Upstream eventLipid Peroxidation
Protein Adduct Formation
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|CYP2E1 activation and formation of protein adducts leading to neurodegeneration||adjacent||High||High|
Life Stage Applicability
Key Event Relationship Description
Two main products of lipid peroxidation are MDA and HNE which are highly reactive electrophilic aldehydes. Protein adduct formation by HNE-modification of proteins is the main reaction which occurs in cells after lipid peroxidation. HNE-adducts are also used as markers for lipid peroxidation. There are two main principles of HNE-modification of proteins, the Schiff’s Base Formation and the Michael Addition. Schiff’s Base Formation is the reaction of the aldehydic group of HNE with an amino group of a protein. Where the Michael Addition is a reaction of the HNE double bond to a protein side chain. HNE has the preference for amino acid modification Cys à His à Lys which results in a covalent adduct with the protein nucleophilic side chain.
Evidence Supporting this KER
In the 80s it was already found that HNE can react with proteins and form adducts. Since HNE is a highly reactive electrophilic aldehyde it can easily react with proteins in a timeframe of seconds to minutes. Because of the high reactivity only 1-8% of the HNE formed will interact with proteins, but the number of proteins which are altered lies in the hundreds. Several detection techniques are known to find HNE-adducts, but since some are at low abundance it is hard to find them all. One example is proteomic analysis performed by Andringa et al. After ethanol exposure in rats HNE modified proteins were detected in mitochondria. In a more recent study a direct link was made between lipid peroxidation and protein modifications. With the use of rapid SERS monitoring detection of lipid peroxidation as well as protein modification was performed.
It is known that protein adducts are formed by HNE after lipid peroxidation, so it is biological plausible.
Uncertainties and Inconsistencies
Other aldehyde products of lipid peroxidation can also form protein adducts with proteins. Since HNE is specific for lipid peroxidation it is widely used as marker.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Ayala, A., Muñoz, M. F. & Argüelles, S. Lipid peroxidation: Production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxidative Medicine and Cellular Longevity 2014, (2014).
Andringa, K. K., Udoh, U. S., Landar, A. & Bailey, S. M. Proteomic analysis of 4-hydroxynonenal (4-HNE) modified proteins in liver mitochondria from chronic ethanol-fed rats. Redox Biol. 2, 1038–1047 (2014).
Sultana, R., Perluigi, M. & Butterfield, D. A. Lipid peroxidation triggers neurodegeneration: A redox proteomics view into the Alzheimer disease brain. Free Radical Biology and Medicine 62, 157–169 (2013).
Castro, J. P., Jung, T., Grune, T. & Siems, W. 4-Hydroxynonenal (HNE) modified proteins in metabolic diseases. Free Radical Biology and Medicine 111, 309–315 (2017).
Poli, G. et al. Enzymatic impairment induced by biological aldehydes in intact rat liver cells. Res. Commun. Chem. Pathol. Pharmacol. 38, (1982).
Siems, W. & Grune, T. Intracellular metabolism of 4-hydroxynonenal. in Molecular Aspects of Medicine 24, 167–175 (2003).
Codreanu, S. G., Zhang, B., Sobecki, S. M., Billheimer, D. D. & Liebler, D. C. Global analysis of protein damage by the lipid electrophile 4-hydroxy-2-nonenal. Mol. Cell. Proteomics 8, 670–80 (2009).
Gong, T. et al. Rapid SERS monitoring of lipid-peroxidation-derived protein modifications in cells using photonic crystal fiber sensor. Journal of Biophotonics 9, 32–37 (2016).