Remote Enzyme Catalysis: Coupling Long Range Electron Transfer to Radical-Mediated Chemistry
The diheme enzyme, MauG catalyzes the completion of tryptophan tryptophylquinone (TTQ) biosynthesis within a precursor protein of methylamine dehydrogenase (MADH), thus generating a catalytic and redox center in the protein from the otherwise inert tryptophan residues. This posttranslational modification is a six-electron oxidation that requires crosslinking of two tryptophan residues, oxygenation of a tryptophan residue and oxidation of the resulting quinol to TTQ. During these reactions MauG cycles through a unique bis-Fe(IV) intermediate with one heme as Fe(IV)=O and the other as Fe(IV) with the two axial ligands provided by histidine and tyrosine residues. The crystal of the MauG-preMADH complex reveals that the hemes of MauG are distant from the site at which preMADH binds. Thus, catalysis does not involve direct contact between the protein substrate and either heme of MauG. Instead, this enzyme performs remote catalysis using a hole-hopping mechanism of electron transfer in which specific intervening amino acid residues of MauG are reversibly oxidized. In this manner, long range electron transfer is efficiently coupled to the radical-mediated chemical reactions that are required for TTQ biosynthesis. If the bis-Fe(IV) intermediate is generated in the absence of the substrate, it is unusually stable but eventual oxidizes specific methionine residues on MauG which inactivates the enzyme. The unusual mechanisms by which the catalytic and self-inactivating reactions occur, and the implications of these results will be discussed.