Relaxed enantioselectivity of human mitochondrial thymidine kinase and chemotherapeutic uses of L-nucleoside analogues. (Articolo in rivista)

Type

• Prodotto della ricerca (Classe)
• Articolo in rivista (Classe)

Label

• Relaxed enantioselectivity of human mitochondrial thymidine kinase and chemotherapeutic uses of L-nucleoside analogues. (Articolo in rivista) (literal)

Anno

• 1997-01-01T00:00:00+01:00 (literal)

Alternative label

• Verri A, Priori G, Spadari S, Tondelli L, Focher F. (1997)
  Relaxed enantioselectivity of human mitochondrial thymidine kinase and chemotherapeutic uses of L-nucleoside analogues.
  in Biochemical journal (Lond., 1984)
  (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori

• Verri A, Priori G, Spadari S, Tondelli L, Focher F. (literal)

Pagina inizio

• 317 (literal)

Pagina fine

• 320 (literal)

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• 328 (literal)

Rivista

• Biochemical journal (Rivista)

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• Istituto di Genetica Biochimica ed Evoluzionistica, Consiglio Nazionale delle Ricerche, Pavia, Italy. (literal)

Titolo

• Relaxed enantioselectivity of human mitochondrial thymidine kinase and chemotherapeutic uses of L-nucleoside analogues. (literal)

Abstract

• Our discovery that Herpes virus thymidine kinase (TK) and cellular deoxycytidine kinase lack enantioselectivity, being able to phosphorylate both D- and L-enantiomers of the substrate, suggested the use of unnatural L-nucleoside analogues as antiviral drugs (Herpes, hepatitis and immunodeficiency viruses). Several L-nucleoside analogues have displayed a short-term cytotoxicity much lower than their corresponding D-counterpart. Since the delayed cytotoxicity of a drug often depends on its effects on mitochondrial metabolism, we have investigated the degree of enantioselectivity of human mitochondrial thymidine kinase (mt-TK). We demonstrate that mt-TK does not show an absolute enantioselectivity, being able to recognize, although with lower efficiency, the L-enantiomers of thymidine, deoxycytidine and modified deoxyuridines, such as (E)-5-(2-bromovinyl)-2'-deoxyuridine and 5-iodo-2'-deoxyuridine. Interestingly, the reported negative co-operativity of mt-TK phosphorylating beta-D-2'-deoxythymidine (D-Thd), disappears when the deoxyribose moiety has the inverted configuration, resulting in the preferential phosphorylation of d-Thd even in the presence of high concentrations of the L-enantiomer. This, coupled with the higher Km for beta-L-2'-deoxythymidine (L-Thd), makes mt-TK resistant to high concentrations of L-Thd and L-Thd analogues, minimizing the mitochondria-dependent delayed cytotoxicity that might be caused by the administration of L-nucleoside analogues as antivirals. (literal)

Prodotto di

• Institute of molecular genetics (IGM) (Istituto)

Autore CNR

• LUISA TONDELLI (Persona)
• SILVIO SPADARI (Unità di personale interno)
• FEDERICO FOCHER (Unità di personale interno)

Incoming links:

Prodotto

• Institute of molecular genetics (IGM) (Istituto)

Autore CNR di

• LUISA TONDELLI (Persona)
• FEDERICO FOCHER (Unità di personale interno)
• SILVIO SPADARI (Unità di personale interno)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#rivistaDi

• Biochemical journal (Rivista)