Bacterial cytochrome c peroxidase (bCCP) enzymes, make use of two heme cofactors to achieve the reduction of hydrogen peroxide to water. Canonical enzymes are marked by high peroxidase activity, a peroxidatic heme, and second c-type heme possessing His/Met coordination. Other family members such as a MauG, possess His/Tyr coordination at the second heme, and are capable of a distinctive, multi-electron oxidation of the precursor protein of methylamine dehydrogenase installing a novel C-C bond in the generation of a TTQ cofactor. Thus, across the bCCP family of enzymes, sometimes H2O2 is a molecule to be detoxified, and other times, a potential oxidant. Aside from the swapping of ligands, there are many conserved features between canonical bCCPs and MauG. Here, the approach of using sequence similarity networks (SSNs) as a bioinformatic tool will be presented to make predictions of novel reactivities, using the case study of heme-based enzymes of the ‘bacterial cytochrome c peroxidase’ superfamily. <i>How does the same protein fold, and the set of redox active heme cofactors achieve such diverse chemistry? </i> Here, the SSN approach reveals that the bCCP_MauG superfamily is much more diverse than previously thought, including a link to novel enzyme found widely in Burkholderia microbes, which we term BthA. The structure-function relationships of BthA and other members of the bCCP family will be described using a combination of x-ray crystallography, spectroscopy and electrochemistry, revealing surprising stability of high oxidation intermediates at the bCCP peroxidatic heme site.  i

When one heme is not enough: Structure, diversity and reactivity of diheme bacterial cytochrome <i>c</i> peroxidases

ACS Fall 2021

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When one heme is not enough: Structure, diversity and reactivity of diheme bacterial cytochrome c peroxidases