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-beta-nucleosides.
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 alpha, terminal transferase and HIV-1 reverse transcriptase. The ability of these enzymes to utilize unnatural L-beta-nucleosides or -nucleotides as substrate may be exploited from chemotherapeutic point of view.
Spadari
S
S
Istituto di Genetica Biochimica ed Evoluzionistica CNR, Pavia, Italy.
Maga
G
G
Verri
A
A
Bendiscioli
A
A
Tondelli
L
L
Capobianco
M
M
Colonna
F
F
Garbesi
A
A
Focher
F
F
D000998:Antiviral Agents / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004259:DNA-Directed DNA Polymerase; D003854:Deoxyribonucleotides / Q000096:biosynthesis; D004798:Enzymes / Q000378:metabolism*; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D009703:Nucleoside-Phosphate Kinase / Q000737:chemistry / Q000378:metabolism; D009705:Nucleosides / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000737:chemistry; D013937:Thymidine Kinase / Q000737:chemistry / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*
D000998:Antiviral Agents; D003854:Deoxyribonucleotides; D004798:Enzymes; D009705:Nucleosides; D014764:Viral Proteins; D004247:DNA; D013937:Thymidine Kinase; D009703:Nucleoside-Phosphate Kinase; D004259:DNA-Directed DNA Polymerase; D013936:Thymidine