jo048975f_si_001.cif (28.93 kB)
Design, Synthesis, and Evaluation of Acyclic C-Nucleoside and N-Methylated Derivatives of the Ribitylaminopyrimidine Substrate of Lumazine Synthase as Potential Enzyme Inhibitors and Mechanistic Probes
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posted on 2004-10-15, 00:00 authored by Jinhua Chen, Thota Sambaiah, Boris Illarionov, Markus Fischer, Adelbert Bacher, Mark CushmanLumazine synthase and riboflavin synthase catalyze the last two steps in the biosynthesis of
riboflavin, a vitamin that is involved in many critical biochemical reactions that are essential for
the maintenance of life. To obtain inhibitors and structural probes that could be useful in studying
the structures of bound reaction intermediates, the ribitylamino N−H moiety of the lumazine
synthase substrate was replaced by CH2 and N−CH3 groups. The CH2 replacement unexpectedly
and completely abolished the affinity for lumazine synthase, thus revealing a critical, yet
unexplained, role of the ribitylamino N−H moiety in conferring affinity for the enzyme. In contrast,
the N−CH3 replacement resulted in an inhibitor of both lumazine synthase and riboflavin synthase.
Replacement of the ribitylamino N−H moiety with epimeric C−F moieties led to inhibition of
lumazine synthase and riboflavin synthase when combined with the replacement of the 5-amino
group with a nitro substituent.