1p62: Difference between revisions

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==Overview==

Human deoxycytidine kinase (dCK) phosphorylates the natural, deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and, deoxyadenosine (dA) and is an essential enzyme for the phosphorylation of, numerous nucleoside analog prodrugs routinely used in cancer and antiviral, chemotherapy. For many of these compounds, the phosphorylation step, catalyzed by dCK is the rate-limiting step in their overall activation, pathway. To determine the factors that limit the phosphorylation, efficiency of the prodrug, we solved the crystal structure of dCK to a, resolution of 1.6 A in complex with its physiological substrate, deoxycytidine and with the prodrugs AraC and gemcitabine. The structures, reveal the determinants of dCK substrate specificity. Especially relevant, to new prodrug development is the interaction between Arg128 and the, hydrogen-bond acceptor at the sugar 2'-arabinosyl position of AraC and, gemcitabine. On the basis of the structures, we designed a catalytically, superior dCK variant that could be used in suicide gene-therapy, applications.

Human deoxycytidine kinase (dCK) phosphorylates the natural deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA) and is an essential enzyme for the phosphorylation of numerous nucleoside analog prodrugs routinely used in cancer and antiviral chemotherapy. For many of these compounds, the phosphorylation step catalyzed by dCK is the rate-limiting step in their overall activation pathway. To determine the factors that limit the phosphorylation efficiency of the prodrug, we solved the crystal structure of dCK to a resolution of 1.6 A in complex with its physiological substrate deoxycytidine and with the prodrugs AraC and gemcitabine. The structures reveal the determinants of dCK substrate specificity. Especially relevant to new prodrug development is the interaction between Arg128 and the hydrogen-bond acceptor at the sugar 2'-arabinosyl position of AraC and gemcitabine. On the basis of the structures, we designed a catalytically superior dCK variant that could be used in suicide gene-therapy applications.

==About this Structure==

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[[Category: p-loop]]

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@@ Line 4: / Line 4: @@
 ==Overview==
-Human deoxycytidine kinase (dCK) phosphorylates the natural, deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and, deoxyadenosine (dA) and is an essential enzyme for the phosphorylation of, numerous nucleoside analog prodrugs routinely used in cancer and antiviral, chemotherapy. For many of these compounds, the phosphorylation step, catalyzed by dCK is the rate-limiting step in their overall activation, pathway. To determine the factors that limit the phosphorylation, efficiency of the prodrug, we solved the crystal structure of dCK to a, resolution of 1.6 A in complex with its physiological substrate, deoxycytidine and with the prodrugs AraC and gemcitabine. The structures, reveal the determinants of dCK substrate specificity. Especially relevant, to new prodrug development is the interaction between Arg128 and the, hydrogen-bond acceptor at the sugar 2'-arabinosyl position of AraC and, gemcitabine. On the basis of the structures, we designed a catalytically, superior dCK variant that could be used in suicide gene-therapy, applications.
+Human deoxycytidine kinase (dCK) phosphorylates the natural deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA) and is an essential enzyme for the phosphorylation of numerous nucleoside analog prodrugs routinely used in cancer and antiviral chemotherapy. For many of these compounds, the phosphorylation step catalyzed by dCK is the rate-limiting step in their overall activation pathway. To determine the factors that limit the phosphorylation efficiency of the prodrug, we solved the crystal structure of dCK to a resolution of 1.6 A in complex with its physiological substrate deoxycytidine and with the prodrugs AraC and gemcitabine. The structures reveal the determinants of dCK substrate specificity. Especially relevant to new prodrug development is the interaction between Arg128 and the hydrogen-bond acceptor at the sugar 2'-arabinosyl position of AraC and gemcitabine. On the basis of the structures, we designed a catalytically superior dCK variant that could be used in suicide gene-therapy applications.
 ==About this Structure==
@@ Line 26: / Line 26: @@
 [[Category: p-loop]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Feb 15 16:39:05 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:25:32 2008''