Physiology, Biochemistry, and Applications of F420- and Fo-Dependent Redox Reactions.
5-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 F420 is 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 F420 in microorganisms and the biochemistry of the various oxidoreductases that mediate these roles. Particular focus is placed on the central roles of F420 in methanogenic archaea in processes such as substrate oxidation, C1 pathways, 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 by Mycobacterium tuberculosis, and degradation of environmental contaminants such as picrate, aflatoxin, and malachite green. The biosynthesis pathways of Fo and F420 are also detailed. We conclude by considering opportunities to exploit deazaflavin-dependent processes in tuberculosis treatment, methane mitigation, bioremediation, and industrial biocatalysis.
The Commonwealth Scientific and Industrial Research Organisation, Land & Water Flagship, Acton, Australian Capital Territory, Australia chris.greening@monash.edu colin.jackson@anu.edu.au.
Chris
C
Greening
Australian National University, Research School of Chemistry, Acton, Australian Capital Territory, Australia.
F Hafna
FH
Ahmed
Australian National University, Research School of Chemistry, Acton, Australian Capital Territory, Australia.
A Elaaf
AE
Mohamed
Australian National University, Research School of Chemistry, Acton, Australian Capital Territory, Australia.
Brendon M
BM
Lee
The Commonwealth Scientific and Industrial Research Organisation, Land & Water Flagship, Acton, Australian Capital Territory, Australia.
Gunjan
G
Pandey
The Commonwealth Scientific and Industrial Research Organisation, Land & Water Flagship, Acton, Australian Capital Territory, Australia.
Andrew C
AC
Warden
The Commonwealth Scientific and Industrial Research Organisation, Land & Water Flagship, Acton, Australian Capital Territory, Australia.
Colin
C
Scott
The Commonwealth Scientific and Industrial Research Organisation, Land & Water Flagship, Acton, Australian Capital Territory, Australia.
John G
JG
Oakeshott
The Commonwealth Scientific and Industrial Research Organisation, Land & Water Flagship, Acton, Australian Capital Territory, Australia.
Matthew C
MC
Taylor
Australian National University, Research School of Chemistry, Acton, Australian Capital Territory, Australia chris.greening@monash.edu colin.jackson@anu.edu.au.
Colin J
CJ
Jackson
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D001105:Archaea / Q000378:metabolism; D019605:Euryarchaeota / Q000378:metabolism; D005415:Flavins / Q000502:physiology*; D006801:Humans; D053858:Metabolic Networks and Pathways; D009161:Mycobacterium / Q000378:metabolism; D009164:Mycobacterium Infections / Q000188:drug therapy; D010084:Oxidation-Reduction; D012256:Riboflavin / Q000031:analogs & derivatives* / Q000502:physiology
D000900:Anti-Bacterial Agents; D005415:Flavins; C019319:5-deazaflavin; C007701:factor 420; D012256:Riboflavin