Protein oxidation

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Fragmentation of a polypeptide chain
A break in a polypeptide strand due to the oxidation of a glutamic acid residue
Polypeptide strand break due to β-cleavage of valine
Cross-link modification: reaction of sugar with a protein-bound lysyl amino group.
Cross-link modification: addition of 4-hydroxynonenal (HNE) to protein-bound lysine (PNH2), histidine (P-His) or cysteine ​​(PSH) residues.
Cross-link modification: addition of malondialdehyde (MDA) to protein amino groups (PNH2).

As protein oxidation refers to molecular changes of proteins caused by oxidants of oxidative stress , such as reactive oxygen or reactive nitrogen species are caused. The term protein oxidation also includes oxidation processes of smaller proteins ( peptides ) and their building blocks, the amino acids . The oxidation of proteins can lead to far-reaching changes in their structure. If the damage to the protein cannot be "repaired" by the cell or if the damaged protein cannot be completely eliminated, this leads to a build-up (accumulation) of defective oxidized proteins in the cell. This accumulation is associated with the aging of the organism and - especially in humans - is associated with a number of pathological conditions , such as diabetes mellitus , arteriosclerosis and various neurodegenerative diseases .

Oxidation processes of proteins

The attack of reactive oxygen and nitrogen species on a protein can take place in different ways. Reaction products of lipid peroxidation , such as 4-hydroxynonenal (HNE) or malondialdehyde (MDA), can also react with the peptides in different ways and are also included in the reactions of protein oxidation. Depending on the reaction mechanism, a distinction is made between the

  • Fragmentation of the polypeptide chain (splitting into two strands),
  • the oxidation of side groups of amino acids and
  • the formation of protein cross-links .

Of the 20 proteinogenic amino acids , more than half can be attacked by oxidative stress. In some cases, reactive groups are formed, such as aldehydes , which can themselves react irreversibly intramolecularly (in the same protein) or intermolecularly (with another protein) with an amino group of lysine or the N-terminus of the protein . The cross-linking of proteins ( protein cross-link ) has a significantly greater effect on the function of a protein than the oxidation of a side group of an amino acid. The cross-linking can result in high-molecular aggregates which can no longer be broken down by proteolysis , for example by the proteasome . These aggregates are then encapsulated and deposited in the cells. An example of such a deposit is the "age pigment" lipofuscin , which mainly accumulates in the cardiomyocytes , hepatocytes and nerve cells . In addition, oxidized proteins are also found in almost all neurodegenerative diseases such as Alzheimer's and Parkinson's disease . In cataracts , cross-links between oxidized proteins are responsible for the development of the disease.

The oxidation of an amino acid in a protein can significantly influence its function, for example as an enzyme or messenger substance . The change in the primary structure can affect both the secondary structure and the tertiary structure . All cell compartments are affected by protein oxidation . It has a significant influence on the homeostasis of the cell. The breakdown of defective (oxidized) proteins is therefore an important task of the proteolytic area of ​​the cell's antioxidant defense system. The slightly oxidized proteins change their tertiary structure massively in that hydrophobic areas of the protein turn outwards. Lysosomal cathepsins and other proteases , as well as the proteasome , recognize these areas as markers and preferentially break down these proteins. On the other hand, more damaged, especially cross-linked proteins are poor substrates for the proteasome and all other proteolytic enzymes and can even inhibit their function . The cross-linking can be obtained by the oxidation of thiol groups (cysteine) to disulfide bonds through the formation of dityrosine of two tyrosine molecules, the reaction of formed by oxidation of aldehyde groups with amino groups to imines (Schiff bases) and the reaction of formed by lipid peroxidation crosslinkers such as 4-hydroxynonenal (HNE) and malondialdehyde (MDA).

The carbonyl proteins formed as a result of the oxidation of proteins can be used in laboratory diagnostics as biomarkers for oxidative stress or for protein oxidation.

further reading

  • R. Widmer: Effect of inhibitors and antioxidants in glial cells in anoxia / reoxygenation and in hepatic encephalopathy. Dissertation, TU Berlin, 2007
  • VI Lushchak: Free radical oxidation of proteins and its relationship with functional state of organisms. In: Biochemistry (Mosc) 72, 2007, pp. 809-827. PMID 17922638 (Review)
  • V. Cecarini et al: Protein oxidation and cellular homeostasis: Emphasis on metabolism. In: Biochim Biophys Acta 1773, 2007, pp. 93-104. PMID 17023064 (Review)
  • B. Chakravarti and DN Chakravarti: Oxidative modification of proteins: age-related changes. In: Gerontology 53, 2007, pp. 128-139. PMID 17164550 (Review)
  • ER Stadtman: Protein oxidation and aging. In: Free Radic Res 40, 2006, pp. 1250-1258. PMID 17090414 (Review)
  • R. Widmer et al: Protein oxidation and degradation during aging: role in skin aging and neurodegeneration. In: Free Radic Res 40, 2006, pp. 1259-1268. PMID 17090415 (Review)
  • TC Squier: Oxidative stress and protein aggregation during biological aging. In: Exp Gerontol 36, 2001, pp. 1539-1550. PMID 11525876 (Review)
  • TC Squier and DJ Bigelow: Protein oxidation and age-dependent alterations in calcium homeostasis. In: Front Biosci 5, 2000, pp. D504-D526. PMID 10799358 (Review)

Individual evidence

  1. ^ ER Stadtman and RL Levine: Chemical modification of proteins by reactive oxygen species. In: Redox Proteomics: From Protein Modifications To Cellular Dysfunction And Diseases. I. Dalle-Donne, A. Scaloni and A. Butterfield (Editors), Wiley Interscience Series on Mass Spectrometry, 2006, ISBN 0-471-72345-2 , p. 4.
  2. ^ ER Stadtman and RL Levine: Chemical modification of proteins by reactive oxygen species. In: Redox Proteomics: From Protein Modifications To Cellular Dysfunction And Diseases. I. Dalle-Donne, A. Scaloni and A. Butterfield (Editors), Wiley Interscience Series on Mass Spectrometry, 2006, ISBN 0-471-72345-2 , p. 5.
  3. ^ ER Stadtman and RL Levine: Chemical modification of proteins by reactive oxygen species. In: Redox Proteomics: From Protein Modifications To Cellular Dysfunction And Diseases. I. Dalle-Donne, A. Scaloni and A. Butterfield (Editors), Wiley Interscience Series on Mass Spectrometry, 2006, ISBN 0-471-72345-2 , p. 6.
  4. ↑ a b c B. S. Berlett and ER Stadtman: Protein oxidation in aging, disease, and oxidative stress. In: J Biol Chem 272, 1997, pp. 20313-20316. PMID 9252331 (Review).
  5. ↑ RT Dean et al.: Biochemistry and pathology of radical-mediated protein oxidation. In: Biochem J 324, 1997, pp. 1-18. PMID 9164834 (Review).
  6. ^ ER Stadtman and RL Levine: Chemical modification of proteins by reactive oxygen species. In: Redox Proteomics: From Protein Modifications To Cellular Dysfunction And Diseases. I. Dalle-Donne, A. Scaloni and A. Butterfield (Editors), Wiley Interscience Series on Mass Spectrometry, 2006, ISBN 0-471-72345-2 , pp. 3-7.
  7. ↑ C. Behl and B. Moosmann: Molecular Mechanisms of Aging About the aging of cells and the influence of oxidative stress on the aging process. In: What is age (es)? UM Staudinger and H. Häfner (editors), Verlag Springer, 2008, doi : 10.1007 / 978-3-540-76711-4 ISBN 978-3-540-76710-7 , pp. 9-32.
  8. ↑ F. Boscia et al: Protein Oxidation and Lens Opacity in Humans. In: Investigative Ophthalmology and Visual Science 41, 2000, pp. 2461-2465. PMID 10937554 .
  9. ^ P. Voss and T. Grune: Degradation and accumulation of oxidized proteins in age-related diseases. In: Redox Proteomics: From Protein Modifications To Cellular Dysfunction And Diseases. I. Dalle-Donne, A. Scaloni and A. Butterfield (Editors), Wiley Interscience Series on Mass Spectrometry, 2006, ISBN 0-471-72345-2 , pp. 527-562.
  10. ↑ B. Catalgol and T. Grune: Protein pool maintenance during oxidative stress. In: Curr Pharm Des 15, 2009, pp. 3043-2051. PMID 19754378 (review).