N5 Is the New C4a: Biochemical Functionalization of Reduced Flavins at the N5 Position.

Brett A Beaupre,Graham R Moran

doi:10.3389/fmolb.2020.598912

Abstract

For three decades the C4a-position of reduced flavins was the known site for covalency within flavoenzymes. The reactivity of this position of the reduced isoalloxazine ring with the dioxygen ground-state triplet established the C4a as a site capable of one-electron chemistry. Within the last two decades new types of reduced flavin reactivity have been documented. These studies reveal that the N5 position is also a protean site of reactivity, that is capable of nucleophilic attack to form covalent bonds with substrates. In addition, though the precise mechanism of dioxygen reactivity is yet to be definitively demonstrated, it is clear that the N5 position is directly involved in substrate oxygenation in some enzymes. In this review we document the lineage of discoveries that identified five unique modes of N5 reactivity that collectively illustrate the versatility of this position of the reduced isoalloxazine ring.

Highlights

Flavins are requisite to all life and are utilized as cofactors by enzymes throughout primary and secondary metabolism
The reduced isoalloxazine ring acts as a nucleophile to generate covalent intermediates. Flavins extend their biochemical utility by covalent modification of the isoalloxazine either as an indelible modification or as a transient adduct (Figure 1)
Multiple lineages of flavin enzymes are known to have evolved the capacity to form unique covalent modifications at the flavin N5 position that expand the known repertoire of flavin catalyzed reactions

Summary

Introduction

Flavins are requisite to all life and are utilized as cofactors by enzymes throughout primary and secondary metabolism. Instead both function as prenyltransferases, catalyzing the formation of a prenylated fourring flavin mononucleotide that is the cofactor for non-oxidative reversible decarboxylation reactions catalyzed by the UbiD and Fdc1 enzymes (Payne et al, 2015; White et al, 2015; Figure 2).

Results

Conclusion