Understanding the riboflavin biosynthesis pathway for the development of antimicrobial agents

Abstract

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.

The role of unconventional T cells in COVID-19

“…Therapeutic targeting of IL-17 is hypothesised to inhibit development of ARDS [ 98 ]. It is possible that MAIT cell functions could also be therapeutically inhibited using inhibitory riboflavin biosynthesis pathway derivatives [ 99 ]. However, given the observed importance of MAIT cell activation in promoting effector T cell vaccine responses and promoting vaccine immunogenicity, it may not be advisable to completely inhibit MAIT cell activation in this setting.…”

Mucosal-Associated Invariant T Cells as a Possible Target to Suppress Secondary Infections at COVID-19

“…Indeed, an immunomodulatory strategy of herpesviruses that functionally disrupts the immune response was defined for MR1 targeting ( 14 ). It was found that riboflavin biosynthesis can be repressed by inhibiting enzymes involved in riboflavin biosynthesis ( 15 ) or at the level of transcription through the flavin mononucleotide (FMN) riboswitch ( 16 ). The FMN riboswitch is a metabolite-dependent RNA element that directly binds FMN and controls the expression of genes responsible for riboflavin biosynthesis since FMN is riboflavin-5′-phosphate ( 17 ).…”

Dynamic Co-Cultivation Process of Corynebacterium glutamicum Strains for the Fermentative Production of Riboflavin

“…In this case, glucose and mannose feed the glycolysis while xylose feeds the PPP, avoiding metabolic burden and reaching the riboflavin titer of 11.7 mg L −1 , the highest titer up to this point of this work (Figure 3C). Ribulose-5-phosphate is a metabolite of the PPP [49], but also it is the initial precursor for riboflavin biosynthesis [50]. When using the oxidoreductase pathway for xylose consumption, the organism generates xylulose-5-phosphate.…”