Abstract
Riboflavin (vitamin B2) and flavin adenine dinucleotide (FAD) are valuable biological flavins mainly used as animal feed supplement and in pharmaceutical formulation. <i>Eremothecium ashbyi</i> is a natural overproducer of FAD along with riboflavin. Flavins overproduction was found to be strongly correlated with stress induction but stress response in E.ashbyi</i> is completely unexplored. Hence, in the present study, flavins production in presence of four oxidative stress modulators (menadione, vitamin E, cAMP, H<sub>2</sub>O<sub>2</sub>) was investigated. Their levels were statistically optimized to maximize the flavins production. The regression model obtained from Central Composite Design indicated that maximum flavins production occurred when 1.09 µM menadione and 1.12 µM vitamin E were supplemented to 24-hour grown fungus. Upon supplementation, total flavins production was significantly increased by 1.34-fold and FAD production was increased by 2.18-fold over untreated control. Intracellular – reactive oxygen species (ROS) level was increased and reduced glutathione (GSH) and oxidized glutathione (GSSG) ratio was decreased indicating oxidative burst experienced by the cell. Furthermore, a concomitant increase in specific activity of glutathione reductase and FAD synthetase was observed. For the first time this study showed that among flavins, FAD was majorly increased along with FAD synthetase activity as a response to oxidative stress. These results indicated that the oxidative stress and flavins overproduction was centered on FAD regulation.
Highlights
Flavins are important biological compounds with common isoalloxazine moiety of tri-heterocyclic structure called flavin ring
flavin adenine dinucleotide (FAD) is used in the treatment of genetically inherited diseases like Friedreich ataxia which is caused by the lack of the mitochondrial protein frataxin [3] and chronic granulomatosis which is caused by mutations in leukocyte NADPH oxidase genes [4]
Increased flux towards FAD synthesis can be due to its direct role as electron mediator in stress response enzymatic reactions. This is a first report on statistical optimization of oxidative stress modulators for increasing flavins production in E.ashbyi
Summary
Flavins are important biological compounds with common isoalloxazine moiety of tri-heterocyclic structure called flavin ring. Riboflavin, FMN and FAD are major flavins involved in several metabolic reactions vital for life. Riboflavin, known as vitamin B2, is used as food and feed additive with nearly 10000 tons of production per year. FMN and FAD are co-enzymes for important oxidation/reduction metabolic reactions [1]. FAD has a pharmaceuticals application and 1000 times more expensive than riboflavin. It is used as an ophthalmic agent and multi-vitamin supplements. FAD is used in the treatment of genetically inherited diseases like Friedreich ataxia which is caused by the lack of the mitochondrial protein frataxin [3] and chronic granulomatosis which is caused by mutations in leukocyte NADPH oxidase genes [4]
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