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A new view on functions of the lysine demalonylase activity of SIRT5

Jarmila Nahálková1

  • 1Biochemistry, Molecular, and Cell Biology Unit, Biochemworld Co., Snickar-Anders väg 17, 74394 Skyttorp, Uppsala County, Sweden.

Life Sciences
|March 15, 2023
PubMed
Abstract

Insights

SIRT5 demalonylation impacts translation and metabolism, with unique substrates offering pharmaceutical potential. This study clarifies SIRT5 malonylome functions beyond glucose control, revealing differences from other SIRT5 activities.

Area of Science:

  • Biochemistry and Molecular Biology
  • Metabolomics
  • Systems Biology

Background:

  • SIRT5, a sirtuin enzyme, plays a role in post-translational modification through lysine demalonylation.
  • The precise substrate specificity and functional implications of SIRT5 demalonylation, particularly concerning its tumor promoter/suppressor roles, remain incompletely understood.
  • Bioinformatic approaches can uncover novel insights into protein function and substrate interactions.

Purpose of the Study:

  • To comprehensively clarify the substrates and pathways regulated by SIRT5-mediated lysine demalonylation.
  • To identify potential pharmaceutical targets by analyzing the functional roles of SIRT5 substrates.
  • To compare SIRT5 malonylome with other SIRT5 enzymatic activities and malonylome in different physiological states.

Main Methods:

  • Bioinformatic analysis of publicly available data.
  • Interaction network analysis of the SIRT5 malonylome in wild-type and obese pre-diabetic (ob/ob) mice using GeneMANIA within Cytoscape.
  • Pathway enrichment and gene function prediction.

Main Results:

  • In wild-type mice, SIRT5 malonylome is implicated in Eukaryotic Translation Elongation (ETE), Amino Acid and Derivative Metabolism (AADM), and Selenoamino Acid Metabolism (SAM).
  • SIRT5's tumor-associated functions involve substrates in AADM (e.g., GLUD1, SHMT1, ACAT1) and SAM (e.g., ALDH9A1, BHMT, GNMT).
  • A regulatory loop exists where selenium stimulates SIRT5 expression, and SIRT5 regulates selenocysteine synthesis. In ob/ob mice, the mTORC1 pathway facilitates SIRT5 functions. Differences were noted compared to SIRT5 succinylome and glutarylome.

Conclusions:

  • SIRT5 malonylome has functions extending beyond glucose metabolism, involving unique substrates and pathways.
  • The identified substrates and pathways present distinct characteristics compared to other SIRT5 enzymatic activities.
  • These findings offer potential avenues for pharmaceutical development targeting SIRT5-mediated demalonylation.
Keywords:
Eukaryotic translation elongationLysine malonylationSIRT5SelenocysteineTumor promoterTumor suppressor

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