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          Institute: MPI für Biochemie     Collection: Structure Research (R. Huber)     Display Documents

ID: 41345.0, MPI für Biochemie / Structure Research (R. Huber)
Incorporation of an amide into 5-phosphonoalkyl-6-D- ribitylaminopyrimidinedione lumazine synthase inhibitors results in an unexpected reversal of selectivity for riboflavin synthase vs lumazine synthase
Authors:Cushman, M.; Yang, D. L.; Mihalic, J. T.; Chen, J. H.; Gerhardt, S.; Huber, R.; Fischer, M.; Kis, K.; Bacher, A.
Date of Publication (YYYY-MM-DD):2002-10-04
Title of Journal:Journal of Organic Chemistry
Journal Abbrev.:J. Org. Chem.
Issue / Number:20
Start Page:6871
End Page:6877
Review Status:Peer-review
Audience:Not Specified
Abstract / Description:Several analogues of a hypothetical intermediate in the reaction catalyzed by lumazine synthase were synthesized and tested as inhibitors of both Bacillus subtilis lumazine synthase and Escherichia coli riboflavin synthase. The new compounds were designed by replacement of a two-carbon fragment of several 5-phosphonoalkyl-6-D-ribitylaminopyrimidinedione lumazine synthase inhibitors with an amide linkage that was envisioned as an analogue of a Schiff base moiety of a hypothetical intermediate in the enzyme-catalyzed reaction. The incorporation of the amide group led to an unexpected reversal in selectivity for inhibition of lumazine synthase vs riboflavin synthase. Whereas the parent 5-phosphonoalkyl-6-D- ribitylaminopyrimidinediones were lumazine synthase inhibitors and did not inhibit riboflavin synthase, the amide-containing derivatives inhibited riboflavin synthase and were only very weak or inactive as lumazine synthase inhibitors. Molecular modeling of inhibitor-lumazine synthase complexes did not reveal a structural basis for these unexpected findings. However, molecular modeling of one of the inhibitors with E. coli riboflavin synthase demonstrated that the active site of the enzyme could readily accommodate two ligand molecules.
Comment of the Author/Creator:Date: 2002, OCT 4
External Publication Status:published
Document Type:Article
Communicated by:N.N.
Affiliations:MPI für Biochemie/Structure Research (Huber)
External Affiliations:Purdue Univ, Dept Med Chem & Mol Pharmacol, Sch Pharm &; Pharmacal Sci, W Lafayette, IN 47907 USA; Purdue Univ, Dept Med Chem & Mol Pharmacol, Sch Pharm & Pharmacal Sci, W Lafayette, IN 47907 USA; Tech Univ Munich, Lehrstuhl Organ Chem & Biochem, D-85747 Garching, Germany
Identifiers:ISI:000178381600002 [ID No:1]
ISSN:0022-3263 [ID No:2]
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