Effects of magnesium and related divalent metal ions in topoisomerase structure and function.
The catalytic steps through which DNA topoisomerases produce their biological effects and the interference of drug molecules with the enzyme-DNA cleavage complex have been thoroughly investigated both from the biophysical and the biochemical point of view. This provides the basic structural insight on how this family of essential enzymes works in living systems and how their functions can be impaired by natural and synthetic compounds. Besides other factors, the physiological environment is known to affect substantially the biological properties of topoisomerases, a key role being played by metal ion cofactors, especially divalent ions (Mg(2+)), that are crucial to bestow and modulate catalytic activity by exploiting distinctive chemical features such as ionic size, hardness and characteristics of the coordination sphere including coordination number and geometry. Indeed, metal ions mediate fundamental aspects of the topoisomerase-driven transphosphorylation process by affecting the kinetics of the forward and the reverse steps and by modifying the enzyme conformation and flexibility. Of particular interest in type IA and type II enzymes are ionic interactions involving the Toprim fold, a protein domain conserved through evolution that contains a number of acidic residues essential for catalysis. A general two-metal ion mechanism is widely accepted to account for the biophysical and biochemical data thus far available.
Sissi
Claudia
C
Department of Pharmaceutical Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy.
Palumbo
Manlio
M
D002413:Cations, Divalent / Q000737:chemistry; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000737:chemistry* / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000378:metabolism; D008274:Magnesium / Q000737:chemistry*; D017434:Protein Structure, Tertiary
D002413:Cations, Divalent; D004247:DNA; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D008274:Magnesium