Enzyme evolution and cancer: hypothesis why natural carcinogens are more potent than synthetic ones.
A great deal of evidence shows that carcinogen induced mutations in human cancers point towards natural rather than man-made agents. Here, we propose a model based on the premise that the evolutionary pressure of nature renders natural carcinogens more potent than artificial ones, present in equal concentration, by suitably modifying kinetic parameters of carcinogen metabolizing enzymes. Enzymes are evolved to bind the transition state of substrates more strongly than substrates themselves, thus obtaining more elevate values of the specificity constant kcat/Km (Ksp). Natural selection optimizing the catalytic power at the proper substrate concentration by suitable raising the Km values, reduce the Gibbs standard activation energy (G(0#)), accelerating the conversion of natural precarcinogens to potent carcinogens. Conversely, "man-made" carcinogens, since the last century in the biosphere, are converted to active metabolites at a lower rate than natural chemicals and the slower rate of activation would allow protective enzymes and DNA repair machinery more time to clean up the damage.
Paolini
M
M
Department of Pharmacology, University of Bologna, Italy. paolini@biocfarm.unibo.it
Biagi
G L
GL
Bauer
C
C
Cantelli-Forti
G
G
D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004798:Enzymes / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D009369:Neoplasms / Q000201:enzymology*; D013379:Substrate Specificity; D013816:Thermodynamics
D002273:Carcinogens; D004798:Enzymes