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, Motoshi 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

Fingerprint

DNA Primase
Sphingosine
Hydroxyl Radical
Dihedral angle
Molecules
Software
Stereoisomerism
Quantitative Structure-Activity Relationship
Structure-Activity Relationship
Restoration
Conformations
Computer program listings
Phosphates
Catalysts
erythro-(2R,3S)-sphingosine

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Ito, Y., Tamiya-Koizumi, K., Koide, Y., Nakagawa, M., Kawade, T., Nishida, A., ... 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
Ito, Y. ; Tamiya-Koizumi, K. ; Koide, Y. ; Nakagawa, M. ; Kawade, T. ; Nishida, A. ; Murate, T. ; Takemura, M. ; Suzuki, Motoshi ; Yoshida, S. / Structural requirements of sphingosine molecules for inhibition of DNA primase : Biochemical and computational analyses. In: Biochemistry. 2001 ; Vol. 40, No. 38. pp. 11571-11577.
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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.",
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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, vol. 40, no. 38, pp. 11571-11577. https://doi.org/10.1021/bi010722i

Structural requirements of sphingosine molecules for inhibition of DNA primase : Biochemical and computational analyses. / Ito, Y.; Tamiya-Koizumi, K.; Koide, Y.; Nakagawa, M.; Kawade, T.; Nishida, A.; Murate, T.; Takemura, M.; Suzuki, Motoshi; Yoshida, S.

In: Biochemistry, Vol. 40, No. 38, 25.09.2001, p. 11571-11577.

Research output: Contribution to journalArticle

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T1 - Structural requirements of sphingosine molecules for inhibition of DNA primase

T2 - Biochemical and computational analyses

AU - Ito, Y.

AU - Tamiya-Koizumi, K.

AU - Koide, Y.

AU - Nakagawa, M.

AU - Kawade, T.

AU - Nishida, A.

AU - Murate, T.

AU - Takemura, M.

AU - Suzuki, Motoshi

AU - Yoshida, S.

PY - 2001/9/25

Y1 - 2001/9/25

N2 - 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.

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Ito Y, Tamiya-Koizumi K, Koide Y, Nakagawa M, Kawade T, Nishida A et al. Structural requirements of sphingosine molecules for inhibition of DNA primase: Biochemical and computational analyses. Biochemistry. 2001 Sep 25;40(38):11571-11577. https://doi.org/10.1021/bi010722i