Hole hopping through tyrosine/tryptophan chains protects proteins from oxidative damage

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Organisms utilize atmospheric dioxygen but must mitigate risks from reactive oxygen species (ROS) and reactive nitrogen species (RNS).
• Polypeptides are vulnerable to irreversible damage from oxidative stress and reactive intermediates during enzymatic catalysis.
• Cellular protective mechanisms are essential to prevent damage to proteins.

Purpose of the Study:

• To investigate the role of redox-active tyrosine and tryptophan (Tyr/Trp) residue chains in protecting proteins from oxidative damage.
• To determine the prevalence and distribution of Tyr/Trp chains in protein structures.
• To explore the functional implications of Tyr/Trp chains in different enzyme classes.

Main Methods:

• Analysis of protein structural databases to identify and quantify Tyr/Trp chains.
• Correlation of Tyr/Trp chain presence and length with protein function and enzyme class.
• Examination of the spatial arrangement of Tyr/Trp chains relative to active sites.

Main Results:

• Approximately one-third of all proteins contain Tyr/Trp chains of three or more residues.
• These chains are prevalent across all enzyme classes, notably in oxidoreductases and hydrolases.
• A significant portion of dioxygen-using oxidoreductases (approx. 50%) exhibit Tyr/Trp chain lengths ≥3 residues.
• Long Tyr/Trp chains are predominantly found in glycoside hydrolases among hydrolases.

Conclusions:

• Redox-active Tyr/Trp chains serve as a protective mechanism against oxidative damage by sequestering reactive equivalents.
• The precise positioning of these chains is crucial for effective protection without compromising protein function.
• While primarily implicated in redox protection, Tyr/Trp chains may also contribute to substrate binding and positioning in certain enzymes, particularly glycoside hydrolases.