Life on earth depends on the biosynthesis of riboflavin, which plays a vital role in biological electron transport processes. Higher mammals obtain riboflavin from dietary sources; however, various microorganisms, including Gram‐negative pathogenic bacteria and yeast, lack an efficient riboflavin‐uptake system and are dependent on endogenous riboflavin biosynthesis. Consequently, the inhibition of enzymes in the riboflavin biosynthesis pathway would allow selective toxicity to a pathogen and not the host. Thus, the riboflavin biosynthesis pathway is an attractive target for designing novel antimicrobial drugs, which are urgently needed to address the issue of multidrug resistance seen in various pathogens. The enzymes involved in riboflavin biosynthesis are lumazine synthase (LS) and riboflavin synthase (RS). Understanding the details of the mechanisms of the enzyme‐catalyzed reactions and the structural changes that occur in the enzyme active sites during catalysis can facilitate the design and synthesis of suitable analogs that can specifically inhibit the relevant enzymes and stop the generation of riboflavin in pathogenic bacteria. The present review is the first compilation of the work that has been carried out over the last 25 years focusing on the design of inhibitors of the biosynthesis of riboflavin based on an understanding of the mechanisms of LS and RS. This review aimed to address the fundamental advances in our understanding of riboflavin biosynthesis as applied to the rational design of a novel class of inhibitors. These advances have been aided by X‐ray structures of ligand‐enzyme complexes, rotational‐echo, double‐resonance nuclear magnetic resonance spectroscopy, high‐throughput screening, virtual screenings, and various mechanistic probes.
Expression of the lactose (lac) operon in the Escherichia coli chromosome has been studied in mixed-sugar chemostat cultures under steady-state and transient conditions. A unified model has been formulated which involves regulation of active inducer (lactose) transport, promoter-operator regulated expression of the lac operon, glucose-mediated inducer exclusion, and catabolite repression. The model of the lac operon control system focuses on the molecular interactions among the regulatory species and the genetic control elements for the initiation of transcription. The role of catabolite modulator factor (CMF) in the regulation of transcription is described. The modeling of glucose-mediated regulation of intracellular cyclic adenosine monophosphate (cAMP) and inducer exclusion is based on the recently elucidated mechanisms of the involvement of the PTS (phosphoen-olpyruvate dependent sugar transport system) enzymes, in the presence of glucose, in regulation of adenylate cyclase and non-PTS sugar transport proteins (i.e. per-meases). The adequacy of the unified model was verified with experimental data.
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