Evolutionary Biochemistry and Redox Medicine, Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Cellular Adaptation Group, Institute for Pathobiochemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
Redox Biol. 2020 Sep;36:101628. doi: 10.1016/j.redox.2020.101628. Epub 2020 Jun 30.
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.
半胱氨酸可以说是研究最充分的生物氨基酸，其巯基基团经常参与蛋白质的催化或配体结合。尽管如此，半胱氨酸在生物中的异常分布仍然是个谜，它在跨膜结构域和可及蛋白质表面的存在显著不足，特别是在需氧生命形式中（“半胱氨酸异常”）。我们注意到亲脂性硫醇已在聚合物化学中被使用了几十年作为自由基链转移剂，因此我们推测疏水分子相中硫基自由基的快速形成可能为半胱氨酸异常提供了一种解释。因此，我们研究了十二硫醇和相关化合物在分离的生物膜、培养的人类细胞和整个动物（秀丽隐杆线虫）中的作用。我们发现，在微摩尔浓度下，亲脂性硫醇是有效的加速剂，但不是脂质过氧化的诱导剂，可催化脂肪酸异构化为反式脂肪酸，并引发与蛋白质和 DNA 损伤相关的大量细胞应激反应。这些作用是亲脂性硫醇特有的，而硫醚、醇或亲水性化合物则没有。硫基自由基的催化链转移活性似乎深刻地影响了生命的结构生物学，这反映在半胱氨酸异常中。链转移剂代表了一类新的生物细胞毒素，它们选择性地在体内加速氧化损伤。
