PMID: 8967971Dec 1, 1996Paper

Identification of enzymes catalyzing two-step phosphorylation of cidofovir and the effect of cytomegalovirus infection on their activities in host cells

Molecular Pharmacology
T Cihlar, M S Chen

Abstract

Cidofovir [CDV; (S)-1-(3-hydroxy-2-phosphonomethoxyethyl)cytosine] is an acyclic nucleotide analog with potent and selective in vitro and in vivo activities against a broad spectrum of herpesviruses and other DNA viruses. We studied the mechanism of enzymatic synthesis of CDV diphosphate, the putative antiviral metabolite of CDV. The phosphorylation is two-step process catalyzed by several enzymes. An enzymatic activity phosphorylating CDV to its monophosphate derivative was purified from human liver and identified as pyrimidine nucleoside monophosphate kinase (EC 2.7.4.14.). CDV (Km = 2.10 +/- 0.18 mM and Vmax = 1.10 +/- 0.05 micromol/min/mg) was found to be a substantially weaker substrate for purified enzyme than CMP, UMP, or dCMP. Pyrimidine nucleoside monophosphate kinase was used for preparative enzymatic synthesis of CDV monophosphate. Pyruvate kinase (EC 2.7.1.40), creatine kinase (EC 2.7.3.2), and nucleoside diphosphate kinase (EC 2.7.4.6) were found to catalyze CDV diphosphate synthesis from CDV monophosphate, whereas phosphoglycerate kinase (EC 2.7.2.3) and succinyl-CoA synthetase (EC 6.2.1.4) did not. Based on Vmax/Km (phosphorylation efficiency) values determined with enzymes purified from human sources, the most e...Continue Reading

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