Reactions of electrophiles with nucleophilic thiolate sites: Relevance to pathophysiological mechanisms and remediation

Richard M. LoPachin, Terrence Gavin

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Electrophiles are electron-deficient species that form covalent bonds with electron-rich nucleophiles. In biological systems, reversible electrophile-nucleophile interactions mediate basal cytophysiological functions (e.g. enzyme regulation through S-nitrosylation), whereas irreversible electrophilic adduction of cellular macromolecules is involved in pathogenic processes that underlie many disease and injury states. The nucleophiles most often targeted by electrophiles are side chains on protein amino acids (e.g. Cys, His, and Lys) and aromatic nitrogen sites on DNA bases (e.g. guanine N7). The sulfhydryl thiol (RSH) side chain of cysteine residues is a weak nucleophile that can be ionized in specific conditions to a more reactive nucleophilic thiolate (RS-). This review will focus on electrophile interactions with cysteine thiolates and the pathophysiological consequences that result from irreversible electrophile modification of this anionic sulfur. According to the Hard and Soft, Acids and Bases (HSAB) theory of Pearson, electrophiles and nucleophiles can be classified as either soft or hard depending on their relative polarizability. HSAB theory suggests that electrophiles will preferentially and more rapidly form covalent adducts with nucleophiles of comparable softness or hardness. Application of HSAB principles, in conjunction with in vitro and proteomic studies, have indicated that soft electrophiles of broad chemical classes selectively form covalent Michael-type adducts with soft, highly reactive cysteine thiolate nucleophiles. Therefore, these electrophiles exhibit a common mechanism of cytotoxicity. As we will discuss, this level of detailed mechanistic understanding is a necessary prerequisite for the rational development of effective prevention and treatment strategies for electrophile-based pathogenic states.

Original languageEnglish (US)
Pages (from-to)195-205
Number of pages11
JournalFree Radical Research
Volume50
Issue number2
DOIs
StatePublished - Feb 1 2016

Fingerprint

Nucleophiles
Remediation
Acids
Electrons
Hardness
Guanine
Sulfur
Sulfhydryl Compounds
Proteomics
Cysteine
Nitrogen
Amino Acids
DNA
Wounds and Injuries
Enzymes
Covalent bonds
Biological systems
Cytotoxicity
Macromolecules
Proteins

Keywords

  • 4-hydroxy-2-nonenal
  • Acrolein
  • mechanisms of cell injury
  • oxidative stress
  • unsaturated aldehyde toxicity

ASJC Scopus subject areas

  • Biochemistry

Cite this

Reactions of electrophiles with nucleophilic thiolate sites : Relevance to pathophysiological mechanisms and remediation. / LoPachin, Richard M.; Gavin, Terrence.

In: Free Radical Research, Vol. 50, No. 2, 01.02.2016, p. 195-205.

Research output: Contribution to journalArticle

@article{f4f0dd4f79a5485c872aeb63707b8376,
title = "Reactions of electrophiles with nucleophilic thiolate sites: Relevance to pathophysiological mechanisms and remediation",
abstract = "Electrophiles are electron-deficient species that form covalent bonds with electron-rich nucleophiles. In biological systems, reversible electrophile-nucleophile interactions mediate basal cytophysiological functions (e.g. enzyme regulation through S-nitrosylation), whereas irreversible electrophilic adduction of cellular macromolecules is involved in pathogenic processes that underlie many disease and injury states. The nucleophiles most often targeted by electrophiles are side chains on protein amino acids (e.g. Cys, His, and Lys) and aromatic nitrogen sites on DNA bases (e.g. guanine N7). The sulfhydryl thiol (RSH) side chain of cysteine residues is a weak nucleophile that can be ionized in specific conditions to a more reactive nucleophilic thiolate (RS-). This review will focus on electrophile interactions with cysteine thiolates and the pathophysiological consequences that result from irreversible electrophile modification of this anionic sulfur. According to the Hard and Soft, Acids and Bases (HSAB) theory of Pearson, electrophiles and nucleophiles can be classified as either soft or hard depending on their relative polarizability. HSAB theory suggests that electrophiles will preferentially and more rapidly form covalent adducts with nucleophiles of comparable softness or hardness. Application of HSAB principles, in conjunction with in vitro and proteomic studies, have indicated that soft electrophiles of broad chemical classes selectively form covalent Michael-type adducts with soft, highly reactive cysteine thiolate nucleophiles. Therefore, these electrophiles exhibit a common mechanism of cytotoxicity. As we will discuss, this level of detailed mechanistic understanding is a necessary prerequisite for the rational development of effective prevention and treatment strategies for electrophile-based pathogenic states.",
keywords = "4-hydroxy-2-nonenal, Acrolein, mechanisms of cell injury, oxidative stress, unsaturated aldehyde toxicity",
author = "LoPachin, {Richard M.} and Terrence Gavin",
year = "2016",
month = "2",
day = "1",
doi = "10.3109/10715762.2015.1094184",
language = "English (US)",
volume = "50",
pages = "195--205",
journal = "Free Radical Research",
issn = "1071-5762",
publisher = "Informa Healthcare",
number = "2",

}

TY - JOUR

T1 - Reactions of electrophiles with nucleophilic thiolate sites

T2 - Relevance to pathophysiological mechanisms and remediation

AU - LoPachin, Richard M.

AU - Gavin, Terrence

PY - 2016/2/1

Y1 - 2016/2/1

N2 - Electrophiles are electron-deficient species that form covalent bonds with electron-rich nucleophiles. In biological systems, reversible electrophile-nucleophile interactions mediate basal cytophysiological functions (e.g. enzyme regulation through S-nitrosylation), whereas irreversible electrophilic adduction of cellular macromolecules is involved in pathogenic processes that underlie many disease and injury states. The nucleophiles most often targeted by electrophiles are side chains on protein amino acids (e.g. Cys, His, and Lys) and aromatic nitrogen sites on DNA bases (e.g. guanine N7). The sulfhydryl thiol (RSH) side chain of cysteine residues is a weak nucleophile that can be ionized in specific conditions to a more reactive nucleophilic thiolate (RS-). This review will focus on electrophile interactions with cysteine thiolates and the pathophysiological consequences that result from irreversible electrophile modification of this anionic sulfur. According to the Hard and Soft, Acids and Bases (HSAB) theory of Pearson, electrophiles and nucleophiles can be classified as either soft or hard depending on their relative polarizability. HSAB theory suggests that electrophiles will preferentially and more rapidly form covalent adducts with nucleophiles of comparable softness or hardness. Application of HSAB principles, in conjunction with in vitro and proteomic studies, have indicated that soft electrophiles of broad chemical classes selectively form covalent Michael-type adducts with soft, highly reactive cysteine thiolate nucleophiles. Therefore, these electrophiles exhibit a common mechanism of cytotoxicity. As we will discuss, this level of detailed mechanistic understanding is a necessary prerequisite for the rational development of effective prevention and treatment strategies for electrophile-based pathogenic states.

AB - Electrophiles are electron-deficient species that form covalent bonds with electron-rich nucleophiles. In biological systems, reversible electrophile-nucleophile interactions mediate basal cytophysiological functions (e.g. enzyme regulation through S-nitrosylation), whereas irreversible electrophilic adduction of cellular macromolecules is involved in pathogenic processes that underlie many disease and injury states. The nucleophiles most often targeted by electrophiles are side chains on protein amino acids (e.g. Cys, His, and Lys) and aromatic nitrogen sites on DNA bases (e.g. guanine N7). The sulfhydryl thiol (RSH) side chain of cysteine residues is a weak nucleophile that can be ionized in specific conditions to a more reactive nucleophilic thiolate (RS-). This review will focus on electrophile interactions with cysteine thiolates and the pathophysiological consequences that result from irreversible electrophile modification of this anionic sulfur. According to the Hard and Soft, Acids and Bases (HSAB) theory of Pearson, electrophiles and nucleophiles can be classified as either soft or hard depending on their relative polarizability. HSAB theory suggests that electrophiles will preferentially and more rapidly form covalent adducts with nucleophiles of comparable softness or hardness. Application of HSAB principles, in conjunction with in vitro and proteomic studies, have indicated that soft electrophiles of broad chemical classes selectively form covalent Michael-type adducts with soft, highly reactive cysteine thiolate nucleophiles. Therefore, these electrophiles exhibit a common mechanism of cytotoxicity. As we will discuss, this level of detailed mechanistic understanding is a necessary prerequisite for the rational development of effective prevention and treatment strategies for electrophile-based pathogenic states.

KW - 4-hydroxy-2-nonenal

KW - Acrolein

KW - mechanisms of cell injury

KW - oxidative stress

KW - unsaturated aldehyde toxicity

UR - http://www.scopus.com/inward/record.url?scp=84955459129&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955459129&partnerID=8YFLogxK

U2 - 10.3109/10715762.2015.1094184

DO - 10.3109/10715762.2015.1094184

M3 - Article

C2 - 26559119

AN - SCOPUS:84955459129

VL - 50

SP - 195

EP - 205

JO - Free Radical Research

JF - Free Radical Research

SN - 1071-5762

IS - 2

ER -