Prooxidative chain transfer activity by thiol groups in biological systems

Abstract

Cysteine is arguably the best-studied biological amino acid, whose thiol group frequently participates in catalysis or ligand binding by proteins. Still, cysteine's unusual biological distribution has remained mysterious, being strikingly underrepresented in transmembrane domains and on accessible protein surfaces, particularly in aerobic life forms (“cysteine anomaly”). Noting that lipophilic thiols have been used for decades as radical chain transfer agents in polymer chemistry, we speculated that the rapid formation of thiyl radicals in hydrophobic phases might provide a rationale for the cysteine anomaly. Hence, we have investigated the effects of dodecylthiol and related compounds in isolated biomembranes, cultivated human cells and whole animals ( C. elegans ). We have found that lipophilic thiols at micromolar concentrations were efficient accelerators, but not inducers of lipid peroxidation, catalyzed fatty acid isomerization to trans -fatty acids, and evoked a massive cellular stress response related to protein and DNA damage. These effects were specific for lipophilic thiols and were absent with thioethers, alcohols or hydrophilic compounds. Catalytic chain transfer activity by thiyl radicals appears to have deeply influenced the structural biology of life as reflected in the cysteine anomaly. Chain transfer agents represent a novel class of biological cytotoxins that selectively accelerate oxidative damage in vivo .

The selective degradation of sirtuins via macroautophagy in the MPP+ model of Parkinson’s disease is promoted by conserved oxidation sites

“…SIRTs were extracted via immunoprecipitation (antibody dilution 1:50) following standard procedure [ 14 ]. Carbonylation of proteins was analyzed via immunoblot according to published protocols [ 58 ].…”

Flux control in the aging cascade

“…Accelerating termination is the designated task of chain-breaking antioxidants like vitamin E. Propagation, though, has never been shown to be specifically influenced by any biomolecule [ 3 ]. It is only modulated by the availability of substrate (S) and the presence (or absence) of chain-transfer catalysts, which increase the propagation constant [ 3 , 8 ]. The two most robust evolutionary adaptations of long-lived animals, lowered polyunsaturated fatty acids [ 4 ], and fewer intramembrane cysteine residues [ 7 ], both slow down propagation, but have no direct connection to initiation or termination [ 3 , 8 ].…”

“…Lowering temperature universally prolongs life in invertebrates but is a rather pleiotropic intervention. Surprisingly specific, though, are the “peroxidation index-lifespan correlation” [ 4 , 6 ], and the “cysteine-lifespan correlation” [ 7 , 8 ]. Long-lived animals exhibit lower contents of polyunsaturated fatty acids, which are the prototypic substrates of lipid peroxidation [ 4 , 5 ].…”

“…Long-lived animals exhibit lower contents of polyunsaturated fatty acids, which are the prototypic substrates of lipid peroxidation [ 4 , 5 ]. In perfect complementation, long-lived animals also exhibit lower numbers of intramembrane cysteine residues (in mitochondria), which avoids chain-transfer catalysis by thiol groups that would otherwise accelerate radical propagation between fatty acids [ 8 ]. Both correlations are valid across phylogenetic boundaries and are by far more robust than any runner-up.…”

“…Both correlations are valid across phylogenetic boundaries and are by far more robust than any runner-up. Moreover, basic experimental evidence of causality has been obtained for each of them [ 6 , 8 ]. Since both adaptations alter the complex molecular architecture of the cell, it becomes increasingly intelligible why longevity is such a slowly evolving trait.…”