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Synthesis and Evaluation of a Stable Isostere of Malonyllysine

Sarah E. Bergholtz, View ORCID ProfileYihang Jing, View ORCID ProfileRhushikesh A. Kulkarni, Thomas T. Zengeya, View ORCID ProfileJordan L. Meier
doi: https://doi.org/10.1101/2020.08.23.263285
Sarah E. Bergholtz
aChemical Biology Laboratory, National Cancer Institute, Frederick MD, 21702, USA
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Yihang Jing
aChemical Biology Laboratory, National Cancer Institute, Frederick MD, 21702, USA
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Rhushikesh A. Kulkarni
aChemical Biology Laboratory, National Cancer Institute, Frederick MD, 21702, USA
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Thomas T. Zengeya
aChemical Biology Laboratory, National Cancer Institute, Frederick MD, 21702, USA
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Jordan L. Meier
aChemical Biology Laboratory, National Cancer Institute, Frederick MD, 21702, USA
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  • ORCID record for Jordan L. Meier
  • For correspondence: jordan.meier@nih.gov
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Abstract

Lysine malonylation is a recently characterized posttranslational modification involved in the regulation of energy metabolism and gene expression. Two unique features of this posttranslational modification are its negative charge and potential susceptibility to decarboxylation, both of which pose possible challenges to its study. As a step towards addressing these challenges, here we report the synthesis and evaluation of a stable isostere of malonyllysine. First, we find that synthetic substitution of the malonyl group with a tetrazole isostere results in amino acids resistant to thermal decarboxylation. Next, we demonstrate that protected variants of this amino acid are readily incorporated into peptides. Finally, we show that tetrazole isosteres of malonyllysine can be recognized by anti-malonyllysine antibodies, validating their ability to mimic features of the endogenous lysine modification. Overall, this study establishes a new chemical strategy for stably mimicking a metabolite-derived posttranslational modification, providing a foothold for tool development and functional analyses.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 24, 2020.
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Synthesis and Evaluation of a Stable Isostere of Malonyllysine
Sarah E. Bergholtz, Yihang Jing, Rhushikesh A. Kulkarni, Thomas T. Zengeya, Jordan L. Meier
bioRxiv 2020.08.23.263285; doi: https://doi.org/10.1101/2020.08.23.263285
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Synthesis and Evaluation of a Stable Isostere of Malonyllysine
Sarah E. Bergholtz, Yihang Jing, Rhushikesh A. Kulkarni, Thomas T. Zengeya, Jordan L. Meier
bioRxiv 2020.08.23.263285; doi: https://doi.org/10.1101/2020.08.23.263285

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