TAILIEUCHUNG - Báo cáo khoa học: Reaction of human UMP-CMP kinase with natural and analog substrates

UMP-CMP kinase catalyses an important step in the phosphorylationofUTP, CTPanddCTP. It is also involved in the necessary phosphorylation by cellular kinases of nucleoside analogs used in antiviral therapies. The reactivity of human UMP-CMP kinase towards natural substrates and nucleotide analogs was reexamined. The expression of the recombinant enzyme and conditions for stability of the enzyme were improved. Substrate inhibition was observed for UMP and CMP at concentrations higher than mM, but not for dCMP. The antiviral analogL-3TCMP was found to be an efficient substrate phosphorylated into L-3TCDP by human UMP-CMP kinase. . | Eur. J. Biochem. 270 1784-1790 2003 FEBS 2003 doi Reaction of human UMP-CMP kinase with natural and analog substrates Claudia Pasti1 t Sarah Gallois-Montbrun1 t Helene Munier-Lehmann2 Michel Veron1 Anne-Marie Gilles2 and Dominique Deville-Bonne1 1 Unite de Regulation Enzymatique des Activates Cellulaires and 2Laboratoire de Chimie Structurale des Macromolecules CNRS URA 2185 Institut Pasteur Paris France UMP-CMP kinase catalyses an important step in the phosphorylation of UTP CTP and dCTP. It is also involved in the necessary phosphorylation by cellular kinases of nucleoside analogs used in antiviral therapies. The reactivity of human UMP-CMP kinase towards natural substrates and nucleotide analogs was reexamined. The expression of the recombinant enzyme and conditions for stability of the enzyme were improved. Substrate inhibition was observed for UMP and CMP at concentrations higher than mM but not for dCMP. The antiviral analog L-3TCMP was found to be an efficient substrate phosphorylated into L-3TCDP by human UMP-CMP kinase. However in the reverse reaction the enzyme did not catalyse the addition of the third phosphate to L-3TCDP which was rather an inhibitor. By molecular modelling L-3TCMP was built in the active site of the enzyme from Dictyostelium. Human UMP-CMP kinase has a relaxed enantiospecificity for the nucleoside monophosphate acceptor site but it is restricted to D-nucleotides at the donor site. Keywords UMP-CMP kinase antiviral analog 3TC AraC phosphorylation. Nucleoside analogs constitute a familly of important antiviral and anticancer drugs. Analogs of thymidine like AZT 2 3 -deoxy-3 azido thymidine d4T 2 3 -dideoxy-2 3 -didehydro-thymidine have been used to treat HIV infection for a number of years as well as analogs with an L-conformation in the sugar like L-3TC. All of these analogs are delivered as nucleosides to the patients and need to be phosphorylated within cells in order to be active on their viral .

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