Coenzyme F420 Explained

Coenzyme F420 should not be confused with Cofactor F430.

Coenzyme F₄₂₀ is a family of coenzymes involved in redox reactions in a number of bacteria and archaea. It is derived from coenzyme F_O (7,8-didemethyl-8-hydroxy-5-deazariboflavin) and differs by having a oligoglutamyl tail attached via a 2-phospho-L-lactate bridge. F₄₂₀ is so named because it is a flavin derivative with an absorption maximum at 420 nm.

F₄₂₀ was originally discovered in methanogenic archaea^[1] and in Actinomycetota (especially in Mycobacterium).^[2] It is now known to be used also by Cyanobacteria and by soil Proteobacteria, Chloroflexi and Firmicutes.^[3] Eukaryotes including the fruit fly Drosophila melanogaster and the algae Ostreococcus tauri also use Coenzyme F_O.^[4]

F₄₂₀ is structurally similar to FMN, but catalytically it is similar to NAD and NADP: it has low redox potential and always transfer a hydride. As a result, it is not only a versatile cofactor in biochemical reactions, but also being eyed for potential as an industrial catalyst. Similar to FMN, it has two states: one reduced state, notated as F₄₂₀-H₂, and one oxidized state, written as just F₄₂₀.^[5] F_O has largely similar redox properties, but cannot carry an electric charge and as a result probably slowly leaks out of the cellular membrane.^[3]

A number of F₄₂₀ molecules, differing by the length of the oligoglutamyl tail, are possible; F₄₂₀-2, for example, refers to the version with two glutamyl units attached. Lengths from 4 to 9 are typical.^[3]

Biosynthesis

Coenzyme F₄₂₀ is synthesized via a multi-step pathway:

• 7,8-didemethyl-8-hydroxy-5-deazariboflavin synthase (FbiC) produces Coenzyme FO (also written F0), itself a cofactor of DNA photolyase (antenna). This is the head portion of the molecule.^[4]
• 2-phospho-L-lactate transferase (FbiA) produces Coenzyme F₄₂₀-0, the portion containing the head, the diphosphate bridge, and ending with a carboxylic acid group.
• (one part of FbiB) puts a glutamate residue at the -COOH end, producing Coenzyme F₄₂₀-1.
• (other part of FbiB) puts a gamma-glutamate residue at the -COOH end, producing Coenzyme F₄₂₀-2, the final compound (in its oxidized form). Also responsible for adding additional units.

Oxidized F₄₂₀ can be converted to reduced F₄₂₀-H₂ by multiple enzymes such as Glucose-6-phosphate dehydrogenase (coenzyme-F420) (Fgd1).^[5]

Function

The coenzyme is a substrate for coenzyme F₄₂₀ hydrogenase,^[6] 5,10-methylenetetrahydromethanopterin reductase and methylenetetrahydromethanopterin dehydrogenase.^{[7] [8]}

A long list of other enzymes use F₄₂₀ to oxidize (dehydrogenate) or F₄₂₀-H₂ to reduce substrates.^[5]

Clinical relevance

Delamanid, a drug used to treat multi-drug-resistant tuberculosis (MDRTB) in combination with other antituberculosis medications, is activated in the mycobacterium by deazaflavin-dependent nitroreductase (Ddn), an enzyme which uses dihydro-F₄₂₀ (reduced form). The activated form of the drug is highly reactive and attacks cell wall synthesis enzymes such as DprE2. Pretomanid works in the same way. Clinical isolates resistant to these two drugs tend to have mutations in the biosynthetic pathway for F₄₂₀.^[9]

See also

• Coenzyme M
• Coenzyme B
• Methanofuran
• Tetrahydromethanopterin

External links

• KEGG:
  • FO
  • F420-0
  • F420-1
  • Reduced F420
  • Oxidised F420

Notes and References

1. Deppenmeier U . Redox-driven proton translocation in methanogenic Archaea . Cellular and Molecular Life Sciences . 59 . 9 . 1513–33 . September 2002 . 12440773 . 10.1007/s00018-002-8526-3 . 23199201 .
2. Selengut JD, Haft DH . Unexpected abundance of coenzyme F(420)-dependent enzymes in Mycobacterium tuberculosis and other actinobacteria . Journal of Bacteriology . 192 . 21 . 5788–98 . November 2010 . 20675471 . 2953692 . 10.1128/JB.00425-10 .
3. Ney . B . Ahmed . FH . Carere . CR . Biswas . A . Warden . AC . Morales . SE . Pandey . G . Watt . SJ . Oakeshott . JG . Taylor . MC . Stott . MB . Jackson . CJ . Greening . C . The methanogenic redox cofactor F(420) is widely synthesized by aerobic soil bacteria. . The ISME Journal . January 2017 . 11 . 1 . 125–137 . 10.1038/ismej.2016.100 . 27505347 . 5315465 . 2017ISMEJ..11..125N . free.
4. Glas AF, Maul MJ, Cryle M, Barends TR, Schneider S, Kaya E, Schlichting I, Carell T . The archaeal cofactor F0 is a light-harvesting antenna chromophore in eukaryotes . Proceedings of the National Academy of Sciences of the United States of America . 106 . 28 . 11540–5 . July 2009 . 19570997 . 2704855 . 10.1073/pnas.0812665106 . 2009PNAS..10611540G . free .
5. Grinter . Rhys . Greening . Chris . Cofactor F420: an expanded view of its distribution, biosynthesis and roles in bacteria and archaea . FEMS Microbiology Reviews . 8 September 2021 . 45 . 5 . 10.1093/femsre/fuab021 . 33851978 . 8498797 . free.
6. Fox JA, Livingston DJ, Orme-Johnson WH, Walsh CT . 8-Hydroxy-5-deazaflavin-reducing hydrogenase from Methanobacterium thermoautotrophicum: 1. Purification and characterization . Biochemistry . 26 . 14 . 4219–27 . July 1987 . 3663585 . 10.1021/bi00388a007 .
7. Hagemeier CH, Shima S, Thauer RK, Bourenkov G, Bartunik HD, Ermler U . Coenzyme F420-dependent methylenetetrahydromethanopterin dehydrogenase (Mtd) from Methanopyrus kandleri: a methanogenic enzyme with an unusual quarternary structure . Journal of Molecular Biology . 332 . 5 . 1047–57 . October 2003 . 14499608 . 10.1016/S0022-2836(03)00949-5 .
8. te Brömmelstroet BW, Geerts WJ, Keltjens JT, van der Drift C, Vogels GD . Purification and properties of 5,10-methylenetetrahydromethanopterin dehydrogenase and 5,10-methylenetetrahydromethanopterin reductase, two coenzyme F420-dependent enzymes, from Methanosarcina barkeri . Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology . 1079 . 3 . 293–302 . September 1991 . 1911853 . 10.1016/0167-4838(91)90072-8 .
9. Abrahams . Katherine A. . Batt . Sarah M. . Gurcha . Sudagar S. . Veerapen . Natacha . Bashiri . Ghader . Besra . Gurdyal S. . DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid . Nature Communications . 28 June 2023 . 14 . 1 . 3828 . 10.1038/s41467-023-39300-z . 37380634 . 10307805 . 2023NatCo..14.3828A . free.