Fumarase deficiency causes protein and metabolite succination and intoxicates Mycobacterium tuberculosis
| Autor: | Kyu Y. Rhee, Pradeepa Jayachandran, Susan E. Puckett, Henrik Molina, Sabine Ehrt, Nadine Ruecker, Carolina Trujillo, Gerardo G. Piroli, Robert S. Jansen, Norma Frizzell |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Fumarase deficiency Metabolite Clinical Biochemistry Citric Acid Cycle Biology Biochemistry Article Microbiology Fumarate Hydratase Mycobacterium tuberculosis 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Bacterial Proteins Fumarates Tandem Mass Spectrometry Drug Discovery medicine Animals Cysteine Molecular Biology Chromatography High Pressure Liquid Pharmacology chemistry.chemical_classification biology.organism_classification medicine.disease Citric acid cycle Mice Inbred C57BL Oxidative Stress 030104 developmental biology Enzyme chemistry Fumarase Molecular Medicine Muscle Hypotonia Transposon mutagenesis Female Psychomotor Disorders Peptides Protein Processing Post-Translational Oxidation-Reduction 030217 neurology & neurosurgery Metabolism Inborn Errors |
| Popis: | Enzymes of central carbon metabolism are essential mediators of Mycobacterium tuberculosis (Mtb) physiology and pathogenicity, but are often perceived to lack sufficient species selectivity to be pursued as potential drug targets. Fumarase (Fum) is an enzyme of the canonical tricarboxylic acid cycle and is dispensable in many organisms. Transposon mutagenesis studies in Mtb, however, indicate that Fum is required for optimal growth. Here, we report the generation and characterization of a genetically engineered Mtb strain in which Fum expression is conditionally regulated. This revealed that Fum deficiency is bactericidal in vitro and during both the acute and chronic phases of mouse infection. This essentiality is linked to marked accumulations of fumarate resulting in protein and metabolite succination, a covalent modification of cysteine thiol residues. These results identify Mtb Fum as a potentially species-specific drug target whose inactivation may kill Mtb through a covalently irreversible form of metabolic toxicity. |
| Databáze: | OpenAIRE |
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