ArticleFree radical biology & medicine2013
Inhibition of Mycobacterium tuberculosis PknG by non-catalytic rubredoxin domain specific modification: reaction of an electrophilic nitro-fatty acid with the Fe-S center.
Article in Free radical biology & medicine, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 33 citations in OpenAlex.
- STING: An Attractive Target for Autoimmune and Inflammatory Diseases.Medicinal research reviews · 2026Review
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- Bacterial effector kinases and strategies to identify their target host substrates.Frontiers in microbiology · 2023Review
- Different modalities of host cell death and their impact onAmerican journal of physiology. Cell physiology · 2022Review
- Nitrated Fatty-Acids Distribution in Storage Biomolecules duringAntioxidants (Basel, Switzerland) · 2022Article
- Cosolvent Sites-Based Discovery ofJournal of medicinal chemistry · 2022Article
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- From infection niche to therapeutic target: the intracellular lifestyle ofMicrobiology (Reading, England) · 2021Review
- Deletion ofAntimicrobial agents and chemotherapy · 2021Article
- Understanding lipidomic basis of iron limitation induced chemosensitization of drug-resistant3 Biotech · 2019Article
- Post-Translational Modification of Proteins Mediated by Nitro-Fatty Acids in Plants: Nitroalkylation.Plants (Basel, Switzerland) · 2019Review
- Nitro-fatty acids are formed in response to virus infection and are potent inhibitors of STING palmitoylation and signaling.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Article
- Electrophilic fatty acid nitroalkenes regulate Nrf2 and NF-κB signaling:A medicinal chemistry investigation of structure-function relationships.Scientific reports · 2018Article
- Protein Kinase G Induces an Immune Response in Cows Exposed toBioMed research international · 2018Article
- PknG senses amino acid availability to control metabolism and virulence of Mycobacterium tuberculosis.PLoS pathogens · 2017Article
- SOCS Proteins as Regulators of Inflammatory Responses Induced by Bacterial Infections: A Review.Frontiers in microbiology · 2017Review
- Oxidative Unfolding of the Rubredoxin Domain and the Natively Disordered N-terminal Region Regulate the Catalytic Activity of Mycobacterium tuberculosis Protein Kinase G.The Journal of biological chemistry · 2016Article
- An Iron Reservoir to the Catalytic Metal: THE RUBREDOXIN IRON IN AN EXTRADIOL DIOXYGENASE.The Journal of biological chemistry · 2015Article
- Mycobacterium tuberculosis Serine/Threonine Protein Kinases.Microbiology spectrum · 2014Review
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Authors and funding
9 authors at 7 institutions in 3 countries.
Funding
Abstract
PknG from Mycobacterium tuberculosis is a Ser/Thr protein kinase that regulates key metabolic processes within the bacterial cell as well as signaling pathways from the infected host cell. This multidomain protein has a conserved canonical kinase domain with N- and C-terminal flanking regions of unclear functional roles. The N-terminus harbors a rubredoxin-like domain (Rbx), a bacterial protein module characterized by an iron ion coordinated by four cysteine residues. Disruption of the Rbx-metal binding site by simultaneous mutations of all the key cysteine residues significantly impairs PknG activity. This encouraged us to evaluate the effect of a nitro-fatty acid (9- and 10-nitro-octadeca-9-cis-enoic acid; OA-NO2) on PknG activity. Fatty acid nitroalkenes are electrophilic species produced during inflammation and metabolism that react with nucleophilic residues of target proteins (i.e., Cys and His), modulating protein function and subcellular distribution in a reversible manner. Here, we show that OA-NO2 inhibits kinase activity by covalently adducting PknG remote from the catalytic domain. Mass spectrometry-based analysis established that cysteines located at Rbx are the specific targets of the nitroalkene. Cys-nitroalkylation is a Michael addition reaction typically reverted by thiols. However, the reversible OA-NO2-mediated nitroalkylation of the kinase results in an irreversible inhibition of PknG. Cys adduction by OA-NO2 induced iron release from the Rbx domain, revealing a new strategy for the specific inhibition of PknG. These results affirm the relevance of the Rbx domain as a target for PknG inhibition and support that electrophilic lipid reactions of Rbx-Cys may represent a new drug strategy for specific PknG inhibition.
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