2 replies to this topic

[geo12the]

interesting:

 

http://www.scienceda...41222111940.htm

 

[geo12the]

abstract of the study discussed in the above link:

 

A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol

• Mathew Sajish
• & Paul Schimmel

• Affiliations
• Contributions
• Corresponding author

Nature   (2014)   doi:10.1038/nature14028 Received   19 March 2014  Accepted   03 November 2014  Published online   22 December 2014

Resveratrol is reported to extend lifespan^1, 2 and provide cardio-neuro-protective³, anti-diabetic⁴, and anti-cancer effects^3, 5 by initiating a stress response² that induces survival genes. Because human tyrosyl transfer-RNA (tRNA) synthetase (TyrRS) translocates to the nucleus under stress conditions⁶, we considered the possibility that the tyrosine-like phenolic ring of resveratrol might fit into the active site pocket to effect a nuclear role. Here we present a 2.1 Å co-crystal structure of resveratrol bound to the active site of TyrRS. Resveratrol nullifies the catalytic activity and redirects TyrRS to a nuclear function, stimulating NAD⁺-dependent auto-poly-ADP-ribosylation of poly(ADP-ribose) polymerase 1 (PARP1). Downstream activation of key stress signalling pathways are causally connected to TyrRS–PARP1–NAD⁺ collaboration. This collaboration is also demonstrated in the mouse, and is specifically blocked in vivo by a resveratrol-displacing tyrosyl adenylate analogue. In contrast to functionally diverse tRNA synthetase catalytic nulls created by alternative splicing events that ablate active sites⁷, here a non-spliced TyrRS catalytic null reveals a new PARP1- and NAD⁺-dependent dimension to the physiological mechanism of resveratrol.

 

 

[bixbyte]

Outsiders to the Controversy

Schimmel and Sajish came to this controversy as outsiders. Schimmel’s laboratory is known for its work not on resveratrol but on an ancient family of enzymes, the tRNA synthetases. The primary and essential function of these enzymes is to help translate genetic material into the amino-acid building blocks that make proteins. But as Schimmel and others have shown since the late 1990s, tRNA synthetases have acquired an extensive set of added functions in mammals.

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Tracking the resveratrol-bound TyrRS in the nucleus, the researchers determined that it grabs and activates the protein, PARP-1, a major stress response and DNA-repair factor thought to have a significance influence on lifespan. The scientists confirmed the interaction in mice injected with resveratrol. TyrRS’s activation of PARP-1 led, in turn, to the activation of a host of protective genes including the tumor-suppressor gene p53 and the longevity genes FOXO3A and SIRT6.

 

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The team’s experiments showed, however, that the TyrRS-PARP-1 pathway can be measurably activated by much lower doses of resveratrol—as much as 1,000 times lower—than were used in some of the more celebrated prior studies, including those focused on SIRT1. “Based on these results, it is conceivable that moderate consumption of a couple glasses of red wine (rich in resveratrol) would give a person enough resveratrol to evoke a protective effect via this pathway,” Sajish said. He also suspects that effects of resveratrol that only appear at unrealistically high doses may have confounded some prior findings.

Why would resveratrol, a protein produced in plants, be so potent and specific in activating a major stress response pathway in human cells? Probably because it does much the same in plant cells, and probably again via TyrRS—a protein so fundamental to life, due to its linkage to an amino acid, that it hasn’t changed much in the hundreds of millions of years since plants and animals went their separate evolutionary ways. “We believe that TyrRS has evolved to act as a top-level switch or activator of a fundamental cell-protecting mechanism that works in virtually all forms of life,” said Sajish.

Whatever activity resveratrol naturally has in mammals may be an example of hormesis: the mild, health-promoting activation of a natural stress response. “If resveratrol brought significant benefits to mammals, they might have evolved a symbiotic relationship with resveratrol-producing plants,” Sajish said.

 

 

http://www.news-medi...hows-study.aspx