8U3P

1.79 Angstrom resolution crystal structure of KatG from Mycobacterium tuberculosis with an MYW cofactor after heat incubation for 60 minutes

Summary for 8U3P

• Entry DOI: 10.2210/pdb8u3p/pdb
• Related: 8CZS
• Descriptor: Catalase-peroxidase, SODIUM ION, PROTOPORPHYRIN IX CONTAINING FE, ... (6 entities in total)
• Functional Keywords: met-tyr-trp cofactor, heme-dependent enzyme, oxidoreductase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 4
• Total formula weight: 327366.12

Authors

Liu, A.,Li, J.,Ran, D. (deposition date: 2023-09-08, release date: 2024-09-11, Last modification date: 2024-12-11)

Primary citation

Li, J.,Duan, R.,Traore, E.S.,Nguyen, R.C.,Davis, I.,Griffth, W.P.,Goodwin, D.C.,Jarzecki, A.A.,Liu, A.
Indole N-Linked Hydroperoxyl Adduct of Protein-Derived Cofactor Modulating Catalase-Peroxidase Functions.
Angew.Chem.Int.Ed.Engl., 63:e202407018-e202407018, 2024

PubMed Abstract: 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 restoring the detoxifying ability of the enzyme against hydrogen peroxide. Thus, the N-linked hydroperoxyl group is releasable. KatG with MYW-OOH represents a catalase dormant, but primed, state of the enzyme. These findings provide insight into chemical strategies targeting the bifunctional enzyme KatG in pathogens, highlighting the role of N-linked hydroperoxyl modifications in enzymatic function.

PubMed: 39300819
DOI: 10.1002/anie.202407018

Experimental method

X-RAY DIFFRACTION (1.79 Å)