediated antifungal drug resistance can be mitigated. Alternative antifungal drugs, such as the echinocandins, that are not efflux pump substrates provide one option. Potential therapeutic approaches that could overcome azole resistance include targeting efflux pump transcriptional regulators and fungal stress response pathways, blockade of energy supply, and direct inhibition of efflux pumps.

518 citations


Cites background from "Complete inventory of ABC proteins ..."

  • ...The topology of the A. terreus transporter 063.1 is an exception because it has two additional TMDs (each containing six TMS) at its C terminus....

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  • ...These fungal PDR proteins appear to share common features on both sides of the two TMDs that separate the cytosolic from the extracytosolic space (Fig....

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  • ...The basic structure of ABC transporters consists of two cytoplasmic NBDs and two TMDs (108, 130, 260) (Fig....

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  • ...It is thought that the two TMDs in the homodimer provide inward-facing sites that bind drugs from the lipid bilayer, or possibly the cytoplasm....

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  • ...The arrangement of the NBDs and TMDs within the pump polypeptide varies according to the type of ABC protein (Fig....

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Journal ArticleDOI
TL;DR: This review summarizes the current knowledge about efflux pump-mediated drug resistance and its regulation in human-pathogenic fungi and identifies the most important drug transporters and mutations that cause the constitutive upregulation of the efflux pumps in drug-resistant clinical isolates.
Abstract: Infections by opportunistic pathogenic fungi, especially Candida species, Cryptococcus neoformans, and Aspergillus fumigatus, are a serious medical problem in immunocompromised patients. Different classes of antimycotic drugs are available to treat fungal infections, but the pathogens can develop resistance to all these agents. A major mechanism of antifungal drug resistance is the overexpression of efflux pumps of the ABC transporter and major facilitator superfamilies, which confer resistance to many structurally and functionally unrelated toxic compounds. For some pathogenic fungi, like Candida albicans and Candida glabrata, the most important drug transporters, transcription factors controlling their expression, and mutations that cause the constitutive upregulation of the efflux pumps in drug-resistant clinical isolates have been identified. For other important pathogens comparatively little is known about the role of transporters in antimycotic resistance. This review summarizes our current knowledge about efflux pump-mediated drug resistance and its regulation in human-pathogenic fungi.

276 citations


Cites background from "Complete inventory of ABC proteins ..."

  • ...The C. albicans genome contains many additional genes encoding ABC transporters and major facilitators (Gaur et al., 2005a, 2008)....

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  • ...The identification of a negative regulatory element suggested that, in addition to transcriptional activators, repressors might also be involved in the regulation of this efflux pump (Gaur et al., 2004, 2005b)....

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Journal ArticleDOI
TL;DR: The current understanding of the transcriptional regulation of drug resistance genes from several fungal pathogens including Candida and Aspergillus species is reviewed.
Abstract: Fungi are primitive eukaryotes and have adapted to a variety of niches during evolution. Some fungal species may interact with other life forms (plants, insects, mammals), but are considered as pathogens when they cause mild to severe diseases. Chemical control strategies have emerged with the development of several drugs with antifungal activity against pathogenic fungi. Antifungal agents have demonstrated their efficacy by improving patient health in medicine. However, fungi have counteracted antifungal agents in several cases by developing resistance mechanisms. These mechanisms rely on drug resistance genes including multidrug transporters and drug targets. Their regulation is crucial for the development of antifungal drug resistance and therefore transcriptional factors critical for their regulation are being characterized. Recent genome-wide studies have revealed complex regulatory circuits involving these genetic and transcriptional regulators. Here, we review the current understanding of the transcriptional regulation of drug resistance genes from several fungal pathogens including Candida and Aspergillus species.

244 citations


Cites background from "Complete inventory of ABC proteins ..."

  • ...Additional ABC transporters (e.g. Cdr3 and Cdr4) among the remaining 26 C. albicans ABC proteins (Gaur et al., 2005) do not seem to contribute to azole resistance as shown by several studies (Balan et al., 1997; Franz et al., 1998)....

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  • ...Transport of ABC transporter substrates across the membrane requires energy from the hydrolysis of ATP carried out at the NBDs. Candida albicans possesses two highly homologous ABC transporters, Candida drug resistance 1 (Cdr1) and Cdr2, which are composed of two homologous halves, each made up of a hydrophilic, cytoplasmic NBD and TMD composed of six TMS, a so-called (NBD–TMD6)2 topology....

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  • ...In yeast, the MFS transporters involved in drug resistance function by proton antiport and are classified into two groups: the drug: H1 antiporter-1 (12 TMS) (DHA1) family and the drug: H1 antiporter-2 (14 TMS) (DHA2) family (Gaur et al., 2008; Sa-Correia et al., 2009)....

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  • ...Most MFS proteins vary between 400 and 600 amino acid residues in length and possess either 12 or 14 putative TMS with an intercalating cytoplasmic loop....

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  • ...Typically, the TMDs are composed of 12 transmembrane a-helices segments (TMS) (Gaur et al., 2005; Prasad et al., 2006)....

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Journal ArticleDOI
TL;DR: Current achievements concerning the structure, molecular mechanism, and physiological functions of yeast Pdr transporters are reviewed.
Abstract: Overexpression of the ATP-binding cassette (ABC) drug transporter P-glycoprotein (P-gp) is often responsible for the failure of chemotherapy as a treatment for human tumors. The presence of proteins homologous to P-gp in organisms ranging from prokaryotes to eukaryotes indicates that drug export is a general mechanism of multidrug resistance. Yeasts are no exception. They have developed a large subfamily of ABC exporters involved in pleiotropic drug resistance (PDR) and in the cellular efflux of a wide variety of drugs. The PDR transporters Pdr5p of Saccharomyces cerevisiae and Cdr1p of Candida albicans are important members of this PDR subfamily, which comprises up to 10 phylogenetic clusters in fungi. Here, we review current achievements concerning the structure, molecular mechanism, and physiological functions of yeast Pdr transporters.

194 citations

Journal ArticleDOI
TL;DR: A phylogenetic analysis of the ABC proteins extracted from the genomes of 27 fungal species from 18 orders representing 5 fungal phyla thereby covering the most important groups demonstrated that some of the subfamilies of ABC proteins remained highly conserved in fungi, while others have undergone a remarkable group-specific diversification.
Abstract: Background: The superfamily of ABC proteins is among the largest known in nature. Its members are mainly, but not exclusively, involved in the transport of a broad range of substrates across biological membranes. Many contribute to multidrug resistance in microbial pathogens and cancer cells. The diversity of ABC proteins in fungi is comparable with those in multicellular animals, but so far fungal ABC proteins have barely been studied. Results: We performed a phylogenetic analysis of the ABC proteins extracted from the genomes of 27 fungal species from 18 orders representing 5 fungal phyla thereby covering the most important groups. Our analysis demonstrated that some of the subfamilies of ABC proteins remained highly conserved in fungi, while others have undergone a remarkable group-specific diversification. Members of the various fungal phyla also differed significantly in the number of ABC proteins found in their genomes, which is especially reduced in the yeast S. cerevisiae and S. pombe. Conclusions: Data obtained during our analysis should contribute to a better understanding of the diversity of the fungal ABC proteins and provide important clues about their possible biological functions.

185 citations


Cites background from "Complete inventory of ABC proteins ..."

  • ...Only few ABC proteins from other fungal species have been functionally characterized, except for those mainly reported to be involved in multidrug resistance in human pathogens such as Candida albicans [19-23], Aspergillus fumigatus [24,25], and Cryptococcus Figure 1 Predicted topology and domain organization of different subfamilies of fungal ABC proteins....

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References
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Journal ArticleDOI
TL;DR: A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original.
Abstract: The BLAST programs are widely used tools for searching protein and DNA databases for sequence similarities. For protein comparisons, a variety of definitional, algorithmic and statistical refinements described here permits the execution time of the BLAST programs to be decreased substantially while enhancing their sensitivity to weak similarities. A new criterion for triggering the extension of word hits, combined with a new heuristic for generating gapped alignments, yields a gapped BLAST program that runs at approximately three times the speed of the original. In addition, a method is introduced for automatically combining statistically significant alignments produced by BLAST into a position-specific score matrix, and searching the database using this matrix. The resulting Position-Specific Iterated BLAST (PSIBLAST) program runs at approximately the same speed per iteration as gapped BLAST, but in many cases is much more sensitive to weak but biologically relevant sequence similarities. PSI-BLAST is used to uncover several new and interesting members of the BRCT superfamily.

70,111 citations


"Complete inventory of ABC proteins ..." refers methods in this paper

  • ...albicans and the closest homologue obtained from BLAST searches [Altschul et al., 1997] were aligned using ClustalW [Thompson et al....

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  • ...In order to indicate the subfamily type, the NBDs of both C. albicans and the closest homologue obtained from BLAST searches [Altschul et al., 1997] were aligned using ClustalW [Thompson et al., 1994]....

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  • ...TBLASTN searches [Altschul et al., 1997] against the Candida genome (downloaded from the NCBI, accession number: AACQ00000000) was carried out with the proteins in the query set....

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Journal ArticleDOI
TL;DR: The sensitivity of the commonly used progressive multiple sequence alignment method has been greatly improved and modifications are incorporated into a new program, CLUSTAL W, which is freely available.
Abstract: The sensitivity of the commonly used progressive multiple sequence alignment method has been greatly improved for the alignment of divergent protein sequences. Firstly, individual weights are assigned to each sequence in a partial alignment in order to down-weight near-duplicate sequences and up-weight the most divergent ones. Secondly, amino acid substitution matrices are varied at different alignment stages according to the divergence of the sequences to be aligned. Thirdly, residue-specific gap penalties and locally reduced gap penalties in hydrophilic regions encourage new gaps in potential loop regions rather than regular secondary structure. Fourthly, positions in early alignments where gaps have been opened receive locally reduced gap penalties to encourage the opening up of new gaps at these positions. These modifications are incorporated into a new program, CLUSTAL W which is freely available.

63,427 citations


"Complete inventory of ABC proteins ..." refers methods in this paper

  • ...In order to indicate the subfamily type, the NBDs of both C. albicans and the closest homologue obtained from BLAST searches [Altschul et al., 1997] were aligned using ClustalW [Thompson et al., 1994]....

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  • ...Initially, 120 ABC protein sequences were selected as query sequences and were aligned using ClustalW [Thompson et al., 1994]....

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Journal ArticleDOI
TL;DR: The neighbor-joining method and Sattath and Tversky's method are shown to be generally better than the other methods for reconstructing phylogenetic trees from evolutionary distance data.
Abstract: A new method called the neighbor-joining method is proposed for reconstructing phylogenetic trees from evolutionary distance data. The principle of this method is to find pairs of operational taxonomic units (OTUs [= neighbors]) that minimize the total branch length at each stage of clustering of OTUs starting with a starlike tree. The branch lengths as well as the topology of a parsimonious tree can quickly be obtained by using this method. Using computer simulation, we studied the efficiency of this method in obtaining the correct unrooted tree in comparison with that of five other tree-making methods: the unweighted pair group method of analysis, Farris's method, Sattath and Tversky's method, Li's method, and Tateno et al.'s modified Farris method. The new, neighbor-joining method and Sattath and Tversky's method are shown to be generally better than the other methods.

57,055 citations


"Complete inventory of ABC proteins ..." refers methods in this paper

  • ...The NJ algorithm [Saitou and Nei, 1987], also from the PHYLIP package, was used to generate the unrooted NJ tree....

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  • ...This distance matrix was then used to compute an unrooted tree by the NJ method [Saitou and Nei, 1987] using the program NEIGHBOR, also from the PHYLIP package....

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Journal Article

16,851 citations

Journal ArticleDOI
TL;DR: This letter extends the heuristic homology algorithm of Needleman & Wunsch (1970) to find a pair of segments, one from each of two long sequences, such that there is no other Pair of segments with greater similarity (homology).
Abstract: The identification of maximally homologous subsequences among sets of long sequences is an important problem in molecular sequence analysis. The problem is straightforward only if one restricts consideration to contiguous subsequences (segments) containing no internal deletions or insertions. The more general problem has its solution in an extension of sequence metrics (Sellers 1974; Waterman et al., 1976) developed to measure the minimum number of “events” required to convert one sequence into another. These developments in the modern sequence analysis began with the heuristic homology algorithm of Needleman & Wunsch (1970) which first introduced an iterative matrix method of calculation. Numerous other heuristic algorithms have been suggested including those of Fitch (1966) and Dayhoff (1969). More mathematically rigorous algorithms were suggested by Sankoff (1972), Reichert et al. (1973) and Beyer et al. (1979) but these were generally not biologically satisfying or interpretable. Success came with Sellers (1974) development of a true metric measure of the distance between sequences. This metric was later generalized by Waterman et al. (1976) to include deletions/insertions of arbitrary length. This metric represents the minimum number of “mutational events” required to convert one sequence into another. It is of interest to note that Smith et al. (1980) have recently shown that under some conditions the generalized Sellers metric is equivalent to the original homology algorithm of Needleman & Wunsch (1970). In this letter we extend the above ideas to find a pair of segments, one from each of two long sequences, such that there is no other pair of segments with greater similarity (homology). The similarity measure used here allows for arbitrary length deletions and insertions.

10,262 citations


"Complete inventory of ABC proteins ..." refers methods in this paper

  • ...For this purpose, pair-wise Smith-Waterman alignments [Smith and Waterman, 1981] of the NBD sequences were carried out using the program PRSS....

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Trending Questions (1)
What phylum is Saccharomyces cerevisiae?

Each subfamily from C. albicans has an equivalent in Saccharomyces cerevisiae suggesting a close evolutionary relationship between the two yeasts.