Protein aggregation caused by aminoglycoside action is prevented by a hydrogen peroxide scavenger

Jiqiang Ling1, Chris Cho, Li-Tao Guo

  • 1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.

Molecular Cell
|November 6, 2012
PubMed

Insights

Streptomycin causes protein aggregation by increasing mistranslation in E. coli. Enhancing cellular defense against hydrogen peroxide reduces this toxicity, offering a new therapeutic strategy for mistranslation-related diseases.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Biochemistry

Background:

  • Protein mistranslation is linked to cellular dysfunction, including bacterial growth arrest, yeast mitochondrial issues, and mammalian neurodegeneration.
  • The precise mechanisms by which mistranslated proteins induce cellular defects are not fully understood.

Purpose of the Study:

  • To investigate the effects of streptomycin, an aminoglycoside antibiotic that promotes ribosomal mistranslation, on protein aggregation in Escherichia coli.
  • To identify cellular components or pathways that mitigate the toxicity associated with protein mistranslation.

Main Methods:

  • Induced protein aggregation using streptomycin in wild-type E. coli.
  • Characterized the aggregated proteome via label-free quantitative mass spectrometry.
  • Screened an overexpression library to identify genes conferring resistance to streptomycin and kanamycin.

Main Results:

  • Streptomycin treatment induced transient protein aggregation in E. coli.
  • Proteins involved in oxidation-reduction pathways were significantly enriched among those conferring resistance.
  • Overexpression of alkyl hydroperoxide reductase subunit F (AhpF) suppressed protein aggregation and increased aminoglycoside resistance.

Conclusions:

  • Cellular defense mechanisms against hydrogen peroxide can reduce the toxicity of protein mistranslation.
  • Targeting oxidative stress pathways may offer a therapeutic approach for conditions associated with protein mistranslation.

Related Concept Videos

Inhibitors of Bacterial Protein Synthesis01:25

Inhibitors of Bacterial Protein Synthesis

Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...
Anticholinesterase Agents: Poisoning and Treatment01:26

Anticholinesterase Agents: Poisoning and Treatment

Anticholinesterases, also known as cholinesterase inhibitors, work by blocking the breakdown of acetylcholine, leading to its accumulation in the synaptic cleft. This accumulation indirectly enhances both muscarinic and nicotinic actions. These agents are classified as reversible or irreversible based on their mechanism of action.     
Irreversible agents form a strong bond with the cholinesterase enzyme, making it inactive. The breakdown of the phosphorylated enzyme is slower than the...
The Electron Transport Chain01:30

The Electron Transport Chain

The electron transport chain or oxidative phosphorylation is an exothermic process in which free energy released during electron transfer reactions is coupled to ATP synthesis. This process is a significant source of energy in aerobic cells, and therefore inhibitors of the electron transport chain can be detrimental to the cell's metabolic processes.
Inhibitors of the electron transport chain
Rotenone, a widely used pesticide, prevents electron transfer from Fe-S cluster to ubiquinone or Q in...
Indirect-Acting Cholinergic Agonists: Mechanism of Action01:18

Indirect-Acting Cholinergic Agonists: Mechanism of Action

Indirect-acting cholinergic agonists work by interacting with an enzyme called acetylcholinesterase (AChE) in the synaptic cleft. They can be reversible or irreversible inhibitors and have different effects on the enzyme.
Reversible inhibitors like edrophonium bind to a specific part of the enzyme called the anionic catalytic site. They form noncovalent bonds, which means they are not strongly attached to the enzyme. This creates a temporary and less stable enzyme–inhibitor complex, leading to...
Inhibitors of Gram-positive Cell Wall Synthesis01:23

Inhibitors of Gram-positive Cell Wall Synthesis

Bacterial cell walls are typically rigid structures composed mainly of peptidoglycan, a mesh-like polymer that provides mechanical strength and maintains cell shape. The synthesis of peptidoglycan is a crucial process in bacterial growth and serves as a primary target for many antibiotics.Mechanism of Action of Beta-Lactam AntibioticsBeta-lactam antibiotics, such as penicillin, inhibit peptidoglycan synthesis in actively growing cells. These antibiotics share a characteristic four-membered...
Antifungal Agents01:15

Antifungal Agents

Amphotericin B is a broad-spectrum antifungal agent that exploits structural differences between fungal and mammalian cell membranes. Its amphipathic structure—featuring a hydrophobic polyene-lactone ring and a hydrophilic region containing mycosamine and carboxylic acid groups—enables selective binding to ergosterol, a sterol predominantly found in fungal plasma membranes. This selective interaction underlies the drug’s antifungal activity, although weak binding to cholesterol contributes to...