Unlike widely perceived, resveratrol (RSV) decreased the average lifespan and extended only the replicative lifespan in yeast. Similarly, although not widely discussed, RSV is also known to evoke neurite degeneration, kidney toxicity, atherosclerosis, premature senescence, and genotoxicity through yet unknown mechanisms. Nevertheless, in vivo animal models of diseases and human clinical trials demonstrate inconsistent protective and beneficial effects. Therefore, the mechanism of action of RSV that elicits beneficial effects remains an enigma. In a previously published work, we demonstrated structural similarities between RSV and tyrosine amino acid. RSV acts as a tyrosine antagonist and competes with it to bind to human tyrosyl-tRNA synthetase (TyrRS). Interestingly, although both isomers of RSV bind to TyrRS, only the cis-isomer evokes a unique structural change at the active site to promote its interaction with poly-ADP-ribose polymerase 1 (PARP1), a major determinant of cellular NAD⁺-dependent stress response. However, retention of trans-RSV in the active site of TyrRS mimics its tyrosine-bound conformation that inhibits the auto-poly-ADP-ribos(PAR)ylation of PARP1. Therefore, we proposed that cis-RSV-induced TyrRS-regulated auto-PARylation of PARP1 would contribute, at least in part, to the reported health benefits of RSV through the induction of protective stress response. This observation suggested that trans-RSV would inhibit TyrRS/PARP1-mediated protective stress response and would instead elicit an opposite effect compared to cis-RSV. Interestingly, most recent studies also confirmed the conversion of trans-RSV and its metabolites to cis-RSV in the physiological context. Therefore, the finding that cis-RSV and trans-RSV induce two distinct conformations of TyrRS with opposite effects on the auto-PARylation of PARP1 provides a potential molecular basis for the observed dichotomic effects of RSV under different experimental paradigms. However, the fact that natural RSV exists as a diastereomeric mixture of its cis and trans isomers and cis-RSV is also a physiologically relevant isoform has not yet gained much scientific attention.

与人们普遍认为的不同，白藜芦醇 (RSV) 会缩短酵母的平均寿命，仅延长其复制寿命。同样，虽然没有广泛讨论，但 RSV 也已知会通过未知的机制引起神经突变性、肾毒性、动脉粥样硬化、过早衰老和遗传毒性。然而，体内疾病动物模型和人体临床试验显示出不一致的保护作用和有益作用。因此，RSV 产生有益作用的作用机制仍然是一个谜。在之前发表的工作中，我们证明了 RSV 和酪氨酸氨基酸之间的结构相似性。 RSV 作为酪氨酸拮抗剂并与其竞争与人酪氨酰-tRNA 合成酶 (TyrRS) 的结合。有趣的是，虽然 RSV 的两种异构体均与 TyrRS 结合，但只有顺式异构体在活性位点引起独特的结构变化，以促进其与聚 ADP 核糖聚合酶 1 (PARP1) 的相互作用，而聚 ADP 核糖聚合酶 1 (PARP1) 是细胞 NAD ⁺依赖性的主要决定因素应激反应。然而，反式RSV 在 TyrRS 活性位点的保留模拟了其酪氨酸结合构象，抑制了 PARP1 的自聚 ADP 核糖 (PAR) 化。因此，我们提出，顺式RSV诱导的TyrRS调节的PARP1自动PARylation将至少部分地通过诱导保护性应激反应而有助于报道的RSV健康益处。这一观察结果表明，反式RSV会抑制TyrRS/PARP1介导的保护性应激反应，并且与顺式RSV相比反而会引起相反的作用。 有趣的是，最近的研究也证实了反式RSV及其代谢物在生理背景下转化为顺式RSV。因此，顺式RSV和反式RSV诱导TyrRS的两种不同构象，对PARP1的自PAR化具有相反的作用，这一发现为在不同实验范式下观察到的RSV二分效应提供了潜在的分子基础。然而，天然RSV以其顺式和反式异构体的非对映异构体混合物存在以及顺式-RSV也是一种生理相关亚型这一事实尚未引起科学界的广泛关注。