Cofactor F420-Dependent Enzymes: An Under-Explored Resource for Asymmetric Redox Biocatalysis

Abstract

The asymmetric reduction of enoates, imines and ketones are among the most important reactions in biocatalysis. These reactions are routinely conducted using enzymes that use nicotinamide cofactors as reductants. The deazaflavin cofactor F420 also has electrochemical properties that make it suitable as an alternative to nicotinamide cofactors for use in asymmetric reduction reactions. However, cofactor F420-dependent enzymes remain under-explored as a resource for biocatalysis. This review considers the cofactor F420-dependent enzyme families with the greatest potential for the discovery of new biocatalysts: the flavin/deazaflavin-dependent oxidoreductases (FDORs) and the luciferase-like hydride transferases (LLHTs). The characterized F420-dependent reductions that have the potential for adaptation for biocatalysis are discussed, and the enzymes best suited for use in the reduction of oxidized cofactor F420 to allow cofactor recycling in situ are considered. Further discussed are the recent advances in the production of cofactor F420 and its functional analog FO-5′-phosphate, which remains an impediment to the adoption of this family of enzymes for industrial biocatalytic processes. Finally, the prospects for the use of this cofactor and dependent enzymes as a resource for industrial biocatalysis are discussed.

Biocatalytic Reduction Reactions from a Chemist's Perspective

“…The recent discovery and characterisation of ene reductase activity by Fraaije on F 420 H 2 ‐dependent reductases (FDRs) has opened the door to new types of catalysts for asymmetric hydrogenations with opposite stereoselectivity to those of OYEs [79] . Unlike OYEs, FDRs use deazaflavin cofactors and can perform cis ‐hydrogenation [80] …”

Biokatalytische Reduktionen aus der Sicht eines Chemikers

“…Erwähnenswert sind Arbeiten von Bashiri, Colin, Scott und Greenings zur Biosynthese des F 420 -Cofaktors. [78] Die kürzlich von Fraaije publizierten F 420 H 2 -abhängigen Reduktasen (FDRs) benutzen diese Deazaflavine [79] für die stereoselektive cis-Hydrierung [80] und erçffnen somit ganz neue Mçglichkeiten für die asymmetrische Reduktion von C = C-Doppelbindungen.…”

Redox Coenzyme F 420 Biosynthesis in Thermomicrobia Involves Reduction by Stand-Alone Nitroreductase Superfamily Enzymes

“…Especially in anaerobic methanogens, another reason might be the extraordinary redox potential of F 420 (E°= ϭ Ϫ340 mV), making it an ideal cofactor to transfer electrons from H 2 (Ϫ410 mV) to NADP (Ϫ320 mV) (13). Since some F 420 -dependent reductions are chemically challenging or stereospecific, deazaflavin-dependent enzymes have risen increasing interest for applications in biocatalysis (14)(15)(16). Unfortunately, F 420 is produced in relatively low yields by microorganisms, thus limiting its use for in vitro applications (16).…”