biostudies-literatureLi JDirectorate for Biological SciencesDirectorate for Mathematical and Physical SciencesWelch FoundationNational Institute of General Medical SciencesNIGMS NIH HHSe202407018https://www.ebi.ac.uk/biostudies/studies/S-EPMC11686441biostudies-literatureUnknown63(49)Bifunctional catalase-peroxidase (KatG) features a posttranslational methionine-tyrosine-tryptophan (MYW) crosslinked cofactor crucial for its catalase function, enabling pathogens to neutralize hydrogen peroxide during infection. We discovered the presence of indole nitrogen-linked hydroperoxyl adduct (MYW-OOH) in Mycobacterium tuberculosis KatG in the solution state under ambient conditions, suggesting its natural occurrence. By isolating predominantly MYW-OOH-containing KatG protein, we investigated the chemical stability and functional impact of MYW-OOH. We discovered that MYW-OOH inhibits catalase activity, presenting a unique temporary lock. Exposure to peroxide or increased temperature removes the hydroperoxyl adduct from the protein cofactor, converting MYW-OOH to MYW and restoringAngewandte Chemie (International ed. in English)Indole N-Linked Hydroperoxyl Adduct of Protein-Derived Cofactor Modulating Catalase-Peroxidase Functions.PMC11686441R01 GM152982F31GM145187CHE-2204225AX-2110-20220331F31 GM145187R01GM108988P30 GM133894MCB-1616059R01 GM108988R01GM152982Davis ILi JNguyen RCJarzecki AAGoodwin DCDuan RGriffth WPLiu ATraore ESfalseIndole N-Linked Hydroperoxyl Adduct of Protein-Derived Cofactor Modulating Catalase-Peroxidase Functions.Bifunctional catalase-peroxidase (KatG) features a posttranslational methionine-tyrosine-tryptophan (MYW) crosslinked cofactor crucial for its catalase function, enabling pathogens to neutralize hydrogen peroxide during infection. We discovered the presence of indole nitrogen-linked hydroperoxyl adduct (MYW-OOH) in Mycobacterium tuberculosis KatG in the solution state under ambient conditions, suggesting its natural occurrence. By isolating predominantly MYW-OOH-containing KatG protein, we investigated the chemical stability and functional impact of MYW-OOH. We discovered that MYW-OOH inhibits catalase activity, presenting a unique temporary lock. Exposure to peroxide or increased temperature removes the hydroperoxyl adduct from the protein cofactor, converting MYW-OOH to MYW and restoring2024-01-01T00:00:00Z2024 Dec2026-05-29T11:37:01.003Z2026-04-08T04:28:12.783ZS-EPMC116864413930081910.1002/anie.202407018