Lack of stereospecificity of some cellular and viral enzymes involved in the synthesis of deoxyribonucleotides and DNA: Molecular basis for the antiviral activity of unnatural l-β-nucleosides

Abstract Among enzymes involved in the synthesis of nucleotides and DNA, some exceptions have recently been found to the universal rule that enzymes act only on one enantiomer of a chiral substrate and that only one of the enantiomeric forms of chiral molecules may bind effectively at the catalytic site, displaying biological activity. The exceptions include: herpes virus thymidine kinases, cellular deoxycytidine kinase and deoxynucloside mono- and diphosphate kinases, cellular and viral DNA polymerases, such as DNA polymerase α, terminal transferase and HIV-I reverse transcriptase. The ability of these enzymes to utilize unnatural l -β-nucleosides or -nucleotides as substrate may be exploited from the chemotherapeutic point of view.