Physiology, Biochemistry, and Applications of F₄₂₀- and F_o-Dependent Redox Reactions

Abstract

SUMMARY5-Deazaflavin cofactors enhance the metabolic flexibility of microorganisms by catalyzing a wide range of challenging enzymatic redox reactions. While structurally similar to riboflavin, 5-deazaflavins have distinctive and biologically useful electrochemical and photochemical properties as a result of the substitution of N-5 of the isoalloxazine ring for a carbon. 8-Hydroxy-5-deazaflavin (Fo) appears to be used for a single function: as a light-harvesting chromophore for DNA photolyases across the three domains of life. In contrast, its oligoglutamyl derivative F420is a taxonomically restricted but functionally versatile cofactor that facilitates many low-potential two-electron redox reactions. It serves as an essential catabolic cofactor in methanogenic, sulfate-reducing, and likely methanotrophic archaea. It also transforms a wide range of exogenous substrates and endogenous metabolites in aerobic actinobacteria, for example mycobacteria and streptomycetes. In this review, we discuss the physiological roles of F420in microorganisms and the biochemistry of the various oxidoreductases that mediate these roles. Particular focus is placed on the central roles of F420in methanogenic archaea in processes such as substrate oxidation, C1pathways, respiration, and oxygen detoxification. We also describe how two F420-dependent oxidoreductase superfamilies mediate many environmentally and medically important reactions in bacteria, including biosynthesis of tetracycline and pyrrolobenzodiazepine antibiotics by streptomycetes, activation of the prodrugs pretomanid and delamanid byMycobacterium tuberculosis, and degradation of environmental contaminants such as picrate, aflatoxin, and malachite green. The biosynthesis pathways of Foand F420are also detailed. We conclude by considering opportunities to exploit deazaflavin-dependent processes in tuberculosis treatment, methane mitigation, bioremediation, and industrial biocatalysis.

The methanogenic redox cofactor F420 is widely synthesized by aerobic soil bacteria

“…Half a century since its discovery (Cheeseman et al, 1972), F 420 is still perceived to be a rare cofactor synonymous with methanogenesis (Greening et al, 2016a). It has been confirmed to be synthesized in just two phyla to date: the Euryarchaeota (Eirich et al, 1979) and Actinobacteria (Eker et al, 1980;Daniels et al, 1985).…”

“…It has a relatively low redox potential of − 340 mV under standard conditions and − 380 mV under certain physiological conditions (de Poorter et al, 2005). This enables reduced F 420 (F 420 H 2 ) to reduce a wide range of organic compounds otherwise recalcitrant to activation (Jacobson and Walsh, 1984;Greening et al, 2016a). As an obligate two-electron carrier, the cofactor can transform alkene, alkyne, alcohol and imine groups through hydride transfer reactions (Shima et al, 2000;Hagemeier et al, 2003;Aufhammer et al, 2004;Shen et al, 2009;Wang et al, 2013).…”

“…Among bacteria, the cofactor has been chemically identified only within the Actinobacteria, where its physiological roles remain under investigation. In these organisms, F 420 reduction is coupled to either glucose 6-phosphate or NADPH oxidation and hence is dependent on the pentose phosphate pathway (Greening et al, 2016a). The reduced cofactor (F 420 H 2 ) is reported to enhance the metabolic flexibility of mycobacteria by facilitating the catalysis of a wide range of reductions of endogenous and exogenous organic compounds (Ahmed et al, 2015;Greening et al, 2016a).…”

“…In these organisms, F 420 reduction is coupled to either glucose 6-phosphate or NADPH oxidation and hence is dependent on the pentose phosphate pathway (Greening et al, 2016a). The reduced cofactor (F 420 H 2 ) is reported to enhance the metabolic flexibility of mycobacteria by facilitating the catalysis of a wide range of reductions of endogenous and exogenous organic compounds (Ahmed et al, 2015;Greening et al, 2016a). F 420 also has roles in antibiotic synthesis and xenobiotic degradation in species of Streptomyces (Wang et al, 2013), Rhodococcus (Heiss et al, 2002) and Nocardioides (Ebert et al, 1999).…”

“…Among them are the one-carbon reactions of methanogenesis (Thauer, 1998;Shima et al, 2000;Hagemeier et al, 2003), the biosynthesis pathways of tetracycline antibiotics (Wang et al, 2013) and the biodegradation of picrate and aflatoxins (Ebert et al, 2001;Taylor et al, 2010;Lapalikar et al, 2012). The cofactor appears to have been selected for these roles because of its unique electrochemical properties compared with the ubiquitous flavin and nicotinamide cofactors FMN (flavin mononucleotide), FAD (flavin adenine dinucleotide) and NAD(P) (nicotinamide adenine dinucleotide (phosphate)) (Walsh, 1986;Greening et al, 2016a). As a 5-deazaflavin, F 420 is structurally and biosynthetically related to FMN and FAD, but exhibits distinct electrochemical properties because of several key substitutions.…”