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Research Article

Computational identification and analysis of deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in the human POR gene: a structural and functional impact

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Pages 1518-1532 | Received 02 Feb 2023, Accepted 02 Apr 2023, Published online: 12 May 2023

References

  • Abraham, M. J., Murtola, T., Schulz, R., Páll, S., Smith, J. C., Hess, B., & Lindahl, E. (2015). GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 1–2, 19–25. https://doi.org/10.1016/j.softx.2015.06.001
  • Agrahari, A. K., Doss, G. P. C., Siva, R., Magesh, R., & Zayed, H. (2019). Molecular insights of the G2019S substitution in LRRK2 kinase domain associated with Parkinson’s disease: A molecular dynamics simulation approach. Journal of Theoretical Biology, 469, 163–171. https://doi.org/10.1016/j.jtbi.2019.03.003
  • Agrahari, A. K., Kumar, A., R, S., Zayed, H., & George Priya Doss, C. (2018). Substitution impact of highly conserved arginine residue at position 75 in GJB1 gene in association with X-linked Charcot-Marie-tooth disease: A computational study. Journal of Theoretical Biology, 437, 305–317. https://doi.org/10.1016/j.jtbi.2017.10.028
  • Agrahari, A. K., Muskan, M., George Priya Doss, C., Siva, R., & Zayed, H. (2018). Computational insights of K1444N substitution in GAP-related domain of NF1 gene associated with neurofibromatosis type 1 disease: A molecular modeling and dynamics approach. Metabolic Brain Disease, 33(5), 1443–1457. https://doi.org/10.1007/s11011-018-0251-1
  • Agrawal, V., Choi, J. H., Giacomini, K. M., & Miller, W. L. (2010). Substrate-specific modulation of CYP3A4 activity by genetic variants of cytochrome P450 oxidoreductase. Pharmacogenetics and Genomics, 20(10), 611–618. https://doi.org/10.1097/FPC.0b013e32833e0cb5
  • Agrawal, V., Huang, N., & Miller, W. L. (2008). Pharmacogenetics of P450 oxidoreductase: Effect of sequence variants on activities of CYP1A2 and CYP2C19. Pharmacogenetics and Genomics, 18(7), 569–576. https://doi.org/10.1097/FPC.0b013e32830054ac
  • Ali, S. K., Sneha, P., Priyadharshini Christy, J., Zayed, H., & George Priya Doss, C. (2017). Molecular dynamics-based analyses of the structural instability and secondary structure of the fibrinogen gamma chain protein with the D356V mutation. Journal of Biomolecular Structure & Dynamics, 35(12), 2714–2724. https://doi.org/10.1080/07391102.2016.1229634
  • Anbarasu, A., Veeraraghavan, B., Vasudevan, K., Basu, S., Arumugam, A., Naha, A., & Ramaiah, S. (2021). Identification of potential carboxylic acid-containing drug candidate to design novel competitive NDM inhibitors: An in-silico approach comprising combined virtual screening and molecular dynamics simulation. https://doi.org/10.1101/2021.07.05.451101
  • Arlt, W. (2007). P450 oxidoreductase deficiency and Antley-Bixler syndrome. Reviews in Endocrine & Metabolic Disorders, 8(4), 301–307. https://doi.org/10.1007/s11154-007-9056-y
  • Arlt, W., Walker, E. A., Draper, N., Ivison, H. E., Ride, J. P., Hammer, F., Chalder, S. M., Borucka-Mankiewicz, M., Hauffa, B. P., Malunowicz, E. M., Stewart, P. M., & Shackleton, C. H. L. (2004). Congenital adrenal hyperplasia caused by mutant P450 oxidoreductase and human androgen synthesis: Analytical study. Lancet (London, England), 363(9427), 2128–2135. https://doi.org/10.1016/S0140-6736(04)16503-3
  • Ashkenazy, H., Abadi, S., Martz, E., Chay, O., Mayrose, I., Pupko, T., & Ben-Tal, N. (2016). ConSurf 2016: An improved methodology to estimate and visualize evolutionary conservation in macromolecules. Nucleic Acids Research, 44(W1), W344–350. https://doi.org/10.1093/nar/gkw408
  • Bai, Y., Li, J., & Wang, X. (2017). Cytochrome P450 oxidoreductase deficiency caused by R457H mutation in POR gene in Chinese: Case report and literature review. Journal of Ovarian Research, 10(1), 16. https://doi.org/10.1186/s13048-017-0312-9
  • Basu, S., Naha, A., Veeraraghavan, B., Ramaiah, S., & Anbarasu, A. (2022). In silico structure evaluation of BAG3 and elucidating its association with bacterial infections through protein-protein and host-pathogen interaction analysis. Journal of Cellular Biochemistry, 123(1), 115–127. https://doi.org/10.1002/jcb.29953
  • Campelo, D., Esteves, F., Brito Palma, B., Costa Gomes, B., Rueff, J., Lautier, T., Urban, P., Truan, G., & Kranendonk, M. (2018). Probing the role of the hinge segment of cytochrome P450 oxidoreductase in the interaction with cytochrome P450. International Journal of Molecular Sciences, 19(12), 3914. https://doi.org/10.3390/ijms19123914
  • Campelo, D., Lautier, T., Urban, P., Esteves, F., Bozonnet, S., Truan, G., & Kranendonk, M. (2017). The hinge segment of human NADPH-cytochrome P450 reductase in conformational switching: The critical role of ionic strength. Frontiers in Pharmacology, 8, 755. https://www.frontiersin.org/article/10.3389/fphar.2017.00755 https://doi.org/10.3389/fphar.2017.00755
  • Capriotti, E., Altman, R. B., & Bromberg, Y. (2013). Collective judgment predicts disease-associated single nucleotide variants. BMC Genomics, 14(Suppl 3), S2. https://doi.org/10.1186/1471-2164-14-S3-S2
  • Capriotti, E., Calabrese, R., & Casadio, R. (2006). Predicting the insurgence of human genetic diseases associated to single point protein mutations with support vector machines and evolutionary information. Bioinformatics (Oxford, England), 22(22), 2729–2734. https://doi.org/10.1093/bioinformatics/btl423
  • Capriotti, E., Fariselli, P., & Casadio, R. (2005). I-Mutant2.0: Predicting stability changes upon mutation from the protein sequence or structure. Nucleic Acids Research, 33(Web Server issue), W306–310. https://doi.org/10.1093/nar/gki375
  • Cargill, M., Altshuler, D., Ireland, J., Sklar, P., Ardlie, K., Patil, N., Shaw, N., Lane, C. R., Lim, E. P., Kalyanaraman, N., Nemesh, J., Ziaugra, L., Friedland, L., Rolfe, A., Warrington, J., Lipshutz, R., Daley, G. Q., & Lander, E. S. (1999). Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature Genetics, 22(3), 231–238. https://doi.org/10.1038/10290
  • Chanock, S. (2001). Candidate genes and single nucleotide polymorphisms (SNPs) in the study of human disease. Disease Markers, 17(2), 89–98. https://doi.org/10.1155/2001/858760
  • Chen, C.-W., Lin, J., & Chu, Y.-W. (2013). iStable: Off-the-shelf predictor integration for predicting protein stability changes. BMC Bioinformatics, 14(S2), S5. https://doi.org/10.1186/1471-2105-14-S2-S5
  • Cheng, J., Randall, A., & Baldi, P. (2006). Prediction of protein stability changes for single-site mutations using support vector machines. Proteins, 62(4), 1125–1132. https://doi.org/10.1002/prot.20810
  • Choi, Y., Sims, G. E., Murphy, S., Miller, J. R., & Chan, A. P. (2012). Predicting the functional effect of amino acid substitutions and indels. PLoS One, 7(10), e46688. https://doi.org/10.1371/journal.pone.0046688
  • Darden, T., York, D., & Pedersen, L. (1993). Particle mesh Ewald: An N⋅log(N) method for Ewald sums in large systems. The Journal of Chemical Physics, 98(12), 10089–10092. https://doi.org/10.1063/1.464397
  • David, C. C., & Jacobs, D. J. (2014). Principal component analysis: A method for determining the essential dynamics of proteins. Methods in Molecular Biology, 1084, 193–226. https://doi.org/10.1007/978-1-62703-658-0_11
  • Esteves, F., Campelo, D., Gomes, B. C., Urban, P., Bozonnet, S., Lautier, T., Rueff, J., Truan, G., & Kranendonk, M. (2020). The role of the FMN-Domain of human cytochrome P450 oxidoreductase in its promiscuous interactions with structurally diverse redox partners. Frontiers in Pharmacology, 11, 299. https://www.frontiersin.org/article/10.3389/fphar.2020.00299 https://doi.org/10.3389/fphar.2020.00299
  • Fernandes, C. L., Sachett, L. G., Pol-Fachin, L., & Verli, H. (2010). GROMOS96 43a1 performance in predicting oligosaccharide conformational ensembles within glycoproteins. Carbohydrate Research, 345(5), 663–671. https://doi.org/10.1016/j.carres.2009.12.018
  • Flück, C. E., Mullis, P. E., & Pandey, A. V. (2010). Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism. Biochemical and Biophysical Research Communications, 401(1), 149–153. https://doi.org/10.1016/j.bbrc.2010.09.035
  • Flück, C. E., Nicolo, C., Pandey, A. V. (2007). Clinical, structural and functional implications of mutations and polymorphisms in human NADP H P450 oxidoreductase. Fundamental & Clinical Pharmacology, 21(4), 399–410. https://doi.org/10.1111/j.1472-8206.2007.00520.x.
  • Flück, C. E., Tajima, T., Pandey, A. V., Arlt, W., Okuhara, K., Verge, C. F., Jabs, E. W., Mendonça, B. B., Fujieda, K., & Miller, W. L. (2004). Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nature Genetics, 36(3), 228–230. https://doi.org/10.1038/ng1300
  • Fukami, M., & Ogata, T. (2014). Cytochrome P450 oxidoreductase deficiency: Rare congenital disorder leading to skeletal malformations and steroidogenic defects. Pediatrics International : Official Journal of the Japan Pediatric Society, 56(6), 805–808. https://doi.org/10.1111/ped.12518
  • George Priya Doss, C., & Zayed, H. (2017). Comparative computational assessment of the pathogenicity of mutations in the Aspartoacylase enzyme. Metabolic Brain Disease, 32(6), 2105–2118. https://doi.org/10.1007/s11011-017-0090-5
  • Gromiha, M. M., An, J., Kono, H., Oobatake, M., Uedaira, H., & Sarai, A. (1999). ProTherm: Thermodynamic database for proteins and mutants. Nucleic Acids Research, 27(1), 286–288. https://doi.org/10.1093/nar/27.1.286
  • Hess, B., Bekker, H., Berendsen, H. J. C., & Fraaije, J. G. E. M. (1997). LINCS: A linear constraint solver for molecular simulations. Journal of Computational Chemistry, 18(12), 1463–1472. https://doi.org/10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H
  • Hossain, M. S., Roy, A. S., & Islam, M. S. (2020). In silico analysis predicting effects of deleterious SNPs of human RASSF5 gene on its structure and functions. Scientific Reports, 10(1), 1-14. https://doi.org/10.1038/s41598-020-71457-1
  • Huang, L.-T., Gromiha, M. M., & Ho, S.-Y. (2007). iPTREE-STAB: Interpretable decision tree based method for predicting protein stability changes upon mutations. Bioinformatics (Oxford, England), 23(10), 1292–1293. https://doi.org/10.1093/bioinformatics/btm100
  • Huang, N., Pandey, A. V., Agrawal, V., Reardon, W., Lapunzina, P. D., Mowat, D., Jabs, E. W., Vliet, G. V., Sack, J., Flück, C. E., & Miller, W. L. (2005). Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. American Journal of Human Genetics, 76(5), 729–749. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1199364/ https://doi.org/10.1086/429417
  • Hubbard, P. A., Shen, A. L., Paschke, R., Kasper, C. B., & Kim, J. J. (2001). NADPH-cytochrome P450 oxidoreductase. Structural basis for hydride and electron transfer. The Journal of Biological Chemistry, 276(31), 29163–29170. https://doi.org/10.1074/jbc.M101731200
  • Hubbard, R. E., & Haider, M. K. (2010). Hydrogen bonds in proteins: Role and strength. In ELS. American Cancer Society, https://doi.org/10.1002/9780470015902.a0003011.pub2
  • Humphrey, W., Dalke, A., & Schulten, K. (1996). VMD: Visual molecular dynamics. Journal of Molecular Graphics, 14(1), 33–38. https://doi.org/10.1016/0263-7855(96)00018-5
  • Iyanagi, T., Xia, C., & Kim, J.-J P. (2012). NADPH-cytochrome P450 oxidoreductase: Prototypic member of the diflavin reductase family. Archives of Biochemistry and Biophysics, 528(1), 72–89. https://doi.org/10.1016/j.abb.2012.09.002
  • Jaenicke, R. (1995). Folding and association versus misfolding and aggregation of proteins. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 348(1323), 97–105. https://doi.org/10.1098/rstb.1995.0050
  • Jayaraman, M., Rajendra, S. K., & Ramadas, K. (2019). Structural insight into conformational dynamics of non-active site mutations in KasA: A Mycobacterium tuberculosis target protein. Gene, 720, 144082. https://doi.org/10.1016/j.gene.2019.144082
  • Jayaraman, M., & Ramadas, K. (2020). An integrated computational investigation to unveil the structural impacts of mutation on the InhA structural gene of Mycobacterium tuberculosis. Journal of Molecular Graphics & Modelling, 101, 107768. https://doi.org/10.1016/j.jmgm.2020.107768
  • Johnson, A. D., Handsaker, R. E., Pulit, S. L., Nizzari, M. M., O'Donnell, C. J., & de Bakker, P. I. W. (2008). SNAP: A web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics (Oxford, England), 24(24), 2938–2939. https://doi.org/10.1093/bioinformatics/btn564
  • Jolliffe, I. T., & Cadima, J. (2016). Principal component analysis: A review and recent developments. Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences, 374(2065), 20150202. https://doi.org/10.1098/rsta.2015.0202
  • Kandel, S. E., & Lampe, J. N. (2014). Role of protein-protein interactions in cytochrome P450-mediated drug metabolism and toxicity. Chemical Research in Toxicology, 27(9), 1474–1486. https://doi.org/10.1021/tx500203s
  • Kragelund, B. B., Poulsen, K., Andersen, K. V., Baldursson, T., Krøll, J. B., Neergård, T. B., Jepsen, J., Roepstorff, P., Kristiansen, K., Poulsen, F. M., & Knudsen, J. (1999). Conserved residues and their role in the structure, function, and stability of acyl-coenzyme A binding protein. Biochemistry, 38(8), 2386–2394. https://doi.org/10.1021/bi982427c
  • Kumar, A., Rajendran, V., Sethumadhavan, R., Shukla, P., Tiwari, S., & Purohit, R. (2014). Computational SNP analysis: Current approaches and future prospects. Cell Biochemistry and Biophysics, 68(2), 233–239. https://doi.org/10.1007/s12013-013-9705-6
  • Kumar, R., Jayaraman, M., Ramadas, K., & Chandrasekaran, A. (2020). Insight into the structural and functional analysis of the impact of missense mutation on cytochrome P450 oxidoreductase. Journal of Molecular Graphics & Modelling, 100, 107708. https://doi.org/10.1016/j.jmgm.2020.107708
  • Maisuradze, G. G., Liwo, A., & Scheraga, H. A. (2009). Principal component analysis for protein folding dynamics. Journal of Molecular Biology, 385(1), 312–329. https://doi.org/10.1016/j.jmb.2008.10.018
  • Martonák, R., Laio, A., & Parrinello, M. (2003). Predicting crystal structures: The Parrinello-Rahman method revisited. Physical Review Letters, 90(7), 075503. https://doi.org/10.1103/PhysRevLett.90.075503
  • McCammon, K. M., Panda, S. P., Xia, C., Kim, J.-J P., Moutinho, D., Kranendonk, M., Auchus, R. J., Lafer, E. M., Ghosh, D., Martasek, P., Kar, R., Masters, B. S., & Roman, L. J. (2016). Instability of the human cytochrome P450 reductase A287P variant is the major contributor to its Antley-Bixler Syndrome-like phenotype. The Journal of Biological Chemistry, 291(39), 20487–20502. https://doi.org/10.1074/jbc.M116.716019
  • Mi, H., & Thomas, P. (2009). PANTHER Pathway: An ontology-based pathway database coupled with data analysis tools. Methods in Molecular Biology, 563, 123–140. https://doi.org/10.1007/978-1-60761-175-2_7
  • Miyamoto, S., & Kollman, P. A. (1992). Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models. Journal of Computational Chemistry, 13(8), 952–962. https://doi.org/10.1002/jcc.540130805
  • Ng, P. C., & Henikoff, S. (2003). SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Research, 31(13), 3812–3814. https://doi.org/10.1093/nar/gkg509
  • Nicolo, C., Flück, C. E., Mullis, P. E., & Pandey, A. V. (2010). Restoration of mutant cytochrome P450 reductase activity by external flavin. Molecular and Cellular Endocrinology, 321(2), 245–252. https://doi.org/10.1016/j.mce.2010.02.024
  • Nikam, R., Kulandaisamy, A., Harini, K., Sharma, D., & Gromiha, M. M. (2021). ProThermDB: Thermodynamic database for proteins and mutants revisited after 15 years. Nucleic Acids Research, 49(D1), D420–D424. https://doi.org/10.1093/nar/gkaa1035
  • P, S., Ebrahimi, E. A., Ghazala, S. A., D, T. K., R, S., Priya Doss C, G., & Zayed, H. (2018). Structural analysis of missense mutations in galactokinase 1 (GALK1) leading to galactosemia type-2. Journal of Cellular Biochemistry, 119(9), 7585–7598. https://doi.org/10.1002/jcb.27097
  • Pandey, A. V., & Flück, C. E. (2013). NADPH P450 oxidoreductase: Structure, function, and pathology of diseases. Pharmacology & Therapeutics, 138(2), 229–254. https://doi.org/10.1016/j.pharmthera.2013.01.010
  • Pandey, A. V., & Sproll, P. (2014). Pharmacogenomics of human P450 oxidoreductase. Frontiers in Pharmacology, 5, 103. https://doi.org/10.3389/fphar.2014.00103
  • Parthiban, V., Gromiha, M. M., & Schomburg, D. (2006). CUPSAT: Prediction of protein stability upon point mutations. Nucleic Acids Research, 34(Web Server issue), W239–242. https://doi.org/10.1093/nar/gkl190
  • Pires, D. E. V., Ascher, D. B., & Blundell, T. L. (2014a). mCSM: Predicting the effects of mutations in proteins using graph-based signatures. Bioinformatics (Oxford, England), 30(3), 335–342. https://doi.org/10.1093/bioinformatics/btt691
  • Pires, D. E. V., Ascher, D. B., & Blundell, T. L. (2014b). DUET: A server for predicting effects of mutations on protein stability using an integrated computational approach. Nucleic Acids Research, 42(Web Server issue), W314–319. https://doi.org/10.1093/nar/gku411
  • Riddick, D. S., Ding, X., Wolf, C. R., Porter, T. D., Pandey, A. V., Zhang, Q.-Y., Gu, J., Finn, R. D., Ronseaux, S., McLaughlin, L. A., Henderson, C. J., Zou, L., & Flück, C. E. (2013). NADPH–cytochrome P450 oxidoreductase: Roles in physiology, pharmacology, and toxicology. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 41(1), 12–23. https://doi.org/10.1124/dmd.112.048991
  • Schüttelkopf, A. W., & van Aalten, D. M. F. (2004). PRODRG: A tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallographica. Section D, Biological Crystallography, 60(Pt 8), 1355–1363. https://doi.org/10.1107/S0907444904011679
  • Shastry, B. S. (2007). SNPs in disease gene mapping, medicinal drug development and evolution. Journal of Human Genetics, 52(11), 871–880. https://doi.org/10.1007/s10038-007-0200-z
  • Sherry, S. T., Ward, M. H., Kholodov, M., Baker, J., Phan, L., Smigielski, E. M., & Sirotkin, K. (2001). dbSNP: The NCBI database of genetic variation. Nucleic Acids Research, 29(1), 308–311. https://doi.org/10.1093/nar/29.1.308
  • Shihab, H. A., Gough, J., Cooper, D. N., Stenson, P. D., Barker, G. L. A., Edwards, K. J., Day, I. N. M., & Gaunt, T. R. (2013). Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden Markov models. Human Mutation, 34(1), 57–65. https://doi.org/10.1002/humu.22225
  • Sim, N.-L., Kumar, P., Hu, J., Henikoff, S., Schneider, G., & Ng, P. C. (2012). SIFT web server: Predicting effects of amino acid substitutions on proteins. Nucleic Acids Research, 40(Web Server issue), W452–457. https://doi.org/10.1093/nar/gks539
  • Stierand, K., & Rarey, M. (2010). PoseView—Molecular interaction patterns at a glance. Journal of Cheminformatics, 2(S1), P50. https://doi.org/10.1186/1758-2946-2-S1-P50
  • Sukumar, S., Krishnan, A., & Banerjee, S. (2021). An overview of bioinformatics resources for SNP analysis. In Advances in bioinformatics (pp. 113–135). Springer. https://doi.org/10.1007/978-981-33-6191-1_7
  • Sunil Krishnan, G., Joshi, A., & Kaushik, V. (2021). Bioinformatics in personalized medicine. In Advances in Bioinformatics (pp. 303–315). Springer. https://doi.org/10.1007/978-981-33-6191-1_15
  • Thirumal Kumar, D., Eldous, H. G., Mahgoub, Z. A., George Priya Doss, C., & Zayed, H. (2018). Computational modelling approaches as a potential platform to understand the molecular genetics association between Parkinson’s and Gaucher diseases. Metabolic Brain Disease, 33(6), 1835–1847. https://doi.org/10.1007/s11011-018-0286-3
  • Venselaar, H., Te Beek, T. A. H., Kuipers, R. K. P., Hekkelman, M. L., & Vriend, G. (2010). Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics, 11(1), 548. https://doi.org/10.1186/1471-2105-11-548
  • Worth, C. L., Preissner, R., & Blundell, T. L. (2011). SDM—a server for predicting effects of mutations on protein stability and malfunction. Nucleic Acids Research, 39(Web Server issue), W215–W222. https://doi.org/10.1093/nar/gkr363
  • Xia, C., Panda, S. P., Marohnic, C. C., Martásek, P., Masters, B. S., & Kim, J.-J P. (2011). Structural basis for human NADPH-cytochrome P450 oxidoreductase deficiency. Proceedings of the National Academy of Sciences of the United States of America, 108(33), 13486–13491. https://doi.org/10.1073/pnas.1106632108
  • Zaki, O. K., Krishnamoorthy, N., El Abd, H. S., Harche, S. A., Mattar, R. A., Al Disi, R. S., Nofal, M. Y., El Bekay, R., Ahmed, K. A., George Priya Doss, C., & Zayed, H. (2017). Two patients with Canavan disease and structural modeling of a novel mutation. Metabolic Brain Disease, 32(1), 171–177. https://doi.org/10.1007/s11011-016-9896-9
  • Zaki, O. K., Priya Doss C, G., Ali, S. A., Murad, G. G., Elashi, S. A., Ebnou, M. S. A., Kumar D, T., Khalifa, O., Gamal, R., El Abd, H. S. A., Nasr, B. N., & Zayed, H. (2017). Genotype-phenotype correlation in patients with isovaleric acidaemia: Comparative structural modelling and computational analysis of novel variants. Human Molecular Genetics, 26(16), 3105–3115. https://doi.org/10.1093/hmg/ddx195
  • Zanger, U. M., & Schwab, M. (2013). Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacology & Therapeutics, 138(1), 103–141. https://doi.org/10.1016/j.pharmthera.2012.12.007

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