Flavoenzymes in Health, Disease and Drug Discovery
Flavoenzymes are versatile and diverse biomolecules that contribute to build and maintain cellular structures, to move molecules among cellular compartments, to eliminate toxins, to facilitate chemical transformations in biosynthetic pathways, while are particularly in charge of cellular bioenergetics and signalling. They have as cofactors the riboflavin (RF, vitamin B2) derivatives flavin mononucleotide (FMN) and/or flavin adenine dinucleotide (FAD), which confer them unique properties. From bacteria to Eukarya, all organisms contain key flavoproteins and flavoenzymes, and many of them are becoming interesting as therapeutic targets or biotechnological tools. In human beings, two thirds of the more than 80 flavoenzymes are associated with diseases caused by allelic variants, making of interest to understand the molecular causes of the disease to develop molecules able to rescue native conformation and function. Flavins and flavoproteins are also relevant components in regulating bacterial stress responses and in the biology of host cells infection and colonization, closely relating flavin metabolism of pathogens to the survival in situations of oxidative stress, microanaerobic conditions or lack of nutrients. Considering that many pathogens are unable to acquire FMN and FAD from the environment, most flavoprotein traits and mechanisms appear speciesspecific, and the flavoprotein content appears widely divergent, flavin homeostasis and bacterial flavoproteomes are interesting targets for the development of chemotherapies to fight infectious diseases. Implementation of such actions requires to understand the relationships between the pathological and molecular mechanisms in which the target protein is involved. In this context, we particularly focus on: i) the understanding of the molecular bases of pathogenicity of some human flavoenzymes (as two members of the apoptosis inducing factor family and pyridoxine 5'-phosphate oxidase); ii) species-specific mechanistic traits of flavoreductases (in ferredoxin-NADP+reductases and UDP-N acetylenolpyruvoylglucosamine reductases) and of the enzymes involved in FMN and FAD biosynthesis (FAD synthase and/or
riboflavin kinase) from selected model pathogens, and iv) the channelling of flavin cofactors from the enzyme catalysing their biosynthesis to the client apo-proteins. In addition, we will explore the relationships among the flavoprotein content and species-specific lifestyles, while the studied flavoenzymes will be also used to explore potential biotechnological applications in the context of human and animal health.