Biopolym. Cell. 2004; 20(3):193-206.
Reviews
On the problem of multidrug resistance: hypermutability as a mechanism to defense metabolic targets from toxic xenobiotics
1Cherepenko E. I., 1Hovorun D. M.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680

Abstract

Multidrug resistance (mdr), a scourge of modern pharmacology, is studied mainly as related to the function of multidrug exporters and cell overcrowding with proteins. However, often it brings no solution to the problem. Here we briefly summarize achievements in the mdr study and analyze our results showing that mdr may emerge due to simultaneous mutations arisen in different tightly linked genes united into a cassette. The latter may be specially localized inside the cell (we dubbed this as an environsome) so that it faces, unlike other genes, the intracellular space and the main intracellular flux. There are ~100 environsomes per cell, the chemoresistant phenotype may be due to a mutation in one of them. In case of a mutagen involved into the flux the cassette is the first to become an area of effective local mutagenesis and develops many mutations simultaneously. If the cassette codes for natively unfolded proteins and the transition disorder/order due to mutations becomes possible it may change the geometry of intracellular space and cause ligand and target sequestration, leading to the cell multiple chemoresistance).

References

[1] Drews J. Genomic sciences and the medicine of tomorrow. Nat Biotechnol. 1996; 14 (11):1516-8.
[2] Bugg C, Carson W, Montgomery J. Drug by design. Sci Amer. 1993; 269:92-8.
[3] Pfost DR. The engineering of drug discovery. Nat Biotechnol. 1998; 16(4): 313.
[4] Scangos G. Drug discovery in the postgenomic era. Nat Biotechnol. 1997; 15 (12):1220-1.
[5] Drews J. Drug discovery: A historical perspective. Science. 2000; 287 (5460): 1960-4.
[6] Torchilin VP, Lukyanov AN. Peptide and protein drug delivery to and into tumors: Challenges and solutions. Drug Discov Today. 2003; 8 (6):259-66.
[7] Phelps MA, Foraker AB, Swaan PW. Cytoskeletal motors and cargo in membrane trafficking: Opportunities for high specificity in drug intervention. Drug Discov Today. 2003; 8 (11):494-502.
[8] Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, Smith HO, et al. The sequence of the human genome. Science. 2001; 291 (5507):1304-51.
[9] Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, et al. Initial sequencing and analysis of the human genome. Nature. 2001; 409 (6822):860-921.
[10] Ewing B, Green P. Analysis of expressed sequence tags indicates 35000 human genes. Nat Genet. 2001; 25:232-4.
[11] Rubenstein K. High throughput screening: Overcoming the innovation deficit (D and MD Rpts). London, 2000; 207 p.
[12] Hemmila IA, Hurskainen P. Novel detection strategies for drug discovery. Drug Discov Today. 2002; 7 (18):S150-6.
[13] Drews J. Strategic trends in the drug industry. Drug Discov Today. 2003; 8(9):411-20.
[14] Hayes JD, Wolf CR. Molecular mechanisms of drug resistance. Biochem J. 1990; 272 (2):281-95.
[15] Bacterial resistance to antimicrobials. Ed. K Lewis. New York, Marcel Dekker, Inc. 2002; 495 p.
[16] Comai L, Sen LC, Stalker DM. An altered aroA gene product confers resistance to the herbicide glyphosate. Science. 1983; 221(4608):370-1.
[17] Song S, Guillaume Wientjes M, Gan Y, Au JL-S. Fibroblast growth factors: An epigenetic mechanism of broad spectrum resistance to anticancer drugs. Proc Nat Acad Sci USA. 2000; 97(15):8658-63.
[18] Davies J. Inactivation of antibiotics and the dissemination of resistance genes. Science. 1994; 264(5157):375-82.
[19] Il'ina TS. [Structural organization and mechanisms of mobility of the gene cassette coding for resistance to antibiotics and bacterial virulence factors]. Mol Gen Mikrobiol Virusol. 2001;(1):3-12. Review. Russian.
[20] Kovalevskaia NP. Mobile gene cassettes and DNA integration elements. Mol Biol (Mosk). 2002;36(2):261-7.
[21] Hooper D. Target modification as a mechanism of antimicrobial resistance. Bacterial resistance to antimicrobials. Ed. K Lewis. New York, Marcel Dekker Inc. 2002; 161-97.
[22] Kishore GM, Shah DM. Amino acid biosynthesis inhibitors as herbicides. Annu Rev Biochem. 1988; 57:627-63.
[23] Padgette SR, Re DB, Barry GL. New weed control opportunities: Development of soybeans with a Roundup ready gene. Herbicide-resistant crops. Boca Raton, CRC publ, 1996; 53-84.
[24] Nikaido H, Saier Jr, MH. Transport proteins in bacteria: Common themes in their design. Science. 1992; 258 (5084):936-42.
[25] Nikaido H. Prevention of drug access to bacterial targets: Permeability barriers and active efflux. Science. 1994; 264 (5157):382-88.
[26] Ames GF-L, Mimura CS, Shyamala V. Bacterial periplasmic permeases belong to a family of transport proteins operating from Escherichia coli to human: Traffic ATPases. FEMS Microbiol Rev. 1990; 75 (4):429-46.
[27] Hyde SC, Emsley P, Hartshorn MJ, Mimmack MM, Gileadi U, Pearce SR, Gallagher MP, Gill DR, Hubbard RE, Higgins CF.. Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport. Nature. 1990; 346 (6282):362-5.
[28] Ames GF-L. Bacterial periplasmic transport systems: Structure, mechanism, and evolution. Annu Rev Biochem. 1986; 55:397-425.
[29] Dana K, Roninson I. Interviews. J NIH Res. 1994; 6:66-74.
[30] Holland IB, Blight MA. ABC-ATPases, adaptable energy generators fuelling transmembrane movement of a variety of molecules in organisms from bacteria to humans. J Mol Biol. 1999; 293 (2):381-99.
[31] Stavrovskaya AA. Cellular mechanisms of multidrug resistance of tumor cells. Biochemistry (Mosc). 2000;65(1):95-106.
[32] Higgins CF. ABC Transporters: From microorganisms to man. Annu Rev Cell Biol. 1992; 8:67-113.
[33] Hipfner DR, Deeley RG, Cole SPC. Structural, mechanistic and clinical aspects of MRP1. Biochim Biophys Acta. 1999;1461(2):359-76.
[34] Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol. 1999; 39:361-98.
[35] Leslie EM, Deeley RG, Cole SPC. Toxicological relevance of the multidrug resistance protein 1, MRP1 (ABCC1) and related transporters. Toxicology. 2001; 167 (1):3-23.
[36] Lee SH, Altenberg GA. Transport of leukotriene C4 by a cysteine-less multidrug resistance protein 1 (MRP1). Biochem J. 2003; 370 (1):357-60.
[37] Paulsen IT, Brown MH, Skurray RA. Proton-dependent multidrug efflux systems. Microbiol Rev. 1996; 60 (4):575-608.
[38] Pao SS, Paulsen IT, Saier MH Jr. Major facilitator family. Microbiol Mol Biol Rev. 1998;62(1):1-34.
[39] Lewis K, Lomovskaya O. Drug efflux. Bacterial resistance to antimicrobials. Ed. K Lewis. New York, Marcel Dekker, Inc. 2002; 61-90.
[40] Steinruecken HC, Amrhein N. The herbicide glyphosate is a potent inhibitor of 5-enolpyruvyl-shikimic acid-3-phosphate synthase. Biochem Biophys Res Commun. 1980; 94 (4):1207-12.
[41] Pipke R, Amrhein N. Carbon-phosphorus lyase activity in permeabilized cells of Arthrobacter sp. GLP-1. FEBS Lett. 1988; 236 (1):135-8.
[42] Cherepenko E. Genetic mechanisms of the resistance of Escherichia coli to amino acid antimetabolites. 2. Study of the frequency of induction and properties of glyphosate resistant mutants. Biopolym Cell. 1997; 13(6):493-96.
[43] Cherepenko EI. Recessive gene of chemoresistance of Escherichia coli which do not define the inflow of substances in a cell. Dopovidi Nats Akad Nauk Ukrainy. 2003; (2):200-3.
[44] Jeffery CJ. Moonlighting proteins. Trends Biochem Sci. 1999; 24(1):8-11.
[45] Neuhard J, Nygaard P. Purines and pyrimidines. Escherichia coli and Salmonella typhimurium: Cellular and molecular biology. Ed. F Neidhardt. Washington, ASM press. 1987; 1:445-73.
[46] Jochimsen B, Nygaard P, Vestergaard T. Location on the chromosome of Escherichia coli of genes governing purine metabolism. Adenosine deaminase (add), guanosine kinase (gsk) and hypoxanthine phosphoribosyltransferase (hpt). Mol Gen Genet. 1975; 143 (1):85-91.
[47] Craig S. Purine salvage enzymes as targets for the chemotherapeutic treatment of parasitic diseases. Biopolym. Cell, 1994;10(6):65-71
[48] Cherepenko E, Craig S. Genetic mechanisms of Escherichia coli resistance to target inactivation. Genes governing purine metabolism in enterobacteria: An unexpected sequence found via complementation selection. Biopolym. Cell. 1997; 13(5):403-7.
[49] Viswanathan M, Lanjuin A, Lovett ST. Identification of RNase T as a high-copy suppressor of the UV sensitivity associated with single-strand DNA exonuclease deficiency in Escherichia coli. Genetics. 1999; 151(3):929-34.
[50] Yavachev L, Fvanov I. What does homology between E. coli tRNAs and RNAs controlling ColEI plasmid replication mean? J Theor Biol. 1988; 131:131-7.
[51] Cherepenko EI. ColEl plasmids can prevent thermoinactivation of phenylalanyl-tRNA synthetase in Escherichia coli. Biopolym. Cell. 1994; 10(3-4):75-8.
[52] Corbin BD, Yu XC, Margolin W. Exloring intracellular space: function of the Min system in round-shape Escherichia coli II. EMBO J. 2002; 21:1998-2008.
[53] Sanford K, Soucaille P, Whited G, Chotani G. Genomics to fluxomics and physiomics - Pathway engineering. Curr Opin Microbiol. 2002; 5(3):318-22.
[54] Miller P, Rather P. Global response systems that cause resistance Bacterial resistance to antimicrobials. Ed. K Lewis. New York, Marcel Dekker, Inc. 2002; 37-60.
[55] Elowitz MB, Surette MG, Wolf P-E, Stock JB, Leibler S. Protein mobility in the cytoplasm of Escherichia coli. J Bacteriol. 1999; 181 (1):197-203.
[56] Ellis RJ. Macromolecular crowding: Obvious but underappreciated Trends in biochemical. Sciences. 2001; 26 (10): 597-604.
[57] Fulton AB. How crowded is the cytoplasm? Cell. 1982; 30 (2):345-7.
[58] Minton AP. The effect of volume occupancy upon the thermodynamic activity of proteins: some biochemical consequences. Mol Cell Biochem. 1983; 55 (2):119-40.
[59] Minton KW, Karmis P, Hahn GM, Minton AP. Nonspecific stabilization of stress susceptible proteins by stressresistant proteins: A model for the biological role of heat-shock proteins. Proc Nat Acad Sci USA. 1982: 79:7109-11.
[60] Zimmerman SB, Trach SO. Estimation of macromolecule concentrations and excluded volume effects for the cytoplasm of Escherichia coli. J Mol Biol. 1991; 222 (3):599-620.
[61] Minton AP. Confinement as a determinant of macromolecular structure and reactivity. Biophys J. 1992; 63 (4):1090-100.
[62] Minton AP, Colclasure GC, Parker JC. Model for the role of macromolecular crowding in regulation of cellular volume. Proc Nat Acad Sci USA. 1992; 89 (21):10504-6.
[63] Zimmerman SB, Minton AP. Macromolecular crowding: Biochemical, biophysical, and physiological consequences. Annu Rev Biophys Biomol Struct. 1993; 22:27-65.
[64] Ellis RJ, Hartl FU. Principles of protein folding in the cellular environment. Curr Opin Struct Biol. 1999; 9 (1):102-10.
[65] Ellis RJ. Molecular chaperones: Avoiding the crowd. Curr Biol. 1997; 7 (9): R531-3.
[66] Dobson CM, Evans PA, Radford SE. Understanding how proteins fold: The lysozyme story so far. Trends Biochem Sci. 1994; 19 (1): 31-7.
[67] Ellis RJ, Hartl F-U. Protein folding in the cell: Competing models of chaperonin function. FASEB J. 1996; 10 (1): 20-6.
[68] Van Den Berg B, Ellis RJ, Dobson CM. Effects of macromolecular crowding on protein folding and aggregation. EMBO J. 1999; 18 (24):6927-33.
[69] Sussman HE. Personalized cancer vaccine promises remission. Drug Discov. Today. 2003; 8 (15):657-8.
[70] Kao HP, Abney JR, Verkman AS. Determinants of the translational mobility of a small solute in cell cytoplasm. J Cell Biol. 1993; 120 (1):175-84.
[71] Wright PE, Dyson HJ. Intrinsically unstructured proteins: Re-assessing the protein structure-function paradigm. J Mol Biol. 1999; 293 (2):321-31.
[72] Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, Ausio J, Nissen MS, Reeves R, Kang C, Kissinger CR, Bailey RW, Griswold MD, Chiu W, Garner EC, Obradovic Z. Intrinsically disordered protein. J Mol Graph Model. 2001; 19 (1):26-59.
[73] Uversky VN. Natively unfolded proteins: A point where biology waits for physics. Protein Sci. 2002; 11 (4):739-56.
[74] Plaxco KW, Gross M. The importance of being unfolded. Nature. 1997; 386 (6626):657-9.
[75] Pontius BW. Close encounters: Why unstructured, polymeric domains can increase rates of specific macromolecular association. Trends Biochem Sci. 1993; 18 (5):181-6.
[76] Cherepenko EI, Karpenko OI, Maluta SS. Genetic mechanisms of Escherichia coli cell resistance to amino acid antimetabolites. 1. Search for genes other than glyphosate target gene. Biopolym. Cell. 1994; 10(3-4):79-83
[77] Cherepenko EI. Multidrug resistance: discovery of the gene cassette in cells of Escherichia coli. Dopovidi Nats Akad Nauk Ukrainy. 2002; (11):163-6.
[78] Rudd KE. Linkage map of Escherichia coli K-12, edition 10: The physical map. Microbiol. Mol. Biol Rev. 1998; 62 (3):985-1019.
[79] Olden K, Wilson S. Environmental health and genomics: Visions and implications. Nat Rev Genet. 2000; 1 (2):149-53.
[80] Cherepenko EI. Recombination in Escherichia coli cells and multiform cytotoxic resistance.Ukr Biokhim Zh. 2003;75(1):25-8.
[81] Hunter AC, Moghimi SM. Therapeutic synthetic polymers: A game of Russian roulette? Drug Discov. Today. 2002; 7 (19):998-1001.
[82] Bogunia-Kubik K, Sugisaka M. From molecular biology to nanotechnology and nanomedicine. BioSystems. 2002; 65 (2-3):123-38.
[83] Koh H-L, Yau W-P, Ong P-S, Hegde A. Current trends in modern pharmaceutical analysis for drug discovery. Drug Discov Today. 2003; 8 (19):889-97.
[84] Collins FS, Green ED, Guttmacher AE, Guyer MS. A vision for the future of genomics research. Nature. 2003; 422 (6934):835-47.