Noncanonical Reactions of Flavoenzymes

Abstract

Enzymes containing flavin cofactors are predominantly involved in redox reactions in numerous cellular processes where the protein environment modulates the chemical reactivity of the flavin to either transfer one or two electrons. Some flavoenzymes catalyze reactions with no net redox change. In these reactions, the protein environment modulates the reactivity of the flavin to perform novel chemistries. Recent mechanistic and structural data supporting novel flavin functionalities in reactions catalyzed by chorismate synthase, type II isopentenyl diphosphate isomerase, UDP-galactopyranose mutase, and alkyl-dihydroxyacetonephosphate synthase are presented in this review. In these enzymes, the flavin plays either a direct role in acid/base reactions or as a nucleophile or electrophile. In addition, the flavin cofactor is proposed to function as a “molecular scaffold” in the formation of UDP-galactofuranose and alkyl-dihydroxyacetonephosphate by forming a covalent adduct with reaction intermediates.

Structure, mechanism, and dynamics of UDP-galactopyranose mutase

“…The flavin-sugar adduct is important in ring opening and activation of the C1 Gal p [27]. In this process, the flavin also functions as a molecular scaffold, providing the structural constraints required for ring contraction (Scheme 2B) [31]. Formation of this intermediate made mechanistic sense and was consistent with the breaking of the anomeric bond determined from PIX studies and the lack of activity observed with the enzyme reconstituted with 5-deaza-FAD.…”

“…Novel roles of flavins in noncanonical redox neutral reactions have been identified in other enzymes [31], however, UGM is the only flavoenzyme that forms a covalent intermediate by acting as a nucleophile [9, 35, 36]. …”

Substrate‐dependent dynamics of UDP‐galactopyranose mutase: Implications for drug design

“…Interestingly, the flavin does not participate in a net redox reaction, rather it acts as a nucleophile that attacks the anomeric carbon atom of the substrate. UGM is thus an example of a noncanonical flavoenzyme …”

“…UGM is thus an example of a noncanonical flavoenzyme. 5 Crystal structures are available for several UGMs. The E. coli UGM structure was reported in 2001 (PDB ID 1I8T), 6 and since then several more structures of bacterial and eukaryotic UGMs have been deposited in the Protein Data Bank.…”

3-Sulfinopropionyl-coenzyme A (3SP-CoA) desulfinase fromAdvenella mimigardefordensisDPN7T: crystal structure and function of a desulfinase with an acyl-CoA dehydrogenase fold

“…S6). Some flavoenzymes catalyze reactions with no net redox change, in which the flavin, acting either as an electron donor and nucleophile or as a base, modulates the reactivity of the protein environment to perform novel reactions (Sobrado, 2012). In the reaction catalyzed by chorismate synthase, the flavin might act as a base/H-atom abstractor for C-H bond cleavage after breakage of the C-O bond (Osborne et al, 2000).…”