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Biochemistry. 1995 Nov 21;34(46):15381-7.

tRNA-guanine transglycosylase from Escherichia coli: structure-activity studies investigating the role of the aminomethyl substituent of the heterocyclic substrate PreQ1.

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  • 1Interdepartmental Program in Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.

Abstract

A series of 5-substituted 2-aminopyrrolo[2,3-d]pyrimidin-4(3H)-ones have been synthesized in order to study the substrate specificity of the tRNA-guanine transglycosylase (TGT) from Escherichia coli. A number of these compounds were initially examined as inhibitors of radiolabeled guanine incorporation into tRNA catalyzed by TGT [Hoops, G. C., Garcia, G. A., & Townsend, L. B. (1992) 204th National Meeting of the American Chemical Society, Washington, DC, August 23-28, 1992, Division of Medicinal Chemistry, Abstract 113]. The kinetic parameters of these analogues as substrates in the TGT reaction have been determined by monitoring the loss of radiolabeled guanine from 8-[14C]G34-tRNA. This study reveals that the tRNA-guanine transglycosylase from E. coli will tolerate a wide variety of substituents at the 5-position. The role of the 5-substituent appears to be entirely in binding/recognition with no apparent effects upon catalysis. A correlation between N7 pKa and Vmax suggests the deprotonation of N7 during the reaction, which must occur prior to subsequent glycosidic bond formation, appears to be partially rate-determining for the natural substrate. Comparison of the Kis of 7-methyl-substituted competitive inhibitors to the Kms of their corresponding substrates suggests that some substrates (including preQ1) are kinetically "sticky" (i.e., Km is equivalent to Kd) and other substrates have Kms that reflect catalytic rates as well as binding.

PMID:
7578154
[PubMed - indexed for MEDLINE]

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