Features of the spermidine-binding site of deoxyhypusine synthase as derived from inhibition studies. Effective inhibition by bis- and mono- guanylated diamines and polyamines

J. Jakus, E. C. Wolff, Hee Park Myung Hee Park, J. E. Folk

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

Several types of basic compounds structurally related to spermidine, one of the substrates for deoxyhypusine synthase, were tested as inhibitors of this enzyme. The results indicate that inhibitory compounds associate with the enzyme at the site of spermidine binding and must possess two charged primary amino or guanidino groups, or one of each. The efficiency of inhibition is related to the maximum possible distance between the primary amino groups and is adversely affected by substitutions on the secondary amino group or in the carbon chains of polyamines. The mono-guanyl derivatives are much more effective inhibitors than the parent amines or their bis-guanylated counterparts, N'-guanyl-1,7-diaminoheptane being the most effective compound with a K(i) value of about 10 nM. Based on these observations we have proposed a model for the spermidine-binding site of deoxyhypusine synthase. Studies with Chinese hamster ovary cells reveal a direct correlation between prevention of hypusine formation by several guanyldiamines and their in vitro inhibition of deoxyhypusine synthase. This evidence for disruption of the initial step in the post-translational maturation of eukaryotic initiation factor 5A provides a basis for the potential control of protein biosynthesis and cell proliferation.

Original languageEnglish
Pages (from-to)13151-13159
Number of pages9
JournalJournal of Biological Chemistry
Volume268
Issue number18
Publication statusPublished - Jan 1 1993

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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