Understanding the riboflavin biosynthesis pathway for the development of antimicrobial agents.
Biswajit KunduDipayan SarkarNamrata RayArindam TalukdarPublished in: Medicinal research reviews (2019)
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.