2',3'-Dideoxynucleoside phosphorylation by deoxycytidine kinase from normal human thymus extracts: activation of potential drugs for AIDS therapy.
As a first step toward improving dideoxynucleoside inhibition of human immunodeficiency virus replication in human lymphocytes, we examined the kinetics of 5'-phosphorylation of a series of 2',3'-dideoxynucleosides, using deoxycytidine kinase purified from human thymus extracts. Nucleosides with the 2'-deoxyribose moiety were activated 30 times faster than were 2',3'-dideoxynucleosides. The adenosine deaminase inhibitor, 2'-deoxycoformycin, showed an unexpected ability to inhibit purine and pyrimidine dideoxynucleoside phosphorylation; such inhibition was not competitive and was not observed when 2'-deoxycytidine was the substrate. 2'-Deoxycytidine, the natural substrate, inhibited dideoxynucleoside phosphorylation in a manner similar to that observed with 2'-deoxycoformycin. Thus, dideoxynucleosides are activated by deoxycytidine kinase through a different catalytic interaction than occurs in 5'-activation of 3'-hydroxynucleosides by this enzyme.
Johnson
M A
MA
Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Johns
D G
DG
Fridland
A
A
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology; D003839:Deoxyadenosines / Q000031:analogs & derivatives* / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism; D003842:Deoxycytidine Kinase / Q000378:metabolism*; D016048:Dideoxyadenosine; D006801:Humans; D007700:Kinetics; D015649:Pentostatin; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013949:Thymus Extracts / Q000378:metabolism*; D013950:Thymus Gland / Q000201:enzymology; D016047:Zalcitabine
D003839:Deoxyadenosines; D013949:Thymus Extracts; D003841:Deoxycytidine; D003070:Coformycin; D015649:Pentostatin; D016048:Dideoxyadenosine; D016047:Zalcitabine; D010770:Phosphotransferases; D003842:Deoxycytidine Kinase