Cholesterol hemisuccinate: a selective inhibitor of family X DNA polymerases.
Biochem Biophys Res Commun
; 354(2): 619-25, 2007 Mar 09.
Article
em En
| MEDLINE
| ID: mdl-17241613
ABSTRACT
Cholesterol hemisuccinate (compound 5), which consists of succinic acid esterified to the beta-hydroxyl group of cholesterol, selectively and strongly inhibited the activities of mammalian DNA polymerases (pols) such as pol beta, pol lambda, and terminal deoxynucleotidyltransferase (TdT), which are family X pols, in vitro, and the IC50 values were 2.9, 6.3, and 6.5 microM, respectively. The compound moderately suppressed the activities of other mammalian pols such as pol A (i.e., pol gamma), pol B (i.e., pols alpha, delta, and epsilon), and pol Y (i.e., pols iota, eta, and kappa) with 50% inhibition observed at concentrations of 131, 89.2-98.0, and 120-125 microM, respectively. The compound had no influence on the activities of plant pols alpha and beta, prokaryotic pols and other DNA metabolic enzymes tested. Since other cholesterol-related compounds such as cholesterol, cholesteryl chloride, cholesteryl bromide, cholesteryl acetate, and cholesteryl-5alpha, 6alpha-epoxide (compounds 1-4 and 6, respectively) did not influence the activities of any enzymes tested, the hemisuccinate group of compound 5 could be important for inhibition of the pol X family. Surface plasmon resonance analysis demonstrated that compound 5 bound selectively to the C-terminal 31 kDa domain of pol beta and pol lambda containing a pol beta-like region. On the basis of these results, the inhibitory mechanism of compound 5 on the pol X family was discussed.
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Base de dados:
MEDLINE
Assunto principal:
Ésteres do Colesterol
/
Inibidores da Síntese de Ácido Nucleico
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article