ABCB4 p.Asn1042Asp
| Predicted by SNAP2: | A: N (87%), C: N (87%), D: N (78%), E: N (87%), F: N (87%), G: N (87%), H: N (97%), I: N (87%), K: N (93%), L: N (87%), M: N (82%), P: N (66%), Q: N (93%), R: N (87%), S: N (97%), T: N (97%), V: N (93%), W: N (66%), Y: N (93%), |
| 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, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Functional complementation of the ste6 gene of Sac... Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8921-5. Volkman SK, Cowman AF, Wirth DF
Functional complementation of the ste6 gene of Saccharomyces cerevisiae with the pfmdr1 gene of Plasmodium falciparum.
Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8921-5., 1995-09-12 [PMID:7568044]
Abstract [show]
The pfmdr1 gene has been associated with a drug-resistant phenotype in Plasmodium falciparum, and overexpression of pfmdr1 has been associated with mefloquine- and halofantrine-resistant parasites, but little is known about the functional role of pfmdr1 in this process. Here, we demonstrate that the pfmdr1 gene expressed in a heterologous yeast system functions as a transport molecule and complements a mutation in ste6, a gene which encodes a mating pheromone a-factor export molecule. In addition, the pfmdr1 gene containing two mutations which are associated with naturally occurring chloroquine resistance abolishes this mating phenotype, suggesting that these genetic polymorphisms alter this transport function. Our results support the functional role of pfmdr1 as a transport molecule in the mediation of drug resistance and provide an assay system to address the nature of this transport function.
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No. Sentence Comment
38 Shuttle plasmids constructed with the pYES-2 vector (Invitrogen) contained either the wild-typepfindrl gene (pYpfmdrl) or a mutantpfindrl gene with a serine to cysteine change at position 1034 and an asparagine to aspartic acid change at position 1042 (pYpfmdrlCD) (2).
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ABCB4 p.Asn1042Asp 7568044:38:200
status: NEW[hide] The ABC transporter genes of Plasmodium falciparum... Drug Resist Updat. 2001 Feb;4(1):66-74. Peel SA
The ABC transporter genes of Plasmodium falciparum and drug resistance.
Drug Resist Updat. 2001 Feb;4(1):66-74., [PMID:11512154]
Abstract [show]
The seminal observations that (a) chloroquine-resistant Plasmodium falciparum strains accumulate less drug than more sensitive parasites, and (b) chloroquine resistance could be modulated in vitro by the classic multidrug-resistance (MDR) modulator verapamil, suggested not only that parasite resistance to multiple drugs may be similar to the MDR phenotype described in mammalian cancer cells, but that homologous proteins may be involved. These findings prompted search for MDR-like genes in the parasite. To date, three full-length ABC transporter genes have been isolated from P. falciparum: two P-glycoprotein-like homologues, pfmdr1 and pfmdr2, and a homologue of the yeast GCN20 gene, pfgcn20.
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No. Sentence Comment
52 Expression of the 7G8 chloroquine-resistance mutations, Cys-1034 and Asp-1042, implicated in chloroquine resistance, resulted in loss-of-function mutants (i.e. abolished the mating phenotype), suggesting that these genetic polymorphisms alter transport function.82 It should be noted that a similar study analyzing quinoline antimalarials in a ste6 mutant strain was recently withdrawn from publication due to contamination of transformants with wild-type ste6 sequences.86,87 The advance of stable transgene transfection of in-vitro cultured P. falciparum has permitted in vivo analysis of the functional significance of Pgh1.88 Elegant experiments by Reed et al.89 have offered the first definitive evidence that polymorphisms in pfmdr 1 can confer resistance to mefloquine, halofantrine, and quinine.These authors also demonstrated that polymorphisms of pfmdr 1 can modulate levels of chloroquine resistance in a strain-specific manner, as well as modulate sensitivity to the structurally unrelated antimalarial artemisinin Three of the 7G8 intra-alleles Ser 1034Cys , Asn 1042Asp , Asp 1246Tyr implicated in chloroquine resistance were examined by allelic exchange of the endogenous pfmdr 1 locus.
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ABCB4 p.Asn1042Asp 11512154:52:1072
status: NEW[hide] The pfmdr1 gene of Plasmodium falciparum confers c... Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9942-7. Ruetz S, Delling U, Brault M, Schurr E, Gros P
The pfmdr1 gene of Plasmodium falciparum confers cellular resistance to antimalarial drugs in yeast cells.
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9942-7., [PMID:8790436]
Abstract [show]
The exact role of the pfmdr1 gene in the emergence of drug resistance in the malarial parasite Plasmodium falciparum remains controversial. pfmdr1 is a member of the ATP binding cassette (ABC) superfamily of transporters that includes the mammalian P-glycoprotein family. We have introduced wild-type and mutant variants of the pfmdr1 gene in the yeast Saccharomyces cerevisiae and have analyzed the effect of pfmdr1 expression on cellular resistance to quinoline-containing antimalarial drugs. Yeast transformants expressing either wild-type or a mutant variant of mouse P-glycoprotein were also analyzed. Dose-response studies showed that expression of wild-type pfmdr1 causes cellular resistance to quinine, quinacrine, mefloquine, and halofantrine in yeast cells. Using quinacrine as substrate, we observed that increased resistance to this drug in pfmdr1 transformants was associated with decreased cellular accumulation and a concomitant increase in drug release from preloaded cells. The introduction of amino acid polymorphisms in TM11 of Pgh-1 (pfmdr1 product) associated with drug resistance in certain field isolates of P. falciparum abolished the capacity of this protein to confer drug resistance. Thus, these findings suggest that Pgh-1 may act as a drug transporter in a manner similar to mammalian P-glycoprotein and that sequence variants associated with drug-resistance pfmdr1 alleles behave as loss of function mutations.
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No. Sentence Comment
88 The expression of the wild-type P. falciparum Pgh-1 protein (A) and mutant variants bearing single S1034C (B) or N1042D (C) mutations or both (D) in permeabilized yeast S. cerevisiae spheroplasts is shown by immunofluorescence using a specific antiserum (rabbit anti-Pgh-1) at a 1:100 dilution, followed by an fluorescein isothiocyanate-coupled goat anti-rabbit antibody at a dilution of 1:800.
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ABCB4 p.Asn1042Asp 8790436:88:113
status: NEW94 Time-dependent cell growth in absence (solid symbols) or presence (open symbols) of MFQ at 150 ,ug/ml was established for JPY201 transformants expressing wild-type Pgh-1, wild-type Mdr3 (Mdr3S), or Pgh-1 variants bearing single S1034C (M1034) or single N1042D (M1042) mutations or both mutations (S1034C/N1042D; DM) in predicted TM11 or a mutant variant of Mdr3 (S939F; Mdr3F).
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ABCB4 p.Asn1042Asp 8790436:94:253
status: NEWX
ABCB4 p.Asn1042Asp 8790436:94:304
status: NEW97 JPY201 cells expressing wild-type Pgh-1, wild-type Mdr3 (Mdr3S), or mutant Pgh-1 variants bearing single S1034C (M1034), single N1042D M1042) mutations, or both mutations (S1034C/N1042D; DM) were evaluated for growth in increasing concentrations of MFQ.
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ABCB4 p.Asn1042Asp 8790436:97:128
status: NEWX
ABCB4 p.Asn1042Asp 8790436:97:179
status: NEW133 JPY201 cells expressing either wild-type Pgh-1 or a double mutant Pgh-1 variant (S1034C/ N1042D; DM) were incubated with QA.
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ABCB4 p.Asn1042Asp 8790436:133:89
status: NEW[hide] Expression of the plasmodial pfmdr1 gene in mammal... Mol Cell Biol. 1994 Apr;14(4):2419-28. van Es HH, Karcz S, Chu F, Cowman AF, Vidal S, Gros P, Schurr E
Expression of the plasmodial pfmdr1 gene in mammalian cells is associated with increased susceptibility to chloroquine.
Mol Cell Biol. 1994 Apr;14(4):2419-28., [PMID:7511206]
Abstract [show]
Chloroquine (CQ)-resistant (CQR) Plasmodium falciparum malaria parasites show a strong decrease in CQ accumulation in comparison with chloroquine-sensitive parasites. Controversy exists over the role of the plasmodial pfmdr1 gene in the CQR phenotype. pfmdr1 is a member of the superfamily of ATP-binding cassette transporters. Other members of this family are the mammalian multidrug resistance genes and the CFTR gene. We have expressed the pfmdr1-encoded protein, Pgh1, in CHO cells and Xenopus oocytes. CHO cells expressing the Pgh1 protein demonstrated an increased, verapamil-insensitive susceptibility to CQ. Conversely, no increase in drug susceptibility to primaquine, quinine, adriamycin, or colchicine was observed in Pgh1-expressing cells. CQ uptake experiments revealed an increased, ATP-dependent accumulation of CQ in Pgh1-expressing cells over the level in nonexpressing control cells. The increased CQ accumulation in Pgh1-expressing cells coincided with an enhanced in vivo inhibition of lysosomal alpha-galactosidase by CQ. CHO cells expressing Pgh1 carrying two of the CQR-associated Pgh1 amino acid changes (S1034C and N1042D) did not display an increased CQ sensitivity. Immunofluorescence experiments revealed an intracellular localization of both mutant and wild-type forms of Pgh1. We conclude from our results that wild-type Pgh1 protein can mediate an increased intracellular accumulation of CQ and that this function is impaired in CQR-associated mutant forms of the protein. We speculate that the Pgh1 protein plays an important role in CQ import in CQ-sensitive malaria parasites.
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No. Sentence Comment
289 We expressed one of these pfmdrl alleles, S1034C/N1042D, in CHO cells and did not see the change in CQ sensitivity and accumulation as observed with wild-type Pghl, the form of Pghl commonly expressed in CQS parasites.
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ABCB4 p.Asn1042Asp 7511206:289:49
status: NEW303 In the absence of other plasmodial proteins, we have shown that at least one CQR-associated allele (S1034C/N1042D) abolishes the Pghl-mediated increase in CQ sensitivity and uptake into CHO cells.
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ABCB4 p.Asn1042Asp 7511206:303:107
status: NEW