ABCC1 p.Ala1347Gly
| Predicted by SNAP2: | C: N (93%), D: D (53%), E: N (53%), F: N (57%), G: N (57%), H: N (61%), I: N (66%), K: D (63%), L: N (57%), M: N (61%), N: N (57%), P: D (66%), Q: N (53%), R: D (59%), S: N (93%), T: N (66%), V: N (78%), W: D (63%), Y: D (53%), |
| Predicted by PROVEAN: | C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: N, T: D, V: D, W: D, Y: D, |
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[hide] Curcumin modulates efflux mediated by yeast ABC mu... Antimicrob Agents Chemother. 2009 Aug;53(8):3256-65. Epub 2009 May 26. Sharma M, Manoharlal R, Shukla S, Puri N, Prasad T, Ambudkar SV, Prasad R
Curcumin modulates efflux mediated by yeast ABC multidrug transporters and is synergistic with antifungals.
Antimicrob Agents Chemother. 2009 Aug;53(8):3256-65. Epub 2009 May 26., [PMID:19470507]
Abstract [show]
Curcumin (CUR), a natural product of turmeric, from rhizomes of Curcuma longa, is a known agent of reversal of drug resistance phenotypes in cancer cells overexpressing ATP-binding cassette (ABC) transporters, viz., ABCB1, ABCG2, and ABCC1. In the present study, we evaluated whether CUR could also modulate multidrug transporters of yeasts that belong either to the ABC family or to the major facilitator superfamily (MFS). The effect of CUR on multidrug transporter proteins was demonstrated by examining rhodamine 6G (R6G) efflux in Saccharomyces cerevisiae cells overexpressing the Candida albicans ABC transporters Cdr1p and Cdr2p (CaCdr1p and CaCdr2p, respectively) and the MFS transporters CaMdr1p and S. cerevisiae Pdr5p. CUR decreased the extracellular concentration of R6G in ABC transporter-expressing cells but had no effect on methotrexate efflux mediated through the MFS transporter CaMdr1p. CUR competitively inhibited R6G efflux and the photolabeling of CaCdr1p by [(125)I]iodoarylazidoprazosin, a drug analogue of the substrate prazosin (50% inhibitory concentration, 14.2 microM). Notably, the mutant variants of CaCdr1p that displayed abrogated efflux of R6G also showed reduced modulation by CUR. Drug susceptibility testing of ABC protein-expressing cells by spot assays and checkerboard tests revealed that CUR was selectively synergistic with drug substrates such as R6G, ketoconazole, itraconazole, and miconazole but not with fluconazole, voriconazole, anisomycin, cycloheximide, or FK520. Taken together, our results provide the first evidence that CUR modulates only ABC multidrug transporters and could be exploited in combination with certain conventional antifungal drugs to reverse multidrug resistance in Candida cells.
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No. Sentence Comment
77 Strain name or mutation Genotype or descriptiona Source 1 AD1-8u- MAT␣ pdr1-3 his1 ura ⌬yor1::hisG ⌬snq2::hisG ⌬pdr5::hisG ⌬pdr10::hisG ⌬pdr11::hisG ⌬ycf1::hisG pdr3::hisG ⌬pdr15::hisG 7 2 AD-CDR1 AD1-8u- cells harboring the CaCDR1-GFP ORF integrated at the PDR5 locus 27 3 A1346G CDR1-GFP cells carrying an A1346G mutation in the CDR1 ORF and integrated at the PDR5 locus 24 4 A1347G CDR1-GFP cells carrying an A1347G mutation in the CDR1 ORF and integrated at the PDR5 locus 24 5 T1351A CDR1-GFP cells carrying a T1351A mutation in the CDR1 ORF and integrated at the PDR5 locus 24 6 F1360A CDR1-GFP cells carrying an F1360A mutation in the CDR1 ORF and integrated at the PDR5 locus 24 7 G1362A CDR1-GFP cells carrying a G1362A mutation in the CDR1 ORF and integrated at the PDR5 locus 24 8 L1358A CDR1-GFP cells carrying an L1358A mutation in the CDR1 ORF and integrated at the PDR5 locus 24 9 T1355A CDR1-GFP cells carrying a T1355A mutation in the CDR1 ORF and integrated at the PDR5 locus 24 10 G682A CDR1-GFP cells carrying a G682A mutation in the CDR1 ORF and integrated at the PDR5 locus Puri et al., unpublished data 11 AD-CaMDR1 AD1-8u- cells harboring the CaMDR1-GFP ORF integrated at the PDR5 locus 22 12 AD-CDR2 AD1-8u- cells harboring the CaCDR2-GFP ORF integrated at the PDR5 locus 17 13 AD-PDR5 AD1-8u- cells harboring the ScPDR5-GFP ORF integrated at the PDR5 locus 17 14 CAI4 ⌬ura3::imm434/⌬ura3::imm434 8 a ORF, open reading frame.
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ABCC1 p.Ala1347Gly 19470507:77:434
status: NEWX
ABCC1 p.Ala1347Gly 19470507:77:468
status: NEW172 Out of 21 residues of transmembrane segment 11, substitution of 5 residues, namely, A1346G, A1347G, T1351A, F1360A, and G1362A, abrogated the efflux of R6G, while the rest of the mutant variants of CaCdr1p showed unaltered efflux (Fig. 6A).
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ABCC1 p.Ala1347Gly 19470507:172:92
status: NEW[hide] Yeast ATP-Binding Cassette Transporters Conferring... Annu Rev Microbiol. 2012 Oct 13;66:39-63. Epub 2012 Jun 11. Prasad R, Goffeau A
Yeast ATP-Binding Cassette Transporters Conferring Multidrug Resistance.
Annu Rev Microbiol. 2012 Oct 13;66:39-63. Epub 2012 Jun 11., [PMID:22703054]
Abstract [show]
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.
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No. Sentence Comment
1152 52 Prasad ·Goffeau Pdr5p A676V Cdr1p Pdr5p T1213A Cdr1p Pdr5p C1294A E1289K C1294S E1289K/ Y1311S Cdr1p Pdr5p G1253A Cdr1p Pdr5p V773A V782I V773I V783I F774A F774Δ Cdr1p Pdr5p W683A C712A C732A S684A Cdr1p Pdr5p Y1311S L1352A L1353A F1354A T1355A M1356A C1357A L1358A N1359A F1360A C1361A G1362A V1363A L1364A A1365A G1366A Cdr1p Pdr5p A1346G S1360F A1347G S1360A N1348A S1360T L1349A A1350A T1364P T1351A T1364S T1364F Cdr1p C632A C635A Pdr5p S648P Pdr5p C1380A T1393I C1402A C1427Y C1418Y C1418A C1441A C1444A T1449I V1456I Cdr1p T1460I/ V1467I Cdr1p T658A A660G V662A L663A L664A A666G M667A V668A I669A Y670A G672A F673A V674A I675A P676A T677A P678A P659A T661A L665A T671A ECL5 TMS5 TMS7 TMS10 TMS8 TMS11 ECL3 TMS6 ECL6TMS9TMS4 TMS2 Cdr1p Pdr5p C1336A C1336S ND Cdr1p S558Y S558Y/ N242K Pdr5p ND ND NDND 12 C 1 2 53 64 87 119 10 N NBD2NBD1 Conservation HighLow Figure 5 A list of residues of Cdr1p and Pdr5p that have been subjected to mutational analyses.
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ABCC1 p.Ala1347Gly 22703054:1152:364
status: NEW