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DNA gyrase, often referred to simply as gyrase, is an enzyme that relieves strain while double-strand DNA is being unwound by helicase. This causes negative supercoiling of the DNA. Bacterial DNA gyrase is the target of many antibiotics, including nalidixic acid, novobiocin, and ciprofloxacin. It supercoils (or relaxes positive supercoils) into DNA by looping the template so as to form a crossing, then cutting one of the double helices and passing the other through it before releasing the break, changing the linking number by two in each enzymatic step. This process occurs in prokaryotes (in particular, in bacteria), whose single circular DNA is cut by DNA gyrase and the two ends are then twisted around each other to form supercoils. Very recently, gyrase has been found in the apicoplast of the malarial parasite Plasmodium falciparum, a unicellular eukaryote.

The unique ability of gyrase to introduce negative supercoils into DNA is what allows bacterial DNA to have free negative supercoils. The ability of gyrase to relax positive supercoils comes into play during DNA replication. The right-handed nature of the DNA double helix causes positive supercoils to accumulate ahead of a translocating enzyme, in the case of DNA replication, a DNA polymerase. The ability of gyrase (and topoisomerase IV) to relax positive supercoils allows superhelical tension ahead of the polymerase to be released so that replication can continue.

Mechanochemical model of gyrase activity

A single molecule study^[1] has characterized gyrase activity as a function of DNA tension (applied force) and ATP, and proposed a mechanochemical model. Upon binding to DNA (the "Gyrase-DNA" state), there is a competition between DNA wrapping and dissociation, where increasing DNA tension increases the probability of dissociation. Upon wrapping and ATP hydrolysis, two negative supercoils are introduced into the template, providing opportunities for subsequent wrapping and supercoiling events.

Inhibition by antibiotics

Gyrase is present in prokaryotes and some eukaryotes, but the enzymes are not entirely similar in structure or sequence, and have different affinities for different molecules. It is not present in humans. This makes gyrase a good target for antibiotics. Two classes of antibiotics that inhibit gyrase are:

The aminocoumarins (including novobiocin). Aminocoumarins work by competitive inhibition of energy transduction of DNA gyrase by binding to the ATPase active site located on the GyrB subunit.
The quinolones (including nalidixic acid and ciprofloxacin). Quinolones bind to these enzymes and prevent them from decatenation replicating DNA. Quinolone-resistant bacteria frequently harbor mutated topoisomerases that resist quinolone binding.

DNA gyrase has two subunits, which in turn have two subunits each, i.e. 2A and 2B SUBUNITS. The A subunit carries out nicking of DNA, B subunit introduces negative supercoils, and then A subunit reseals the strands. Fluorquinolones bind to the A subunit and interfere with its strand cutting and resealing function.

References

^ Gore J, Bryant Z, Stone MD, Nollmann M, Cozzarelli NR, Bustamante C, "Mechanochemical Analysis of DNA Gyrase Using Rotor Bead Tracking", Nature 2006 Jan 5 (Vol. 439): 100-104.

Literature

Molecular Cloning of Apicoplast-Targeted Plasmodium falciparum DNA Gyrase Genes: Unique Intrinsic ATPase Activity and ATP-Independent Dimerization of PfGyrB Subunit.(2007) EUKARYOTIC CELL, Mar. 2007, p. 398–412

A unique 45 amino acid region in the Toprim domain of Plasmodium falciparum GyraseB is essential for its activity.(2009)Eukaryotic Cell,11(8), 1759-69.

UpToDate Contents

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1. フルオロキノロン類 fluoroquinolones
2. 薬剤耐性結核の疫学および分子メカニズム epidemiology and molecular mechanisms of drug resistant tuberculosis
3. フルオロキノロン類、ドキシサイクリン、およびトリメトプリムスルファメトキサゾールに対する肺炎レンサ球菌の耐性 resistance of streptococcus pneumoniae to the fluoroquinolones doxycycline and trimethoprim sulfamethoxazole
4. 腸炎エルシニアおよび偽結核菌感染症の治療および予防 treatment and prevention of yersinia enterocolitica and yersinia pseudotuberculosis infection
5. アエロモナス感染症 aeromonas infections

English Journal

Epidemiology, Clinical Presentation, Laboratory Diagnosis, Antimicrobial Resistance, and Antimicrobial Management of Invasive Salmonella Infections.

Crump JA1, Sjölund-Karlsson M2, Gordon MA3, Parry CM4.
Clinical microbiology reviews.Clin Microbiol Rev.2015 Oct;28(4):901-37. doi: 10.1128/CMR.00002-15.
Salmonella enterica infections are common causes of bloodstream infection in low-resource areas, where they may be difficult to distinguish from other febrile illnesses and may be associated with a high case fatality ratio. Microbiologic culture of blood or bone marrow remains the mainstay of labora
PMID 26180063

Effect of Qnr on Plasmid Gyrase Toxins CcdB and ParE.

Kwak YG1, Jacoby GA2, Hooper DC3.
Antimicrobial agents and chemotherapy.Antimicrob Agents Chemother.2015 Aug;59(8):5078-9. doi: 10.1128/AAC.00524-15. Epub 2015 Jun 8.
Plasmid toxins CcdB and ParE are part of addiction systems promoting plasmid maintenance. Both target host DNA gyrase, as do quinolones and plasmid-determined Qnr proteins that protect gyrase from quinolone inhibition. We cloned qnrB4, qnrS1, ccdB, parE, and the antitoxin-encoding genes ccdA and par
PMID 26055367

Effects of a Mutation in the gyrA Gene on the Virulence of Uropathogenic Escherichia coli.

Sánchez-Céspedes J1, Sáez-López E2, Frimodt-Møller N3, Vila J4, Soto SM5.
Antimicrobial agents and chemotherapy.Antimicrob Agents Chemother.2015 Aug;59(8):4662-8. doi: 10.1128/AAC.00665-15. Epub 2015 May 26.
Fluoroquinolones are among the drugs most extensively used for the treatment of bacterial infections in human and veterinary medicine. Resistance to quinolones can be chromosome or plasmid mediated. The chromosomal mechanism of resistance is associated with mutations in the DNA gyrase- and topoisome
PMID 26014933