This activity variation is highly correlated for the two aflatoxins and also for the two furanocoumarins Euphorbia factor L3 angelicin and 8-MOP, but there is very little correlation between activities for the aflatoxin and the two furanocoumarin substrates. The aflatoxins and coumarins in this study may represent only a small proportion of the possible substrates for these enzymes because the a,b-unsaturated lactone moiety that appears to be required for activity occurs in a wide variety of xenobiotics and antibiotics. Such compounds may include UV oxidised polyaromatic hydrocarbons, plant derived lactones such as digitalis and other antibiotics including leptomycin. It remains to be determined as to whether the aflatoxins or coumarins are in fact physiological substrates for any of the enzymes here; some of the host organisms have ecologies which would not likely encompass these specific compounds. Once the coumarins are reduced by the FDR-As they are likely to be further catabolized in the Actinomycetales through the catechol catabolic pathway, providing substrates for the citric acid cycle. In the case of coumarin, dihydrocoumarin resulting from the FDR-catalyzed reduction reaction would be spontaneously hydrolyzed to 3-hydroxyphenyl propionic acid, which could be further hydrolyzed to 2,3-dihydroxyphenyl propionic acid by melilotate hydroxylase, enabling ring meta-cleavage by extradiol dioxygenases. After cleavage, the resulting succinate would enter the citric acid cycle. The other furanocoumarin compounds are Choline Chloride similarly reduced by the FDRs and after further hydrolysis should be ring cleaved by extradiol dioxygenases and lysed to produce succinate, thus also providing a carbon source. Other metabolic fates might also be possible for the possible hydrolyzed intermediates, such as through condensation by 4-coumarate-CoA ligase. Genes encoding FDR-As in Streptomyces species have been found in antibiotic biosynthetic operons, although their exact role in the biosynthesis has not been determined. No operons with at least partially conserved gene complements were found for the genes encoding enzymes in the FDR subclades -A2, -A3 or in the FDR-AA and -B clades. F420 has been shown to be a non-essential cofactor in M. smegmatis but this and other studies have shown that F420 is required for the metabolism of several otherwise recalcitrant molecules. As noted above, the aflatoxins and plant furanocoumarins studied here may only be model substrates for most of the FDR-A enzymes, many of which are in organisms found in environments not likely to encounter such compounds. The FDRAs are a divergent family with few conserved amino acids, thus suggesting the ability to adapt to new substrates and perhaps new cofactors. We have proposed a role of these enzymes in the secondary metabolism of toxic compounds, including antibiotic biosynthesis.