DNA gyrase is a type of topoisomerase, a class of enzymes that manage the complex structure of deoxyribonucleic acid (DNA). These enzymes control the physical state of the DNA molecule, specifically its degree of winding or unwinding, known as supercoiling. Topoisomerases resolve tangles and twists that naturally arise in the long, double-helical strand of genetic material. DNA gyrase represents a specific subset within this larger family of topological enzymes.
The Necessity of DNA Topoisomerases
The double-helix structure of DNA creates logistical problems for the cell’s machinery during fundamental processes like replication and transcription. When the two strands of the helix are pulled apart, the section ahead of the separation point begins to twist tighter, similar to separating a coiled rope. This over-twisting is called positive supercoiling, which generates torsional stress on the molecule.
If this tension is not relieved, DNA-processing enzymes, such as DNA and RNA polymerases, would eventually halt, impeding cell function. DNA topoisomerases relieve this stress, ensuring the genetic material remains accessible. They function by temporarily cutting the DNA backbone, allowing the strands to unwind or untangle, and then resealing the break immediately afterward. This management of DNA topology is fundamental for the survival of all cell types.
The Two Major Classes of Topoisomerases
Topoisomerases are broadly categorized into two major classes based on their structure and mechanistic action on the DNA strand. Type I topoisomerases operate by creating a transient break in only one of the two DNA strands, essentially creating a swivel point. This single-strand break allows the intact strand to pass through the gap, which relaxes the supercoiling without requiring an external energy source like adenosine triphosphate (ATP). Each cycle of this enzyme changes the linking number of the DNA molecule by a single unit.
Type II topoisomerases transiently cut both strands of the DNA double helix. This double-strand break creates a gate that allows an entire segment of a different DNA helix to pass through the opening before the break is resealed. Because this process involves conformational changes and strand passage, Type II enzymes require the energy supplied by ATP hydrolysis to function. A single catalytic cycle of a Type II topoisomerase changes the DNA’s linking number by two units.
DNA Gyrase and Its Unique Function as a Type II Enzyme
DNA gyrase is classified as a Type IIA topoisomerase, found prominently in bacteria as a heterotetramer composed of two GyrA and two GyrB subunits. While most Type II topoisomerases primarily function to relax existing supercoils, DNA gyrase possesses a unique capability. It is the only known topoisomerase that can actively introduce negative supercoils into the DNA helix, a process driven by the hydrolysis of ATP.
Negative supercoiling involves twisting the DNA in the opposite direction of the natural helix, which helps compact the bacterial chromosome. This pre-stressing of the DNA is essential in prokaryotes because it facilitates the unwinding required at the start of replication and transcription. The enzyme works by wrapping the DNA segment around itself, cleaving both strands, and then passing a second segment through the break before rejoining the ends. This dual function of introducing negative supercoils and relaxing positive supercoils makes DNA gyrase indispensable for bacterial survival.
Targeting Topoisomerases in Medicine
The necessity of topoisomerases for managing DNA topology has made them targets for various therapeutic drugs. Since DNA gyrase is found in bacteria and is structurally distinct from human topoisomerases, its inhibition offers a way to selectively kill bacterial cells without harming the host. This principle is the basis for the fluoroquinolone class of antibiotics, which includes common drugs like ciprofloxacin.
These drugs act as “topoisomerase poisons” by binding to the gyrase-DNA complex after the enzyme has cut the DNA strands but before resealing them. This action traps the enzyme in a lethal state, preventing the re-ligation of the DNA and leading to fragmentation of the bacterial chromosome, causing cell death. Drugs targeting eukaryotic Type II topoisomerases are utilized in cancer chemotherapy to prevent the proliferation of rapidly dividing tumor cells. By interfering with the human topoisomerase II enzyme, these agents disrupt the DNA replication and segregation process in cancer cells.