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Open AccessArticle

New Factors Enhancing the Reactivity of Cysteines in Molten Globule-Like Structures

Department of Chemical Sciences and Technologies, University of Rome “Tor Vergata”, 00133 Rome, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Int. J. Mol. Sci. 2020, 21(18), 6949; https://doi.org/10.3390/ijms21186949
Received: 10 September 2020 / Accepted: 16 September 2020 / Published: 22 September 2020
(This article belongs to the Special Issue Protein Folding and Misfolding ---- Structure and Functions)
Protein cysteines often play crucial functional and structural roles, so they are emerging targets to design covalent thiol ligands that are able to modulate enzyme or protein functions. Some of these residues, especially those involved in enzyme mechanisms—including nucleophilic and reductive catalysis and thiol-disulfide exchange—display unusual hyper-reactivity; such a property is expected to result from a low pKa and from a great accessibility to a given reagent. New findings and previous evidence clearly indicate that pKa perturbations can only produce two–four-times increased reactivity at physiological pH values, far from the hundred and even thousand-times kinetic enhancements observed for some protein cysteines. The data from the molten globule-like structures of ribonuclease, lysozyme, bovine serum albumin and chymotrypsinogen identified new speeding agents, i.e., hydrophobic/electrostatic interactions and productive complex formations involving the protein and thiol reagent, which were able to confer exceptional reactivity to structural cysteines which were only intended to form disulfides. This study, for the first time, evaluates quantitatively the different contributions of pKa and other factors to the overall reactivity. These findings may help to clarify the mechanisms that allow a rapid disulfide formation during the oxidative folding of many proteins. View Full-Text
Keywords: oxidative folding; molten globule; cysteine reactivity; chemical kinetics; hydrophobic interaction; transient complex; bovine serum albumin; lysozyme; ribonuclease; chymotrypsinogen oxidative folding; molten globule; cysteine reactivity; chemical kinetics; hydrophobic interaction; transient complex; bovine serum albumin; lysozyme; ribonuclease; chymotrypsinogen
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MDPI and ACS Style

Gambardella, G.; Cattani, G.; Bocedi, A.; Ricci, G. New Factors Enhancing the Reactivity of Cysteines in Molten Globule-Like Structures. Int. J. Mol. Sci. 2020, 21, 6949. https://doi.org/10.3390/ijms21186949

AMA Style

Gambardella G, Cattani G, Bocedi A, Ricci G. New Factors Enhancing the Reactivity of Cysteines in Molten Globule-Like Structures. International Journal of Molecular Sciences. 2020; 21(18):6949. https://doi.org/10.3390/ijms21186949

Chicago/Turabian Style

Gambardella, Giorgia; Cattani, Giada; Bocedi, Alessio; Ricci, Giorgio. 2020. "New Factors Enhancing the Reactivity of Cysteines in Molten Globule-Like Structures" Int. J. Mol. Sci. 21, no. 18: 6949. https://doi.org/10.3390/ijms21186949

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