Nucleoside diphosphate kinase and the activation of antiviral phosphonate analogs of nucleotides: binding mode and phosphorylation of tenofovir derivatives.

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Koch K, Chen Y, Feng JY, Borroto-Esoda K, Deville-Bonne D, Gallois-Montbrun S, Janin J, Morera S

Nucleoside diphosphate kinase and the activation of antiviral phosphonate analogs of nucleotides: binding mode and phosphorylation of tenofovir derivatives.

Nucleosides Nucleotides Nucleic Acids. 2009 Aug;28(8):776-92. doi: 10.1080/15257770903155899.

PubMed ID

20183617 [ View in PubMed

]

Abstract

Tenofovir is an acyclic phosphonate analog of deoxyadenylate used in AIDS and hepatitis B therapy. We find that tenofovir diphosphate, its active form, can be produced by human nucleoside diphosphate kinase (NDPK), but with low efficiency, and that creatine kinase is significantly more active. The 1.65 A x-ray structure of NDPK in complex with tenofovir mono- and diphosphate shows that the analogs bind at the same site as natural nucleotides, but in a different conformation, and make only a subset of the Van der Waals and polar interactions made by natural substrates, consistent with their comparatively low affinity for the enzyme.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Tenofovir disoproxil	Creatine Kinases (Protein Group)	Protein group	Humans	Unknown	Substrate Inducer	Details
Tenofovir disoproxil	Nucleoside diphosphokinase (Protein Group)	Protein group	Humans	Unknown	Substrate	Details