Structural requirements of sphingosine molecules for inhibition of DNA primase: Biochemical and computational analyses

Y. Ito, K. Tamiya-Koizumi, Y. Koide, M. Nakagawa, T. Kawade, A. Nishida, T. Murate, M. Takemura, M. Suzuki, S. Yoshida

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Using 28 chemically well-defined compounds containing D-erythro-sphingosine and its analogues, we analyzed structure-activity relationships for DNA primase inhibition. Biochemical studies demonstrated a positively charged amino group at C2 and a long aliphatic chain to be absolutely required for inhibition. Whereas C2-amino group is intact, sphingosine 1-phosphate was totally inactive. This result could be due to cancellation of positive charge of the amino group by the interaction with negatively charged C1-phosphate, since simulations with the software INSIGHT II showed these two groups to be close enough to interact. The hydroxyl group at C3 and trans-double bond at C4-C5 were also found to be important for the inhibition. Dehydroxylation of C3, as well as saturation or cis-conversion of the trans-double bond led to decrease of inhibitory activity. Despite saturation of the double bond, introduction of a hydroxyl group into C4 of dihydrosphingosine resulted in restoration of inhibition. Conversion of the double bond into a triple bond did not abolish but rather enhanced the inhibitory activity. Among sphingosine stereoisomers, the naturally occurring D-erythro-sphingosine proved to be the strongest inhibitor. To ascertain the contribution of the total conformation to the inhibition, especially of the long aliphatic chain, we constructed a 3D-quantitative structure-activity relationship model using the computer program Catalyst/HipHop on the basis of information described above. Analysis of the hypothesis model for active compounds revealed that the orientation of aliphatic chain, represented by the dihedral angle of C2-3-4-5, correlated well with the inhibition. Modifications such as deletion of the hydroxyl group at C3 or saturation of the C4-C5 double bond caused shifts in the dihedral angle of C2-3-4-5, with concomitant decrease in inhibitory activity.

Original languageEnglish
Pages (from-to)11571-11577
Number of pages7
JournalBiochemistry
Volume40
Issue number38
DOIs
Publication statusPublished - 25-09-2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry

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    Ito, Y., Tamiya-Koizumi, K., Koide, Y., Nakagawa, M., Kawade, T., Nishida, A., Murate, T., Takemura, M., Suzuki, M., & Yoshida, S. (2001). Structural requirements of sphingosine molecules for inhibition of DNA primase: Biochemical and computational analyses. Biochemistry, 40(38), 11571-11577. https://doi.org/10.1021/bi010722i