Protein damage by reactive electrophiles: targets and consequences

Area of Science:

• Toxicology and Molecular Biology
• Chemical Carcinogenesis and Drug Toxicity

Background:

• Protein covalent binding by carcinogens was first described 60 years ago.
• Initially overshadowed by DNA adducts, protein binding re-emerged as crucial for drug and chemical toxicity in the 1970s.
• Technological limitations in characterizing protein adducts were overcome by mass spectrometry-based proteomics in the late 1990s.

Purpose of the Study:

• To review the progress in characterizing protein targets of electrophiles and the consequences of protein damage.
• To highlight the current technological capabilities for mapping electrophile damage.
• To emphasize the link between protein adducts and clinically relevant health effects.

Main Methods:

• Integration of novel affinity chemistries for electrophile probes.
• Application of shotgun proteomics methods.
• Utilization of systems modeling tools for analysis.

Main Results:

• Identification of hundreds of protein targets for electrophiles in mammalian systems.
• Capability to map damage to critical signaling pathways and metabolic networks.
• Understanding of damage mechanisms at a systems level.

Conclusions:

• Sensitive and specific analyses for protein adducts are now available.
• These analyses can link damage from xenobiotic and endogenous electrophiles to health outcomes.
• This approach offers a means to connect chemical exposures and disease processes to clinical health effects.