Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation

Abstract

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-ADPribose 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 autopoly-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/PARP1mediated 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. Keywords Resveratrol (RSV). Aminoacyl-tRNA synthetases (aaRSs). Tyrosyl-tRNA synthetase (YARS. TyrRS). Nicotinamide adenine nucleotide (NAD +). Poly-ADP-ribose polymerase (PARP). Sirtuins (SIRT). AMP-activated protein kinase (AMPK). Nicotinamide (NAM) GeroScience

Role of Resveratrol in Prevention and Control of Cardiovascular Disorders and Cardiovascular Complications Related to Covid-19 Disease: Mode of Action and Approaches Explored to Increase Its Bioavailability

“…When exposed to UV and visible light, trans-resveratrol converts to cis-resveratrol (Z) by photo-isomerization [4]. Cisresveratrol is not well explored despite the findings from in vivo intestinal epithelial model studies that trans-resveratrol converts to cis-resveratrol in vivo [5] and that cisresveratrol is also biologically active form [6]. The glucose-bound form of resveratrol, piceid (also named Polydatin), is the major resveratrol derivative in food sources and it is converted to trans-resveratrol by hydrolysis.…”

“…The studies indicate a biphasic dose-response of resveratrol wherein the low doses of resveratrol have health-promoting effects while higher dose treatments reveal detrimental effects. This hormetic dose-response is characterized by low-dose stimulation and a highdose inhibition [6].…”

“…Structure of SIRT 1 in complex with the AMC peptide revealed that two out of three bound RESV molecules mediated the interaction between the AMC peptide and the N-terminal domain (NTD) of SIRT 1 (Figure 3A) thus promoting tighter binding and stimulation of SIRT 1 activity [173]. Aligning amino acid sequences of yeast sirtuin 2 (Sir2) and its mammalian homologue SIRT 1 to other 6 mammalian SIRTs (2)(3)(4)(5)(6)(7) shows that the NTD is unique to Sir2 and SIRT1 (Figure 3B), which may explain RESVs selectivity toward the isoform 1 [174]. The allosteric model of RESV enhanced substrate activation of SIRT 1 has some limitations, such as it does not explain why RESV has no activity toward the native p53 substrate.…”

Role of Resveratrol in Prevention and Control of Cardiovascular Disorders and Cardiovascular Complications Related to COVID-19 Disease: Mode of Action and Approaches Explored to Increase Its Bioavailability

“…When exposed to UV and visible light, trans -resveratrol converts to cis -resveratrol (Z) by photo-isomerization [ 4 ]. Cis -resveratrol is not well explored despite the findings from in vivo intestinal epithelial model studies that trans -resveratrol converts to cis -resveratrol in vivo [ 5 ] and that cis -resveratrol is also a biologically active form [ 6 ]. The glucose-bound form of resveratrol, piceid (also named Polydatin), is the major resveratrol derivative in food sources and it is converted to trans -resveratrol by hydrolysis.…”

“…The studies indicate a biphasic dose-response of resveratrol wherein the low doses of resveratrol have health-promoting effects while higher dose treatments reveal detrimental effects. This hormetic dose-response is characterized by low-dose stimulation and a high-dose inhibition [ 6 ].…”