ABCMdb

ABCB1 p.Arg467Ile

Predicted by SNAP2:	A: D (85%), C: D (85%), D: D (95%), E: D (95%), F: D (91%), G: D (91%), H: D (85%), I: D (91%), K: D (91%), L: D (91%), M: D (91%), N: D (91%), P: D (95%), Q: D (85%), S: D (91%), T: D (85%), V: D (91%), W: D (95%), Y: D (91%),
Predicted by PROVEAN:	A: D, 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, S: D, T: D, V: D, W: D, Y: D,

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Publications
[hide] Application of real-time quantitative PCR to molec... Antimicrob Agents Chemother. 2004 Jun;48(6):2124-31. Chau AS, Mendrick CA, Sabatelli FJ, Loebenberg D, McNicholas PM
Application of real-time quantitative PCR to molecular analysis of Candida albicans strains exhibiting reduced susceptibility to azoles.
Antimicrob Agents Chemother. 2004 Jun;48(6):2124-31., [PMID:15155210]

Abstract [show]
Real-time quantitative PCR was used to measure expression levels of genes encoding efflux pumps, ERG11 and two control genes, ACT1 and PMA1, in a collection of 14 fluconazole-susceptible Candida albicans isolates. For each gene, average expression levels and variations within the population were determined. These values were then used as reference points to make predictions about the molecular basis of resistance in 38 clinical isolates (the majority of which were resistant to fluconazole) obtained from 18 patients treated with posaconazole for refractory oropharyngeal candidiasis. For each of the 38 isolates, the expression levels of genes encoding efflux pumps, ERG11 and the control genes, were measured as above. Comparison of the two data sets revealed that expression of ACT1 and PMA1 did not vary significantly between the two sets of isolates. In contrast, MDR1, ERG11, CDR1, and CDR2 were overexpressed in 3, 4, 14, and 35, respectively, of the isolates from patients treated with azoles. In addition to these changes, the patient isolates all had at least one and often multiple missense mutations in ERG11. Select ERG11 alleles were expressed in Saccharomyces cerevisiae; all of the alleles tested conferred reduced susceptibility to fluconazole. Despite both the increases in pump expression and the ERG11 mutations, only one of the patient isolates exhibited a large decrease in posaconazole susceptibility.

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No. Sentence Comment
126 MICa (␮g/ml) ⌬CT b Substitution(s) in Erg11p POS ITZ FLZ VOR ACT1 PMA1 ERG11 MDR1 CDR1 CDR2 1 C482 0.25 0.5 16 0.5 7.9 7.5 10.4 13.7 9.2 9.4 A107T C486 0.25 1 16 0.25 8.0 8.1 9.8 12.3 11.2 10.1 A107T 2 C491 0.12 0.25 2 0.03 7.4 7.2 8.9 12.9 10.1 10.0 D116E C504 0.25 0.25 16 0.25 7.3 6.2 7.9 15.5 8.2 7.7 F449S 3 C498 0.008 0.06 1 0.008 7.4 5.4 9.6 12.6 8.2 10.8 F145L, E266D, V488I C502 0.008 0.06 1 0.008 7.2 5.9 7.4 11.7 10.6 10.8 F145L, E266D, V488I C513 0.25 0.25 16 0.12 6.7 6.4 7.5 10.6 7.6 5.8 F145L, E266D, V488I 4 C527 0.12 0.5 256 4 7.5 6.6 9.1 12.6 8.9 8.6 Y132H, G450E C528 0.12 0.5 256 4 7.3 5.9 9.0 11.7 7.7 7.7 Y132H, G450E C530 0.12 0.25 256 0.5 7.0 6.3 8.5 12.0 8.8 9.9 G450E, G464S C534 0.12 0.5 256 4 7.3 6.4 8.1 11.0 8.3 8.8 Y132H, G450E C546 0.12 0.25 128 2 8.1 7.5 9.6 11.9 9.4 9.4 Y132H, G450E C536 0.25 0.5 256 4 8.2 7.7 9.8 11.7 9.2 9.4 Y132H, G450E C572 0.25 0.25 Ͼ256 8 8.0 7.4 9.5 12.1 9.5 9.2 Y132H, G450E 5 C481 0.25 0.5 32 0.5 7.9 7.2 9.9 15.7 9.4 9.0 F128T, F145L C483 0.25 0.5 8 0.12 8.2 7.3 11.0 14.8 10.0 9.5 F145L 6 C535 0.5 2 256 8 7.7 7.1 9.8 9.0 9.6 10.9 Y132H, G448V C539 0.25 2 128 8 7.2 6.8 11.0 8.3 6.6 7.1 Y132H, G448V 7 C516 0.12 0.25 32 0.5 7.3 7.1 9.8 14.0 9.7 9.7 K128T, Y132F, F145L 8 C470 0.5 0.5 32 0.25 7.3 7.0 9.0 13.5 8.7 8.5 S405F C478 0.5 0.5 64 0.5 7.6 6.9 8.6 12.6 9.1 8.5 S405F 9 C490 0.5 1 32 0.25 8.3 7.8 10.6 9.4 9.0 9.2 V452A C497 0.5 2 64 0.5 8.4 7.7 9.1 12.5 10.0 9.3 K128T, V452A 10 C526 0.5 1 32 0.5 7.8 7.1 9.6 13.6 9.2 9.2 V509M C533 0.5 0.5 32 1 7.9 7.4 9.8 13.6 9.3 9.9 V509M 11 C594 0.5 2 128 16 7.2 6.5 9.0 11.3 8.2 7.5 Y132H, S405F C600 1 4 Ͼ256 16 7.7 7.1 8.5 12.3 9.4 8.2 Y132H, S405F 12 C577 0.06 0.06 128 0.5 6.5 5.0 9.0 5.3 8.1 12.9 G464S C583 0.25 0.25 256 1 6.8 5.5 9.4 5.7 6.9 10.7 G464S C587 0.5 0.5 256 4 7.7 7.3 9.2 8.2 10.2 9.6 G464S 13 C480 0.03 0.12 128 8 8.3 7.4 9.3 9.2 12.2 15.1 K128T, G464S, R467I 14 C438 0.5 0.5 128 2 6.6 6.0 7.9 13.3 7.1 7.5 Y257H, G464S C439 1 4 Ͼ256 16 7.1 6.2 7.6 13.5 7.7 7.5 Y257H, G464S, G307S C440 4 8 Ͼ256 Ͼ16 7.3 6.4 8.0 13.5 7.9 7.7 Y257H, G464S, G307S, A61V 15 C444 0.5 0.5 256 0.5 7.0 5.8 7.4 13.2 7.8 7.8 K143R 16 C489 0.25 0.25 128 1 7.2 6.1 8.8 12.8 10.1 9.5 Y132H, Y257H, E266D 17 C477 1 0.25 256 16 7.6 6.1 9.3 7.3 10.5 15.3 K128T, G464S, R467I 18 C507 1 2 64 8 6.1 7.2 8.6 10.5 8.3 8.4 Y132H, H283R, G464S a See Table 2, footnote a. b Values that fall outside the 3-SD range measured in the azole-susceptible isolates (see text for details) are shown in boldface italic. Login to comment
186 MIC (␮g/ml) ⌬CT Substitution(s) in Erg11p POS ITZ FLZ VOR ACT1 PMA1 ERG11 MDR1 CDR1 CDR2 4 C527 0.12 0.5 256 4 7.5 6.6 9.1 12.6 8.9 8.6 Y132H, G450E C528 0.12 0.5 256 4 7.3 5.9 9.0 11.7 7.7 7.7 Y132H, F155L, G450E C534 0.12 0.5 256 4 7.3 6.4 8.1 11.0 8.3 8.8 Y132H, G450E C546 0.12 0.25 128 2 8.1 7.5 9.6 11.9 9.4 9.4 Y132H, G450E C536 0.25 0.5 256 4 8.2 7.7 9.8 11.7 9.2 9.4 Y132H, G450E C572 0.25 0.25 Ͼ256 8 8.0 7.4 9.5 12.1 9.5 9.2 Y132H, G450E 6 C535 0.5 2 256 8 7.7 7.1 9.8 9.0 9.6 10.9 Y132H, G448V C539 0.25 2 128 8 7.2 6.8 11.0 8.3 6.6 7.1 Y132H, G448V 11 C594 0.5 2 128 16 7.2 6.5 9.0 11.3 8.2 7.5 Y132H, S405F C600 1 4 Ͼ256 16 7.7 7.1 8.5 12.3 9.4 8.2 Y132H, S405F 12 C587 0.5 0.5 256 4 7.7 7.3 9.2 8.2 10.2 9.6 G464S 13 C480 0.03 0.12 128 8 8.3 7.4 9.3 9.2 12.2 15.1 K128T, G464S, R467I 14 C438 0.5 0.5 128 2 6.6 6.0 7.9 13.3 7.1 7.5 Y257H, G464S C439 1 4 Ͼ256 16 7.1 6.2 7.6 13.5 7.7 7.5 Y257H, G464S, G307S C440 4 8 Ͼ256 Ͼ16 7.3 6.4 8.0 13.5 7.9 7.7 Y257H, G464S, G307S, A61V 17 C477 1 0.25 256 16 7.6 6.1 9.3 7.3 10.5 15.3 K128T, G464S, R467I 18 C507 1 2 64 8 6.1 7.2 8.6 10.5 8.3 8.4 Y132H, H283R, G464S a See Table 2, footnote a, and Table 3, footnote b. TABLE 5. Login to comment
187 Changes in azole susceptibility resulting from expressing C. albicans ERG11 alleles in S. cerevisiae Original C. albicans isolate Substitution(s) in expressed C. albicans Erg11p MICa (␮g/ml) POS ITZ FLZ VOR None None (vector alone) 0.06 0.125 4 0.016 C43 None (wild type) 0.06 0.5 16 0.125 C441 K143R 0.25 1 Ͼ256 1 C587 G464S 0.25 1 Ͼ256 1 C477 K128T, G464S, R467I 0.125 0.5 32 0.25 C530 G450E, G464S 1 1 128 1 C600 Y132H, S405F 0.5 Ͼ8 Ͼ256 16 C535 Y132H, G448V 0.25 1 Ͼ256 0.03 C572 Y132H, G450E 0.5 2 Ͼ256 8 C438 Y257H, G464S 0.5 1 128 4 C439 Y257H, G464S, G307S 1 1 Ͼ256 8 C440 Y257H, G464S, G307S, A61V 4 8 Ͼ256 16 NAb A61V 0.25 0.5 16 0.125 a See Table 2, footnote a. b NA, not applicable; mutation was engineered into a wild-type ERG11 gene. Login to comment