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.
• Coenzyme F420-0:L-glutamate ligase (one part of FbiB) puts a glutamate residue at the -COOH end, producing Coenzyme F₄₂₀-1.
• Coenzyme F420-1:gamma-L-glutamate ligase (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]