3'-Azido-3'-deoxythymidine potently inhibits protein glycosylation. A novel mechanism for AZT cytotoxicity.
3'-Azido-3'-deoxythymidine (AZT) is one of the primary chemotherapeutic agents used in the treatment of human immunodeficiency virus (HIV) infection. Unfortunately, AZT therapy is accompanied by severe side effects. Using Golgi-enriched membrane fractions, we have determined that 3'-azido-3'-deoxythymidine monophosphate, the primary AZT metabolite in treated cells, potently inhibits protein glycosylation. This inhibition results from direct competition with several pyrimidine-sugars for transport into Golgi membranes. This potential mechanism of cytotoxicity does not involve 3'-azido-3'-deoxythymidine triphosphate, the AZT metabolite most likely responsible for its antiviral effects; thus, it may be possible to develop novel therapeutic strategies that prevent inhibition of glycosylation without affecting the anti-HIV properties of AZT.
Hall
E T
ET
Department of Chemistry and Biochemistry, University of Colorado, Boulder 80309-0215.
Yan
J P
JP
Melançon
P
P
Kuchta
R D
RD
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003569:Cytidine Monophosphate N-Acetylneuraminic Acid / Q000378:metabolism; D054306:Dideoxynucleotides; D006031:Glycosylation / Q000187:drug effects; D006056:Golgi Apparatus / Q000378:metabolism; D006678:HIV / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D007700:Kinetics; D008565:Membrane Proteins / Q000378:metabolism*; D009702:Nucleoside Diphosphate Sugars / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013942:Thymine Nucleotides / Q000633:toxicity; D014531:Uridine Diphosphate Galactose / Q000378:metabolism; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism; D015215:Zidovudine / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*
D054306:Dideoxynucleotides; D008565:Membrane Proteins; D009702:Nucleoside Diphosphate Sugars; D013942:Thymine Nucleotides; D014531:Uridine Diphosphate Galactose; C057287:3'-azido-3'-deoxythymidine 5'phosphate; D003569:Cytidine Monophosphate N-Acetylneuraminic Acid; D015215:Zidovudine; D014537:Uridine Diphosphate N-Acetylglucosamine; C052873:zidovudine triphosphate