ABCC1 p.Ala893Pro
| Predicted by SNAP2: | C: N (82%), D: N (82%), E: N (82%), F: N (78%), G: N (87%), H: N (78%), I: N (93%), K: N (93%), L: N (87%), M: N (87%), N: N (93%), P: N (78%), Q: N (93%), R: N (87%), S: N (93%), T: N (93%), V: N (87%), W: N (78%), Y: N (87%), |
| Predicted by PROVEAN: | C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: D, Y: N, |
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[hide] ABC multidrug transporters: structure, function an... Pharmacogenomics. 2008 Jan;9(1):105-27. Sharom FJ
ABC multidrug transporters: structure, function and role in chemoresistance.
Pharmacogenomics. 2008 Jan;9(1):105-27., [PMID:18154452]
Abstract [show]
Three ATP-binding cassette (ABC)-superfamily multidrug efflux pumps are known to be responsible for chemoresistance; P-glycoprotein (ABCB1), MRP1 (ABCC1) and ABCG2 (BCRP). These transporters play an important role in normal physiology by protecting tissues from toxic xenobiotics and endogenous metabolites. Hydrophobic amphipathic compounds, including many clinically used drugs, interact with the substrate-binding pocket of these proteins via flexible hydrophobic and H-bonding interactions. These efflux pumps are expressed in many human tumors, where they likely contribute to resistance to chemotherapy treatment. However, the use of efflux-pump modulators in clinical cancer treatment has proved disappointing. Single nucleotide polymorphisms in ABC drug-efflux pumps may play a role in responses to drug therapy and disease susceptibility. The effect of various genotypes and haplotypes on the expression and function of these proteins is not yet clear, and their true impact remains controversial.
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312 However, the nonsynonymous mutations of G2677T/A/C, which result in the amino acid changes A893S, A893T and A893P, gave changes in both substrate specificity and ATPase kinetic properties as measured with 41 different test compounds [139].
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ABCC1 p.Ala893Pro 18154452:312:108
status: NEW[hide] ABCB1 and ABCC1 expression in peripheral mononucle... Biochem Pharmacol. 2009 Jan 1;77(1):66-75. Epub 2008 Sep 21. Rebecchi IM, Rodrigues AC, Arazi SS, Genvigir FD, Willrich MA, Hirata MH, Soares SA, Bertolami MC, Faludi AA, Bernik MM, Dorea EL, Dagli ML, Avanzo JL, Hirata RD
ABCB1 and ABCC1 expression in peripheral mononuclear cells is influenced by gene polymorphisms and atorvastatin treatment.
Biochem Pharmacol. 2009 Jan 1;77(1):66-75. Epub 2008 Sep 21., 2009-01-01 [PMID:18851956]
Abstract [show]
This study investigated the effects of atorvastatin on ABCB1 and ABCC1 mRNA expression on peripheral blood mononuclear cells (PBMC) and their relationship with gene polymorphisms and lowering-cholesterol response. One hundred and thirty-six individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). Blood samples were collected for serum lipids and apolipoproteins measurements and DNA and RNA extraction. ABCB1 (C3435T and G2677T/A) and ABCC1 (G2012T) gene polymorphisms were identified by polymerase chain reaction-restriction (PCR)-RFLP and mRNA expression was measured in peripheral blood mononuclear cells by singleplex real-time PCR. ABCB1 polymorphisms were associated with risk for coronary artery disease (CAD) (p<0.05). After atorvastatin treatment, both ABCB1 and ABCC1 genes showed 50% reduction of the mRNA expression (p<0.05). Reduction of ABCB1 expression was associated with ABCB1 G2677T/A polymorphism (p=0.039). Basal ABCB1 mRNA in the lower quartile (<0.024) was associated with lower reduction rate of serum low-density lipoprotein (LDL) cholesterol (33.4+/-12.4%) and apolipoprotein B (apoB) (17.0+/-31.3%) when compared with the higher quartile (>0.085: LDL-c=40.3+/-14.3%; apoB=32.5+/-10.7%; p<0.05). ABCB1 substrates or inhibitors did not affect the baseline expression, while ABCB1 inhibitors reversed the effects of atorvastatin on both ABCB1 and ABCC1 transporters. In conclusion, ABCB1 and ABCC1 mRNA levels in PBMC are modulated by atorvastatin and ABCB1 G2677T/A polymorphism and ABCB1 baseline expression is related to differences in serum LDL cholesterol and apoB in response to atorvastatin.
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26 The G2677T/A/C (rs2032582) is a non-synonymous polymorphism in the exon 21 with three distinct amino acid changes (Ala893Ser, Ala893Thr, and Ala893Pro, respectively) that is located at the transmembrane domain of the protein and it has a great impact on both the activity and the substrate specificity of ABCB1 toward different test compounds [10].
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ABCC1 p.Ala893Pro 18851956:26:141
status: NEW[hide] Emerging new technologies in Pharmacogenomics: rap... Pharmacol Ther. 2010 Apr;126(1):69-81. Epub 2010 Feb 4. Ishikawa T, Sakurai A, Hirano H, Lezhava A, Sakurai M, Hayashizaki Y
Emerging new technologies in Pharmacogenomics: rapid SNP detection, molecular dynamic simulation, and QSAR analysis methods to validate clinically important genetic variants of human ABC Transporter ABCB1 (P-gp/MDR1).
Pharmacol Ther. 2010 Apr;126(1):69-81. Epub 2010 Feb 4., [PMID:20138191]
Abstract [show]
Pharmacogenomics, the study of the influence of genetic factors on drug action, is increasingly important for predicting pharmacokinetics profiles and/or adverse reactions to drugs. Drug transporters as well as drug-metabolism play pivotal roles in determining the pharmacokinetic profiles of drugs and, by extension, their overall pharmacological effects. There are an increasing number of reports addressing genetic polymorphisms of drug transporters. A key requirement for the development of individualized medicine or personalized therapy is the ability to rapidly and conveniently test patients for genetic polymorphisms and/or mutations. We have recently developed a rapid and cost-effective method for single nucleotide polymorphism (SNP) detection, named Smart Amplification Process 2 (SmartAmp2), which enables us to detect genetic polymorphisms or mutations in 30 to 45min under isothermal conditions without DNA isolation and PCR amplification. Furthermore, high-speed functional screening, quantitative structure-activity relationship (QSAR) analysis, and molecular dynamic (MD) simulation methods have been developed to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function and substrate specificity. These methods would provide powerful and practical tools for screening synthetic and natural compounds, and the deduced data can be applied to the molecular design of new drugs. This review addresses such new methods for validating genetic polymorphisms of human ABC transporter ABCB1 (P-gp/MDR1) which is critically involved in the pharmacokinetics of drugs.
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352 While the A893P variant (2677GNC) is a rare mutation, triallelic SNPs of 2677G, 2677 T, and 2677A exhibit wide ethnic differences in allele frequency (Fig. 1A).
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ABCC1 p.Ala893Pro 20138191:352:10
status: NEW363 The A893P (Pro893) variant is a rare mutation (rs2032582) recorded in the NCBI dbSNP data base.
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ABCC1 p.Ala893Pro 20138191:363:4
status: NEW413 To understand the molecular mechanisms underlying the observed differences in the ATPase activity among ABCB1 WT, A893P, A893S, and A893T (Sakurai et al., 2007), we performed MD simulation based on the homology model of ABCB1.
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ABCC1 p.Ala893Pro 20138191:413:114
status: NEW441 The initial three-dimensional structure of each variant protein (A893S, A893T, or A893P) was deduced from the ABCB1 structure template by using the LEAP module in the AMBER (Assisted model building and energy refinement) simulation package.
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ABCC1 p.Ala893Pro 20138191:441:82
status: NEW452 Thus, MD calculation was performed to simulate the movement of the intracellular loop located between TM10 and TM11 for each variant protein (A893S, A893T, or A893P) as well as the WT.
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ABCC1 p.Ala893Pro 20138191:452:159
status: NEW453 Fig. 4B demonstrates the loop structures of WT, A893S, A893T, or A893P calculated from the trajectory data of MD simulations at 310 K (37˚C) for 3 ns.
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ABCC1 p.Ala893Pro 20138191:453:65
status: NEW454 Our MD simulation clearly shows that multiple kinks are formed in the intracellular loop between TM10 and TM11 in the A893P protein.
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ABCC1 p.Ala893Pro 20138191:454:118
status: NEW455 The RMSF value of alpha carbon of each amino acid residue was calculated from the trajectory data for the intracellular loop of WT, A893S, A893T, and A893P.
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ABCC1 p.Ala893Pro 20138191:455:150
status: NEW456 The A893P variant exhibited notably great fluctuations in the intracellular loop, in particular, at the region of amino acids 910 - 920 (data not shown).
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ABCC1 p.Ala893Pro 20138191:456:4
status: NEW457 It is suggested that the A893P mutation promotes multiple kinks in this cytoplasmic helical region and modify the interaction of coupling helix 2 with the ATP-binding domain.
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ABCC1 p.Ala893Pro 20138191:457:25
status: NEW459 The A893P variant (2677GNC), a rare mutation, exhibited markedly high activity of ATPase toward different test compounds (Fig. 5).
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ABCC1 p.Ala893Pro 20138191:459:4
status: NEW461 The MD simulation results may provide an explanation, in part, for the effect of the A893P mutation on ATP hydrolysis.
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ABCC1 p.Ala893Pro 20138191:461:85
status: NEW478 To functionally validate the non-synonymous polymorphisms of ABCB1 (P-glycoprotein/MDR1) in vitro, we generated SNP variant forms (i.e., S400N, R492C, R669C, I849M, A893P, A893S, A893T, M986V, A999T, P1051A, and G1063A; refer to Fig. 6) and expressed them in Sf9 cells.
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ABCC1 p.Ala893Pro 20138191:478:165
status: NEW480 The effect of test compounds on the ATPase activity of ABCB1 WT, A893P, A893S, and A893T.
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ABCC1 p.Ala893Pro 20138191:480:65
status: NEW500 SNP Km Vmax Vmax / Km (µM) (nmol/min/mg protein) WT 5.8±2.3 62.4±7.8 10.8 S400N 5.8±2.8 46.7±5.3⁎⁎ 8.0 R492C 5.6±1.9 49.6±10.0⁎ 8.9 R669C 3.2±1.6⁎ 64.7±6.9 20.1 I849M 1.5±0.7⁎⁎ 80.3±9.5⁎⁎ 51.8 A893P 1.5±0.5⁎⁎ 405.2±16.5⁎⁎ 274.6 A893S 11.1±5.4 43.1±7.1⁎⁎ 3.9 A893T 4.3±1.4 98.9±9.5⁎⁎ 22.9 M986V 5.1±1.1 114.9±13.6⁎⁎ 22.5 A999T 2.0±0.8⁎⁎ 143.1±21.2⁎⁎ 70.9 P1051A 6.2±3.0 52.1±13.6 8.4 G1063A 6.2±3.7 117.9±16.4⁎⁎ 19.0 Data are expressed as mean±S.D., n=6.
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ABCC1 p.Ala893Pro 20138191:500:304
status: NEW