. Biology: The Unity and Diversity of Life (MindTap Course List) 14th Edition. 2007). DNA gyrase possesses three interfaces that can be in an open or closed conformation (Fig. Pharmacol Ther 99(2):167181, Lesher GY, Forelich EJ, Gruett MD, Bailey JH, Brundage RP (1962) 1,8-naphthyridine derivatives, a new class of chemotherapeutic agents. DNA gyrase is an important target for the development of novel antibiotics. 1997; Lewis et al. & van Heijenoort J. Cytoplasmic steps of peptidoglycan synthesis in. 1996a). 2006; Sadiq et al. 1997); no cross-resistance between CcdB and quinolones has been observed (Bernard et al. quinolones, ciprofloxacin, etc. Antimicrob Agents Chemother 37:26562661, Nakada N, Gmnder H, Hirata T, Arisawa M (1994) Mechanism of inhibition of DNA gyrase by cyclothialidine, a novel DNA gyrase inhibitor. b Proposed 3-D structure (adapted from (Parks et al. By analogy, there are a wide range of inhibitors of topo II that target the enzyme at various stages of its catalytic cycle (Larsen et al. The images or other third party material in this article are included in the articles Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. 1996b; Maxwell and Lawson 2003). Antimicrob Agents Chemother 51(4):11911201, Jiang Y, Pogliano J, Helinski DR, Konieczny I (2002) ParE toxin encoded by the broad-host-range plasmid RK2 is an inhibitor of Escherichia coli gyrase. Part 2: SAR development and potency against multidrug-resistant strains. From the foregoing discussion, it is clear that it is possible to develop small molecule inhibitors of bacterial gyrase that can be utilised in a clinical context. k O RNA grase Repair of a single damaged DNA base occurs via: Non-homologous end joining. Lower: structure of the N-terminal sub-domain of GyrB (GyrB24) complexed with novobiocin (blue) showing the overlap with bound ATP (Lewis et al. Strong steric overlaps (red) with the CAP domains are observed. J Med Chem 5:10631065, Lewis RJ, Singh OMP, Smith CV, Skarynski T, Maxwell A, Wonacott AJ, Wigley DB (1996a) The nature of inhibition of DNA gyrase by the coumarins and the cyclothialidines revealed by X-ray crystallography. FEMS Microbiol Lett 279(1):4047, Sengupta S, Nagaraja V (2008b) YacG from Escherichia coli is a specific endogenous inhibitor of DNA gyrase. However, the fact that peptides derived from GyrI also inhibit gyrase suggests that it ought to be possible to generate small molecules that emulate its activity. Chagas Disease Chemotherapy: What Do We Know So Far? Fluoroquinolones have been the most successful antibacterial agents targeted to gyrase, but these compounds have been extensively explored both in terms of improving spectrum and potency, and overcoming bacterial resistance, and we may have reached the limits of what these compounds can provide. Hiasa H., Shea M. E., Richardson C. M. & Gwynn M. N. Koujima I., Hayashi H., Tomochika K., Okabe A. Clipboard, Search History, and several other advanced features are temporarily unavailable. Bethesda, MD 20894, Web Policies Zarkan Pharmacy. A mutation to Gly164 (to Val) also confers resistance and also a temperature-sensitive phenotype (Contreras and Maxwell 1992). The DNA is wrapped around GyrA presenting the T segment over the G segment (4). Proteins 1(3):230238, De Jonge N, Garcia-Pino A, Buts L, Haesaerts S, Charlier D, Zangger K, Wyns L, De Greve H, Loris R (2009) Rejuvenation of CcdB-poisoned gyrase by an intrinsically disordered protein domain. The details of this mechanism are still under investigation, but a model, generically known as the two-gate mechanism (Roca and Wang 1992, 1994), is strongly supported by biochemical and structural data. J Antibiot (Tokyo) 53(8):779787, Schoeffler AJ, Berger JM (2008) DNA topoisomerases: harnessing and constraining energy to govern chromosome topology. Targeting the gyrase of Plasmodium falciparum with topoisomerase poisons, Ciprofloxacin treatment of drug-resistant falciparum malaria, Ciprofloxacin does not achieve radical cure of. It is unique in catalyzing the negative supercoiling of DNA and is essential for efficient DNA replication, transcription, and recombination. DNA gyrase, also known as topoisomerase II or simply as gyrase, is an enzyme that relieves strain while double-stranded DNA is being unwound by helicase.This causes negative supercoiling of the DNA. We thank David Lawson for comments on the manuscript. It seems that in our race to combat drug-resistant bacterial pathogens, the exploitation of DNA gyrase as an antibacterial target provides diverse and realistic possibilities. 2009). The first-generation quinolones, nalidixic acid and oxolinic acid have relatively weak antimicrobial activity, but the synthesis of the fluoroquinolones and their improvement over several generations, e.g., norfloxacin and ciprofloxacin (second generation), levofloxacin (third gen.) and moxifloxacin and gemifloxacin (fourth gen.), has led to a range of potent antibacterial compounds that have enjoyed enormous clinical and commercial success (Emmerson and Jones 2003; King et al. Several cycles of (5) to (6a) transition may occur prior to CcdB binding. It is cleavage-complex stabilisation that has been found to be the most effective mode of action of inhibitors of gyrase and other topoisomerases (Anderson and Osheroff 2001; Drlica et al. 2010). J Antibiot (Tokyo) 31(5):398404, Martinez-Martinez L, Pascual A, Jacoby GA (1998) Quinolone resistance from a transferable plasmid. Biochemistry 45(1):110, Videnov G, Kaiser D, Brooks M, Jung G (1996) Synthesis of the DNA gyrase inhibitor microcin B17, a 43-peptie antibiotic with eight heterocycles in its backbone. Disclaimer, National Library of Medicine 2010; Schoeffler et al. In: Hooper DC, Rubinstein E (eds) Quinolone antimicrobial agents, 3rd edn. EMBO J 10:467476, Wang JC (2009) A journey in the world of DNA rings and beyond. J Bacteriol 173:642648, Hooper DC (2003) Mechanisms of quinolone resistance. The peptide is post-translationally modified to convert serine- and cysteine- residues into oxazole, thiazole, and oxazolethiazole fused rings (Yorgey et al. a.) J Bacteriol 176:30723075, San Millan JL, Hernandez-Chico C, Pereda P, Moreno F (1985) Cloning and mapping of the genetic determinants for microcin B17 production and immunity. 2) is an example of a cleavage-complex stabilising agent. 1993). CRC Crit Rev Biochem Mol Biol 26:335375, Richter S, Gatto B, Fabris D, Takao K, Kobayashi S, Palumbo M (2003) Clerocidin alkylates DNA through its epoxide function: evidence for a fine tuned mechanism of action. Future Med Chem 2(11):16191622, Wiener JJ, Gomez L, Venkatesan H, Santillan A Jr, Allison BD, Schwarz KL, Shinde S, Tang L, Hack MD, Morrow BJ, Motley ST, Goldschmidt RM, Shaw KJ, Jones TK, Grice CA (2007) Tetrahydroindazole inhibitors of bacterial type II topoisomerases. The major component of this mixture, albicidin, is bactericidal to E. coli and inhibits DNA synthesis (Birch and Patil 1985). 2002). Simocyclinones also contain the aminocoumarin moiety but in addition contain an angucyclinone polyketide group (Schimana et al. ParD possesses features reminiscent of the exit gate of GyrA (Dalton and Crosson 2010); this structure could therefore form a useful start point for modelling the ParEGyrA interaction. 2009; Flatman et al. Infections caused in cattle are usually asymptomatic but cause endocarditis and bacteremia. This residue makes key contacts with residues at the C-terminal end of CcdB. 56 terms. In the following sections, we will summarise what is currently known about such agents and speculate on the possibilities for the development of new therapeutic agents that target gyrase. Although much has been learned about the formation, repair, and biological consequences of DPCs in the nucleus, little is known regarding mitochondrial DPCs. 2009; Flatman et al. If the cell lacks DNA gyrase, the torsio View the full answer Transcribed image text: Question 41 1 pts How would the replication be affected if there were no DNA gyrase (also known as topoisomerase) present in the cell? J Antibiot 46:526530, Miki T, Chang Z-T, Horiuchi T (1984) Control of cell division by sex factor F in Escherichia coli II. 2010; Schimana et al. Residues Arg462 of both monomers of GyrA59 are highlighted. DNA gyrase is a tetrameric A2B2 protein. Copyright @ 2022 | PubGenius Inc. | Suite # 217 691 S Milpitas Blvd Milpitas CA 95035, USA. Appl Microbiol Biotechnol 92, 479497 (2011). For example, mutations at Asp73 (to Asn) and Asn46 (to Asp and Leu) in E. coli GyrB have been made (Kampranis et al. Although gyrase is the target for quinolones in Gram-negative bacteria, topo IV can be the preferred target in some Gram-positive organisms (Hooper 2003), this being dependent on the particular organism and the quinolone (Ferrero et al. It was further shown that they inhibit the gyrase ATPase reaction by competing with ATP for binding to GyrB (Mizuuchi et al. Clerocidin differs from other topoisomerase poisons in that it creates a break at the guanine immediately preceding the topoisomerase DNA-cleavage site. 4 Hydrolysis of one ATP allows GyrB to rotate, the GyrA opening to widen and the transport of the T segment through the cleaved G segment. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. J Bacteriol 178(15):45904596, Sadiq AA, Patel MR, Jacobson BA, Escobedo M, Ellis K, Oppegard LM, Hiasa H, Kratzke RA (2009) Anti-proliferative effects of simocyclinone D8 (SD8), a novel catalytic inhibitor of topoisomerase II. Jan 2008 - Aug 20091 year 8 months. Antimicrob Agents Chemother 40(4):10501052, Loris R, Dao-Thi M-H, Bahassi EM, Van Melderen LV, Poortmans F, Liddington RC, Couturier M, Wyns L (1999) Crystal structure of CcdB, a topoisomerase poison from E. coli. 1986). 2008). 2000), where its target appears to be human topoisomerase II (Flatman et al. Topoisomerase is also known as DNA gyrase in E. coli. 2003). 6a; Smith and Maxwell 2006). M. tuberculosis DNA gyrase is thus a validated target for anti-tubercular drug discovery. Extraction of DNA was performed as described above. Studies on the ParE2 toxin from Vibrio cholerae have shown that its mode of inhibition of gyrase is quite distinct in that it requires ATP and inhibits supercoiling but not relaxation (Yuan et al. Infect Disord Drug Targets 7(1):39, Vetting MW, Hegde SS, Fajardo JE, Fiser A, Roderick SL, Takiff HE, Blanchard JS (2006) Pentapeptide repeat proteins. it is also known as Topoisomerase. 1). Biochemistry 38:1350213511, Wohlkonig A, Chan PF, Fosberry AP, Homes P, Huang J, Kranz M, Leydon VR, Miles TJ, Pearson ND, Perera RL, Shillings AJ, Gwynn MN, Bax BD (2010) Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance. 1993). This evidence, added to the fact that the only known MccB17-resistant mutation is at amino acid 751 of GyrB (W751R; Vizn et al. The mechanism of gyrase action has been well studied and is known in some detail: GyrA contains the catalytic domain that cleaves one segment of double-stranded DNA through which a second strand is passed. Structure 15(3):329339, Cove ME, Tingey AP, Maxwell A (1997) DNA gyrase can cleave short DNA fragments in the presence of quinolone drugs. The bacteriostatic effects are largely a consequence of replication-fork arrest by quinolonegyrase (or quinolonetopo IV) complexes on DNA. Oxford University Press, Oxford, Bates AD, Maxwell A (2007) Energy coupling in type ii topoisomerases: why do they hydrolyze atp? 2008). DNA - Wikipedia. Alt S., Mitchenall L. A., Maxwell A. This generates a protein that retains catalytic activity, i.e., the ability to carry our DNA breakage-reunion and that emulates the structure of eukaryotic topo II (Berger et al. Aubry A., Fisher L. M., Jarlier V. & Cambau E. First functional characterization of a singly expressed bacterial type II topoisomerase: the enzyme from, Escherichia coli topoisomerase IV. Antimicrob Agents Chemother 50(4):11361142, Fu G, Wu J, Liu W, Zhu D, Hu Y, Deng J, Zhang XE, Bi L, Wang DC (2009) Crystal structure of DNA gyrase B domain sheds lights on the mechanism for T-segment navigation. 2005), presumably by preventing the binding of the enzyme to DNA, a mode of action reminiscent of simocyclinones. 2007; Bates and Maxwell 2007). Salih EYA, Julkunen-Tiitto R, Luukkanen O, Sipi M, Fahmi MKM, Fyhrquist PJ. 2008; Richter et al. 1978). 1999b). The unique ability of gyrase to introduce negative supercoils into DNA is what allows bacterial DNA to have free negative supercoils. 1992). Resistance to fluoroquinolones remains uncommon in clinical isolates of M. tuberculosis. Gibson EG, Blower TR, Cacho M, Bax B, Berger JM, Osheroff N. ACS Infect Dis. Clerocidin has been shown to promote in vitro cleavage by Streptococcus pneumoniae gyrase and topo IV (Pan et al. 2002). S.N. In Silico Pharmacol. DNA gyrase also known as topoisomerase II is an essential bacterial enzyme that catalyzes the ATP-dependent negative super coiling of double-stranded closed circular DNA. The two CcdB monomers are drawn in orange and red and the two GyrA14 monomers in two shades of blue. This causes negative supercoiling of the DNA. Trans. Specific sequences of these bases, known as genes, form codes that contain all of an organism's genetic . Biotechnol Adv 27(6):10061014, Herrero M, Moreno F (1986) Microcin B17 blocks DNA replication and induces the SOS system in Escherichia coli. 1993). The purified PCR product obtained from the mutants was sequenced as described above for wild-type Y. pestis gyrA. 1991; Yoshida et al. By the end of this section, you will be able to: Describe the structure of DNA Explain the Sanger method of DNA sequencing Discuss the similarities and differences between eukaryotic and prokaryotic DNA 20894, Web Policies Zarkan Pharmacy TR, Cacho M, Bax b, Berger,... Been shown to promote in vitro cleavage by Streptococcus pneumoniae gyrase and topo IV ( Pan al. 10:467476, Wang JC ( 2009 ) a journey in the world of DNA rings and.... Life ( MindTap Course List ) 14th Edition poisons in that it a... 691 S Milpitas Blvd Milpitas CA 95035, USA by competing with for... Mkm, Fyhrquist PJ preventing the binding of the enzyme to DNA, a mode of action reminiscent simocyclinones... 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Remains uncommon in clinical isolates of m. tuberculosis DNA gyrase is an example of cleavage-complex... List ) 14th Edition ATP-dependent negative super coiling of double-stranded closed circular DNA So... Infect Dis been shown to promote in vitro cleavage by Streptococcus pneumoniae gyrase and topo (..., Maxwell a Disease Chemotherapy: What Do We Know So Far human. | PubGenius Inc. | Suite # 217 691 S Milpitas Blvd Milpitas CA 95035 USA... Ciprofloxacin does not achieve radical cure of against multidrug-resistant strains poisons in that it creates a break at the immediately..., Maxwell a where its target appears to be human topoisomerase II ( Flatman et al 95035, USA Val! Strong steric overlaps ( red ) with the CAP domains are observed wild-type Y. pestis GyrA in cattle are asymptomatic... Both monomers of GyrA59 are highlighted 95035, USA Biotechnol 92, 479497 ( 2011 ) occur to... Disease Chemotherapy: What Do We Know So Far ( eds ) Quinolone agents! Moiety but in addition contain an angucyclinone polyketide group ( Schimana et.! Dna rings and beyond van Heijenoort J. Cytoplasmic steps of peptidoglycan synthesis in other topoisomerase poisons, treatment. Atpase reaction by competing with ATP for binding to GyrB ( Mizuuchi et al potency against multidrug-resistant.... G segment ( 4 ) poisons in that it creates a break at the guanine immediately preceding topoisomerase! To Gly164 ( to Val ) also confers resistance and also a temperature-sensitive phenotype ( Contreras Maxwell.
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