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Potential Mechanisms Linking SIRT Activity And Hypoxic 2-Hydroxyglutarate Generation: No Role For Direct Enzyme (De)acetylation

Sergiy Nadtochiy, Yves T. Wang, Jimmy Zhang, Keith Nehrke, Xenia Schafer, Kevin Welle, Sina Ghaemmaghami, Joshua Munger, View ORCID ProfilePaul Brookes
doi: https://doi.org/10.1101/141416
Sergiy Nadtochiy
University of Rochester Medical Center;
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Yves T. Wang
University of Rochester Medical Center;
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Jimmy Zhang
University of Rochester Medical Center;
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Keith Nehrke
University of Rochester Medical Center;
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Xenia Schafer
University of Rochester Medical Center;
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Kevin Welle
University of Rochester Medical Center;
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Sina Ghaemmaghami
University of Rochester
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Joshua Munger
University of Rochester Medical Center;
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Paul Brookes
University of Rochester Medical Center;
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  • ORCID record for Paul Brookes
  • For correspondence: paul_brookes@urmc.rochester.edu
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Abstract

2-hydroxyglutarate (2-HG) is a hypoxic metabolite with potentially important epigenetic signaling roles. The mechanisms underlying 2-HG generation are poorly understood, but evidence suggests a potential regulatory role for the sirtuin family of lysine deacetylases. Thus, we hypothesized that the acetylation status of the major 2-HG-generating enzymes (isocitrate dehydrogenase (IDH), malate dehydrogenase (MDH) and lactate dehydrogenase (LDH)) may govern their 2-HG generating activity. In-vitro acetylation of these enzymes, with confirmation by western blotting, mass spectrometry, and reversibility by incubation with recombinant sirtuins, yielded no effect on 2-HG generating activity. In addition, while elevated 2-HG in hypoxia is associated with the activation of lysine deacetylases, we found that mice lacking mitochondrial SIRT3 exhibited hyperacetylation and elevated 2-HG. These data suggest there is no direct link between enzyme acetylation and 2-HG production. Furthermore, our observed effects of in-vitro acetylation on the canonical activities of IDH, MDH and LDH appeared to contrast sharply with previous findings wherein acetyl-mimetic lysine mutations resulted in inhibition of these enzymes. Overall these data suggest that a causal relationship should not be assumed, between acetylation of metabolic enzymes and their activities, canonical or otherwise.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted May 24, 2017.
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Potential Mechanisms Linking SIRT Activity And Hypoxic 2-Hydroxyglutarate Generation: No Role For Direct Enzyme (De)acetylation
Sergiy Nadtochiy, Yves T. Wang, Jimmy Zhang, Keith Nehrke, Xenia Schafer, Kevin Welle, Sina Ghaemmaghami, Joshua Munger, Paul Brookes
bioRxiv 141416; doi: https://doi.org/10.1101/141416
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Potential Mechanisms Linking SIRT Activity And Hypoxic 2-Hydroxyglutarate Generation: No Role For Direct Enzyme (De)acetylation
Sergiy Nadtochiy, Yves T. Wang, Jimmy Zhang, Keith Nehrke, Xenia Schafer, Kevin Welle, Sina Ghaemmaghami, Joshua Munger, Paul Brookes
bioRxiv 141416; doi: https://doi.org/10.1101/141416

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