Abstract:
:Antiviral alpha-P-borano substituted NTPs are promising chain terminators targeting HIV reverse transcriptase (RT). Activation of antiviral nucleoside diphosphates (NDPs) to NTPs may be carried out by pyruvate kinase (PK) and creatine kinase (CK). Herein, are presented the effects of nucleobase, ribose, and alpha-phosphate substitutions on substrate specificities of CK and PK. Both enzymes showed two binding modes and negative cooperativity with respect to substrate binding. The stereospecificity and inhibition of ADP phosphorylation by alpha-P-borano substituted NDP (NDPalphaB) stereoisomers were also investigated. The Sp-ADPalphaB isomer was a 70-fold better substrate for CK than the Rp isomer, whereas PK preferred the Rp isomer of NDPalphaBs. For CK, the Sp-ADPalphaB isomer was a competitive inhibitor; for PK, the Rp-ADPalphaB isomer was a poor competitive inhibitor and the Sp-ADPalphaB isomer was a poor non-competitive inhibitor. Taken together, these data suggest that, although the Rp-NDPalphaB isomer would be minimally phosphorylated by CK or PK, it should not inhibit either enzyme.
journal_name
Bioorg Chemjournal_title
Bioorganic chemistryauthors
Wennefors CK,Dobrikov MI,Xu Z,Li P,Shaw BRdoi
10.1016/j.bioorg.2008.03.001subject
Has Abstractpub_date
2008-08-01 00:00:00pages
169-77issue
4eissn
0045-2068issn
1090-2120pii
S0045-2068(08)00017-5journal_volume
36pub_type
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