Login Register Cart 0
Generic placeholder image

Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Structural Modeling of Drosophila melanogaster Gut Cytochrome P450s and Docking Comparison of Fruit Fly Gut and Human Cytochrome P450s

Author(s): Vijay Nirusimhan, Daniel Andrew Gideon*, Abhinav Parashar, Sangavi Jeyachandran, Jeyakanthan Jeyaraman, Gowthamkumar Subbaraj and Langeswaran Kulanthaivel*

Volume 23, Issue 4, 2022

Published on: 02 June, 2022

Page: [299 - 316] Pages: 18

DOI: 10.2174/1389200223666220511162234

Price: $65

conference banner
Abstract

Drosophila melanogaster is a prominent organism in developmental biology research and in studies related to pathophysiological conditions like cancer and Alzheimer’s disease. The fruit fly gut contains several cytochrome P450s (CYP450s), which have central roles in Drosophila development and in the normal physiology of the gut. Since the crystal structures of these proteins have not been deciphered yet, we modeled the structure of 29 different D. melanogaster gut CYP450s using Prime (Schrödinger). The sequences of chosen D. melanogaster gut CYP450s were compared with that of their human counterparts. The common gut (and liver) microsomal CYP450s in humans were chosen for structural comparison to find the homology and identity % of D. melanogaster CYPs with that of their human counterparts. The modeled structures were validated using PROCHECK and the best fit models were used for docking several known human pharmacological agents/drugs to the modeled D. melanogaster gut CYP450s. Based on the binding affinities (ΔG values) of the selected drug molecules with the modeled fly gut CYPs, the plausible differences in metabolism of the prominent drugs in humans and flies were projected. The gut is involved in the absorption of oral drugs/pharmacological agents, and hence, upregulation of intestinal CYP450 and their reactions with endobiotics and xenobiotics is envisaged. The insights gleaned from this work can validate D. melanogaster as a model organism for studying intestinal drug metabolism, particularly in the context of a) toxicology of pharmacological agents to the gut cells and b) how gut P450 metabolites/products can influence gut homeostasis. This work can help establish a platform for further in vitro investigations on how intestinal CYP450 metabolism can influence gut health. The data from this work can be used for further in silico studies and this work can serve as a platform for future in vitro investigations on intestinal CYP450-mediated metabolism of endo- and xeno-biotics in D. melanogaster.

Keywords: Drosophila cytochrome P450, gut CYP450, sequence alignment, molecular docking, ADME, Alzheimer’s disease.

« Previous Next »
Graphical Abstract

[1]
Guengerich, F.P. Mechanisms of cytochrome P450-catalyzed oxidations. ACS Catal., 2018, 8(12), 10964-10976.
[http://dx.doi.org/10.1021/acscatal.8b03401] [PMID: 31105987]
[2]
Massey, V. Activation of molecular oxygen by flavins and flavoproteins. J. Biol. Chem., 1994, 269(36), 22459-22462.
[http://dx.doi.org/10.1016/S0021-9258(17)31664-2] [PMID: 8077188]
[3]
Huang, X.; Groves, J.T. Oxygen activation and radical transformations in heme proteins and metalloporphyrins. Chem. Rev., 2018, 118(5), 2491-2553.
[http://dx.doi.org/10.1021/acs.chemrev.7b00373] [PMID: 29286645]
[4]
Winterbourn, C.C. Reconciling the chemistry and biology of reactive oxygen species. Nat. Chem. Biol., 2008, 4(5), 278-286.
[http://dx.doi.org/10.1038/nchembio.85] [PMID: 18421291]
[5]
Zhao, Y.; Fan, J.; Wang, C.; Feng, X.; Li, C. Enhancing oleanolic acid production in engineered Saccharomyces cerevisiae. Bioresour. Technol., 2018, 257, 339-343.
[http://dx.doi.org/10.1016/j.biortech.2018.02.096] [PMID: 29526355]
[6]
Modi, S.R.; Collins, J.J.; Relman, D.A. Antibiotics and the gut microbiota. J. Clin. Invest., 2014, 124(10), 4212-4218.
[http://dx.doi.org/10.1172/JCI72333] [PMID: 25271726]
[7]
Meunier, B.; de Visser, S.P.; Shaik, S. Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes. Chem. Rev., 2004, 104(9), 3947-3980.
[http://dx.doi.org/10.1021/cr020443g] [PMID: 15352783]
[8]
Nath, A.; Atkins, W.M. A quantitative index of substrate promiscuity. Biochemistry, 2008, 47(1), 157-166.
[http://dx.doi.org/10.1021/bi701448p] [PMID: 18081310]
[9]
Atkins, W.M. Non-michaelis-menten kinetics in cytochrome P450-catalyzed reactions. Annu. Rev. Pharmacol. Toxicol., 2005, 45, 291-310.
[http://dx.doi.org/10.1146/annurev.pharmtox.45.120403.100004] [PMID: 15832445]
[10]
Ludington, W.B.; Ja, W.W. Drosophila as a model for the gut microbiome. PLoS Pathog., 2020, 16(4), e1008398.
[http://dx.doi.org/10.1371/journal.ppat.1008398] [PMID: 32324814]
[11]
Douglas, A.E. The Drosophila model for microbiome research. Lab Anim. (NY), 2018, 47(6), 157-164.
[http://dx.doi.org/10.1038/s41684-018-0065-0] [PMID: 29795158]
[12]
Bost, A.; Martinson, V.G.; Franzenburg, S.; Adair, K.L.; Albasi, A.; Wells, M.T.; Douglas, A.E. Functional variation in the gut microbiome of wild Drosophila populations. Mol. Ecol., 2018, 27(13), 2834-2845.
[http://dx.doi.org/10.1111/mec.14728] [PMID: 29802796]
[13]
Wong, C.N.A.; Ng, P.; Douglas, A.E. Low-diversity bacterial community in the gut of the fruitfly Drosophila melanogaster. Environ. Microbiol., 2011, 13(7), 1889-1900.
[http://dx.doi.org/10.1111/j.1462-2920.2011.02511.x] [PMID: 21631690]
[14]
Sugimoto, H.; Shiro, Y. Diversity and substrate specificity in the structures of steroidogenic cytochrome P450 enzymes. Biol. Pharm. Bull., 2012, 35(6), 818-823.
[http://dx.doi.org/10.1248/bpb.35.818] [PMID: 22687469]
[15]
Yang, Y.; Iji, P.; Choct, M. Dietary modulation of gut microflora in broiler chickens: A review of the role of six kinds of alternatives to in-feed antibiotics. Worlds Poult. Sci. J., 2009, 65(1), 97-114.
[http://dx.doi.org/10.1017/S0043933909000087]
[16]
Yoo, D-H.; Kim, I.S.; Van Le, T.K.; Jung, I.H.; Yoo, H.H.; Kim, D.H. Gut microbiota-mediated drug interactions between lovastatin and anti-biotics. Drug Metab. Dispos., 2014, 42(9), 1508-1513.
[http://dx.doi.org/10.1124/dmd.114.058354] [PMID: 24947972]
[17]
Mohammed, B. Understanding the mechanisms involved in the regulation of cytochrome P450 gene expression in Drosophila melanogaster (Diptera: Drosophilidae). Entomol Ornithol Herpetol, 2017, 6(189), 2161-0983.1000189.
[18]
Hovemann, B.T.; Sehlmeyer, F.; Malz, J. Drosophila melanogaster NADPH-cytochrome P450 oxidoreductase: Pronounced expression in antennae may be related to odorant clearance. Gene, 1997, 189(2), 213-219.
[http://dx.doi.org/10.1016/S0378-1119(96)00851-7] [PMID: 9168130]
[19]
Panda, S. El khader, I.; Casellas, F.; López Vivancos, J.; García Cors, M.; Santiago, A.; Cuenca, S.; Guarner, F.; Manichanh, C. Short-term effect of antibiotics on human gut microbiota. PLoS One, 2014, 9(4), e95476.
[http://dx.doi.org/10.1371/journal.pone.0095476] [PMID: 24748167]
[20]
Karle, P.; Renner, M.; Salmons, B.; Günzburg, W.H. Necrotic, rather than apoptotic, cell death caused by cytochrome P450-activated ifosfamide. Cancer Gene Ther., 2001, 8(3), 220-230.
[http://dx.doi.org/10.1038/sj.cgt.7700290] [PMID: 11332993]
[21]
Li, A.P.; Alam, N.; Amaral, K.; Ho, M.D.; Loretz, C.; Mitchell, W.; Yang, Q. Cryopreserved human intestinal mucosal epithelium: A novel in vitro experimental system for the evaluation of enteric drug metabolism, cytochrome P450 induction, and enterotoxicity. Drug Metab. Dispos., 2018, 46(11), 1562-1571.
[http://dx.doi.org/10.1124/dmd.118.082875] [PMID: 30006371]
[22]
Ervin, S.M.; Ramanan, S.V.; Bhatt, A.P. Relationship between the gut microbiome and systemic chemotherapy. Dig. Dis. Sci., 2020, 65(3), 874-884.
[http://dx.doi.org/10.1007/s10620-020-06119-3] [PMID: 32026181]
[23]
Zhang, J.; Zhang, J.; Wang, R. Gut microbiota modulates drug pharmacokinetics. Drug Metab. Rev., 2018, 50(3), 357-368.
[http://dx.doi.org/10.1080/03602532.2018.1497647] [PMID: 30227749]
[24]
Chung, H.; Sztal, T.; Pasricha, S.; Sridhar, M.; Batterham, P.; Daborn, P.J. Characterization of Drosophila melanogaster cytochrome P450 genes. Proc. Natl. Acad. Sci. USA, 2009, 106(14), 5731-5736.
[http://dx.doi.org/10.1073/pnas.0812141106] [PMID: 19289821]
[25]
Tijet, N.; Helvig, C.; Feyereisen, R. The cytochrome P450 gene superfamily in Drosophila melanogaster: Annotation, intron-exon organization and phylogeny. Gene, 2001, 262(1-2), 189-198.
[http://dx.doi.org/10.1016/S0378-1119(00)00533-3] [PMID: 11179683]
[26]
Edson, K.Z.; Rettie, A.E. CYP4 enzymes as potential drug targets: Focus on enzyme multiplicity, inducers and inhibitors, and therapeutic modulation of 20-hydroxyeicosatetraenoic acid (20-HETE) synthase and fatty acid ω-hydroxylase activities. Curr. Top. Med. Chem., 2013, 13(12), 1429-1440.
[http://dx.doi.org/10.2174/15680266113139990110] [PMID: 23688133]
[27]
Burns, K.; Helsby, N.A. Cytochrome P450 in GtoPdb v. 2021.2. IUPHAR/BPS Guide to Pharmacology CITE. 2021, 2021(2)
[28]
Cifuentes, D.; Chynoweth, R.; Guillén, J.; De la Rúa, P.; Bielza, P. Novel cytochrome P450 genes, CYP6EB1 and CYP6EC1, are over-expressed in acrinathrin-resistant Frankliniella occidentalis (Thysanoptera: Thripidae). J. Econ. Entomol., 2012, 105(3), 1006-1018.
[http://dx.doi.org/10.1603/EC11335] [PMID: 22812142]
[29]
Niwa, R.; Matsuda, T.; Yoshiyama, T.; Namiki, T.; Mita, K.; Fujimoto, Y.; Kataoka, H. CYP306A1, a cytochrome P450 enzyme, is essential for ecdysteroid biosynthesis in the prothoracic glands of Bombyx and Drosophila. J. Biol. Chem., 2004, 279(34), 35942-35949.
[http://dx.doi.org/10.1074/jbc.M404514200] [PMID: 15197185]
[30]
Saner, C.; Weibel, B.; Wurgler, F.E.; Sengstag, C. Metabolism of promutagens catalyzed by Drosophila melanogaster CYP6A2 enzyme in Saccharomyces cerevisiae. Environ. Mol. Mutagen., 1996, 27(1), 46-58.
[http://dx.doi.org/10.1002/(SICI)1098-2280(1996)27:1<46:AID-EM7>3.0.CO;2-C] [PMID: 8625948]
[31]
Dunkov, B.C.; Rodriguez-Arnaiz, R.; Pittendrigh, B. ffrench-Constant, R.H.; Feyereisen, R. Cytochrome P450 gene clusters in Drosophila melanogaster. Mol. Gen. Genet., 1996, 251(3), 290-297.
[PMID: 8676871]
[32]
Daborn, P.J.; Lumb, C.; Boey, A.; Wong, W.; Ffrench-Constant, R.H.; Batterham, P. Evaluating the insecticide resistance potential of eight Drosophila melanogaster cytochrome P450 genes by transgenic over-expression. Insect Biochem. Mol. Biol., 2007, 37(5), 512-519.
[http://dx.doi.org/10.1016/j.ibmb.2007.02.008] [PMID: 17456446]
[33]
Jones, R.T.; Bakker, S.E.; Stone, D.; Shuttleworth, S.N.; Boundy, S.; McCart, C.; Daborn, P.J. ffrench-Constant, R.H.; van den Elsen, J.M. Homology modelling of Drosophila cytochrome P450 enzymes associated with insecticide resistance. Pest Manag. Sci., 2010, 66(10), 1106-1115.
[http://dx.doi.org/10.1002/ps.1986] [PMID: 20583201]
[34]
Marx, V. Method of the Year: Protein structure prediction. Nat. Methods, 2022, 19(1), 5-10.
[http://dx.doi.org/10.1038/s41592-021-01359-1] [PMID: 35017741]
[35]
Sievers, F.; Wilm, A.; Dineen, D.; Gibson, T.J.; Karplus, K.; Li, W.; Lopez, R.; McWilliam, H.; Remmert, M.; Söding, J.; Thompson, J.D.; Higgins, D.G. Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol. Syst. Biol., 2011, 7(1), 539.
[http://dx.doi.org/10.1038/msb.2011.75] [PMID: 21988835]
[36]
Yu, J.; Zhou, Y.; Tanaka, I.; Yao, M. Roll: A new algorithm for the detection of protein pockets and cavities with a rolling probe sphere. Bioinformatics, 2010, 26(1), 46-52.
[http://dx.doi.org/10.1093/bioinformatics/btp599] [PMID: 19846440]
[37]
Pandiyan, S.; Kulanthaivel, L. Computational study on identification of potential elephantiasis inhibitors against UDP-Galactopyranose Mu-tase (UGM). Curr. Enzym. Inhib., 2021, 17(1), 57-70.
[http://dx.doi.org/10.2174/1573408016666200831171943]
[38]
Hofmann, K.; Stoffel, W.T. Available from: https://embnet. vital-it. ch/software Accessed on 7 July 2019.
[39]
Rost, B.; Yachdav, G.; Liu, J. The predict protein server. Nucleic Acids Res., 2004, 32(Web Server issue)(Suppl. 2), W321-6.
[PMID: 15215403]
[40]
Bhachoo, J.; Beuming, T. Investigating protein–peptide interactions using the Schrödinger computational suite. Modeling Peptide-protein Interactions, 2017, 235-254.
[http://dx.doi.org/10.1007/978-1-4939-6798-8_14]
[41]
Laskowski, R.A. PROCHECK: A program to check the stereochemical quality of protein structures. J. Appl. Cryst., 1993, 26(2), 283-291.
[http://dx.doi.org/10.1107/S0021889892009944]
[42]
Ioakimidis, L. Benchmarking the reliability of QikProp. Correlation between experimental and predicted values. QSAR Comb. Sci., 2008, 27(4), 445-456.
[http://dx.doi.org/10.1002/qsar.200730051]
[43]
Roos, K.; Wu, C.; Damm, W.; Reboul, M.; Stevenson, J.M.; Lu, C.; Dahlgren, M.K.; Mondal, S.; Chen, W.; Wang, L.; Abel, R.; Friesner, R.A.; Harder, E.D. OPLS3e: Extending force field coverage for drug-like small molecules. J. Chem. Theory Comput., 2019, 15(3), 1863-1874.
[http://dx.doi.org/10.1021/acs.jctc.8b01026] [PMID: 30768902]
[44]
Nebert, D.W.; Gonzalez, F.J. P450 genes: Structure, evolution, and regulation. Annu. Rev. Biochem., 1987, 56(1), 945-993.
[http://dx.doi.org/10.1146/annurev.bi.56.070187.004501] [PMID: 3304150]
[45]
Broderick, N.A.; Lemaitre, B. Gut-associated microbes of Drosophila melanogaster. Gut Microbes, 2012, 3(4), 307-321.
[http://dx.doi.org/10.4161/gmic.19896] [PMID: 22572876]
[46]
Poulos, T.L.; Finzel, B.C.; Howard, A.J. High-resolution crystal structure of cytochrome P450cam. J. Mol. Biol., 1987, 195(3), 687-700.
[http://dx.doi.org/10.1016/0022-2836(87)90190-2] [PMID: 3656428]
[47]
Scott, E.E.; Halpert, J.R. Structures of cytochrome P450 3A4. Trends Biochem. Sci., 2005, 30(1), 5-7.
[http://dx.doi.org/10.1016/j.tibs.2004.11.004] [PMID: 15653318]
[48]
Zawaira, A.; Ching, L.Y.; Coulson, L.; Blackburn, J.; Wei, Y.C. An expanded, unified substrate recognition site map for mammalian cyto-chrome P450s: Analysis of molecular interactions between 15 mammalian CYP450 isoforms and 868 substrates. Curr. Drug Metab., 2011, 12(7), 684-700.
[http://dx.doi.org/10.2174/138920011796504554] [PMID: 21740382]
[49]
Hasler, J.A. Pharmacogenetics of cytochromes P450. Mol. Aspects Med., 1999, 20(1-2), 12-24, 25-137.
[http://dx.doi.org/10.1016/S0098-2997(99)00005-9] [PMID: 10575648]
[50]
Esteves, F.; Campelo, D.; Gomes, B.C.; Urban, P.; Bozonnet, S.; Lautier, T.; Rueff, J.; Truan, G.; Kranendonk, M. The role of the FMN-domain of human cytochrome P450 oxidoreductase in its promiscuous interactions with structurally diverse redox partners. Front. Pharmacol., 2020, 11, 299.
[http://dx.doi.org/10.3389/fphar.2020.00299] [PMID: 32256365]
[51]
Gonzalez, F.J. Molecular genetics of the P-450 superfamily. Pharmacol. Ther., 1990, 45(1), 1-38.
[http://dx.doi.org/10.1016/0163-7258(90)90006-N] [PMID: 2405431]
[52]
Timsit, Y.E.; Negishi, M. CAR and PXR: The xenobiotic-sensing receptors. Steroids, 2007, 72(3), 231-246.
[http://dx.doi.org/10.1016/j.steroids.2006.12.006] [PMID: 17284330]
[53]
Omura, T.; Gotoh, O. Evolutionary origin of mitochondrial cytochrome P450. J. Biochem., 2017, 161(5), 399-407.
[http://dx.doi.org/10.1093/jb/mvx011] [PMID: 28338801]
[54]
Ohta, D.; Mizutani, M. Redundancy or flexibility: Molecular diversity of the electron transfer components for P450 monooxygenases in high-er plants. Front. Biosci., 2004, 9, 1587-1597.
[http://dx.doi.org/10.2741/1356] [PMID: 14977570]
[55]
Coelho, A.; Fraichard, S.; Le Goff, G.; Faure, P.; Artur, Y.; Ferveur, J.F.; Heydel, J.M. Cytochrome P450-dependent metabolism of caffeine in Drosophila melanogaster. PLoS One, 2015, 10(2), e0117328.
[http://dx.doi.org/10.1371/journal.pone.0117328] [PMID: 25671424]
[56]
Trinder, M.; Daisley, B.A.; Dube, J.S.; Reid, G. Drosophila melanogaster as a high-throughput model for host–microbiota interactions. Front. Microbiol., 2017, 8, 751.
[http://dx.doi.org/10.3389/fmicb.2017.00751] [PMID: 28503170]
[57]
Manoj, K.M.; Baburaj, A.; Ephraim, B.; Pappachan, F.; Maviliparambathu, P.P.; Vijayan, U.K.; Narayanan, S.V.; Periasamy, K.; George, E.A.; Mathew, L.T. Explaining the atypical reaction profiles of heme enzymes with a novel mechanistic hypothesis and kinetic treatment. PLoS One, 2010, 5(5), e10601.
[http://dx.doi.org/10.1371/journal.pone.0010601] [PMID: 20498847]
[58]
Manoj, K.M.; Parashar, A.; Gade, S.K.; Venkatachalam, A. Functioning of microsomal cytochrome P450s: Murburn concept explains the metabolism of xenobiotics in hepatocytes. Front. Pharmacol., 2016, 7, 161.
[http://dx.doi.org/10.3389/fphar.2016.00161] [PMID: 27445805]
[59]
Paoli, M.; Marles-Wright, J.; Smith, A. Structure-function relationships in heme-proteins. DNA Cell Biol., 2002, 21(4), 271-280.
[http://dx.doi.org/10.1089/104454902753759690] [PMID: 12042067]
[60]
Simões, M.M.; Neves, C.M.; Pires, S.M.; Neves, M.G.P.; Cavaleiro, J.A. Mimicking P450 processes and the use of metalloporphyrins. Pure Appl. Chem., 2013, 85(8), 1671-1681.
[http://dx.doi.org/10.1351/PAC-CON-12-11-15]
[61]
Parashar, A.; Manoj, K.M. Murburn precepts for cytochrome P450 mediated drug/xenobiotic metabolism and homeostasis. Curr. Drug Metab., 2021, 22(4), 315-326.
[http://dx.doi.org/10.2174/1389200222666210118102230] [PMID: 33461459]
[62]
Geldenhuys, W.J.; Allen, D.D.; Bloomquist, J.R. Novel models for assessing blood-brain barrier drug permeation. Expert Opin. Drug Metab. Toxicol., 2012, 8(6), 647-653.
[http://dx.doi.org/10.1517/17425255.2012.677433] [PMID: 22468700]
[63]
Matsumoto, Y. Facilitating drug discovery in human disease models using insects. Biol. Pharm. Bull., 2020, 43(2), 216-220.
[http://dx.doi.org/10.1248/bpb.b19-00834] [PMID: 32009109]
[64]
Hamamoto, H.; Tonoike, A.; Narushima, K.; Horie, R.; Sekimizu, K. Silkworm as a model animal to evaluate drug candidate toxicity and metabolism. Comp. Biochem. Physiol. C Toxicol. Pharmacol., 2009, 149(3), 334-339.
[http://dx.doi.org/10.1016/j.cbpc.2008.08.008] [PMID: 18804554]
[65]
Abdelli, N.; Peng, L.; Keping, C. Silkworm, Bombyx mori, as an alternative model organism in toxicological research. Environ. Sci. Pollut. Res. Int., 2018, 25(35), 35048-35054.
[http://dx.doi.org/10.1007/s11356-018-3442-8] [PMID: 30374720]
[66]
Panthee, S.; Paudel, A.; Hamamoto, H.; Sekimizu, K. Advantages of the silkworm as an animal model for developing novel antimicrobial agents. Front. Microbiol., 2017, 8, 373.
[http://dx.doi.org/10.3389/fmicb.2017.00373] [PMID: 28326075]
[67]
Asha, S.; Vidyavathi, M. Cunninghamella-a microbial model for drug metabolism studies--a review. Biotechnol. Adv., 2009, 27(1), 16-29.
[http://dx.doi.org/10.1016/j.biotechadv.2008.07.005] [PMID: 18775773]
[68]
Nauen, R.; Zimmer, C.T.; Vontas, J. Heterologous expression of insect P450 enzymes that metabolize xenobiotics. Curr. Opin. Insect Sci., 2021, 43, 78-84.
[http://dx.doi.org/10.1016/j.cois.2020.10.011] [PMID: 33186746]
[69]
Manoj, K.M.; Parashar, A.; Venkatachalam, A.; Goyal, S. Satyalipsu; Singh, P.G.; Gade, S.K.; Periyasami, K.; Jacob, R.S.; Sardar, D.; Singh, S.; Kumar, R.; Gideon, D.A. Atypical profiles and modulations of heme-enzymes catalyzed outcomes by low amounts of diverse additives suggest diffusible radicals’ obligatory involvement in such redox reactions. Biochimie, 2016, 125, 91-111.
[http://dx.doi.org/10.1016/j.biochi.2016.03.003] [PMID: 26969799]

Rights & Permissions Print Cite
Article Metrics
25
1
© 2024 Bentham Science Publishers | Privacy Policy