Towards resolving the enigma of the dichotomy of resveratrol: cis - and trans- resveratrol have opposite effects on TyrR
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ORIGINAL ARTICLE
Towards resolving the enigma of the dichotomy of resveratrol: cis- and trans-resveratrol have opposite effects on TyrRS-regulated PARP1 activation Megha Jhanji
&
Chintada Nageswara Rao
&
Mathew Sajish
Received: 21 July 2020 / Accepted: 28 October 2020 # American Aging Association 2020
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 autoPARylation 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 cisRSV in the physiological context. Therefore, the finding that cis-RSV and trans-RSV induce two distinct conformations of TyrRS with opposite effects on the autoPARylation 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.
M. Jhanji : C. N. Rao : M. Sajish (*) Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA e-mail: [email protected]
Natural resveratrol (RSV or 3,5,4′-trihydroxystilbene) is an important constituent of the ayurvedic medicine “Drakshasava,” a well-known Indian herbal preparation from grapes prescribed as a cardiotonic [1]. (Draksha is the Sanskrit word for grape. “Asava” means “distillate,”
Keywords Resveratrol (RSV) . Aminoacyl-tRNA synthetases (aaRSs) . Tyrosyl-tRNA synthetase (YARS . TyrRS)
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