MauG, a diheme enzyme that catalyzes tryptophan tryptophylquinone biosynthesis by remote catalysis

• MauG catalyzes the final three two-electron oxidation reactions to complete TTQ biosynthesis.
• The two hemes of MauG, Trp93 and a bound Ca2+ are critical for the function of the diheme cofactor.
• MauG forms a bis-FeIV redox state with one heme FeIV = O and the other FeIV with His–Tyr ligation.
• Hole hopping via Trp199 of MauG is required to achieve remote catalysis of the protein substrate.

MauG contains two c-type hemes with atypical physical and catalytic properties. While most c-type cytochromes function simply as electron transfer mediators, MauG catalyzes the completion of tryptophan tryptophylquinone (TTQ)1 biosynthesis within a precursor protein of methylamine dehydrogenase. This posttranslational modification is a six-electron oxidation that requires crosslinking of two Trp residues, oxygenation of a Trp residue and oxidation of the resulting quinol to TTQ. These reactions proceed via a bis-FeIV state in which one heme is present as FeIVO and the other is FeIV with axial heme ligands provided by His and Tyr side chains. Catalysis does not involve direct contact between the protein substrate and either heme of MauG. Instead it is accomplished by remote catalysis using a hole hopping mechanism of electron transfer in which Trp residues of MauG are reversibly oxidized. In this process, long range electron transfer is coupled to the radical mediated chemical reactions that are required for TTQ biosynthesis.

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