Flavogenomics – a genomic and structural view of flavin‐dependent proteins

Abstract

Riboflavin (vitamin B 2) serves as the precursor for FMN and FAD in almost all organisms that utilize the redox‐active isoalloxazine ring system as a coenzyme in enzymatic reactions. The role of flavin, however, is not limited to redox processes, as ∼ 10% of flavin‐dependent enzymes catalyze nonredox reactions. Moreover, the flavin cofactor is also widely used as a signaling and sensing molecule in biological processes such as phototropism and nitrogen fixation. Here, we present a study of 374 flavin‐dependent proteins analyzed with regard to their function, structure and distribution among 22 archaeal, eubacterial, protozoan and eukaryotic genomes. More than 90% of flavin‐dependent enzymes are oxidoreductases, and the remaining enzymes are classified as transferases (4.3%), lyases (2.9%), isomerases (1.4%) and ligases (0.4%). The majority of enzymes utilize FAD (75%) rather than FMN (25%), and bind the cofactor noncovalently (90%). High‐resolution structures are available for about half of the flavoproteins. FAD‐containing proteins predominantly bind the cofactor in a Rossmann fold (∼ 50%), whereas FMN‐containing proteins preferably adopt a (βα)8‐(TIM)‐barrel‐like or flavodoxin‐like fold. The number of genes encoding flavin‐dependent proteins varies greatly in the genomes analyzed, and covers a range from ∼ 0.1% to 3.5% of the predicted genes. It appears that some species depend heavily on flavin‐dependent oxidoreductases for degradation or biosynthesis, whereas others have minimized their flavoprotein arsenal. An understanding of ‘flavin‐intensive’ lifestyles, such as in the human pathogen Mycobacterium tuberculosis, may result in valuable new intervention strategies that target either riboflavin biosynthesis or uptake.