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Updated: Dec 8, 2025

Deacetylation Assays to Unravel the Interplay between Sirtuins SIRT2 and Specific Protein-substrates
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Human SIRT1 Multispecificity Is Modulated by Active-Site Vicinity Substitutions during Natural Evolution.

Adi Hendler1,2, Eyal Akiva3, Mahakaran Sandhu4

  • 1Department of Life Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel.

Molecular Biology and Evolution
|September 21, 2020
PubMed
Summary
This summary is machine-generated.

The evolution of sirtuin-1 (SIRT1) multispecificity was investigated. Amino acid changes in sirtuins altered substrate specificity, suggesting ancient origins for enzyme multispecificity.

Keywords:
deacetylationmultispecificitysirtuins

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Area of Science:

  • Biochemistry
  • Evolutionary Biology
  • Molecular Biology

Background:

  • Enzymes catalyzing protein post-translational modifications often exhibit multispecificity.
  • The molecular basis and evolutionary trajectory of enzyme multispecificity remain largely unexplored.

Purpose of the Study:

  • To investigate the evolutionary origins of multispecificity in sirtuin-1 (SIRT1).
  • To identify key amino acid substitutions driving changes in SIRT1 substrate specificity.

Main Methods:

  • Combined bioinformatics analysis of sirtuin orthologs and substrates.
  • Experimental investigation of mutant human SIRT1 (hSIRT1) activity.
  • Ancestral sequence reconstruction.

Main Results:

  • Bioinformatics identified critical amino acid substitutions during sirtuin evolution in Metazoa and Fungi.
  • Mutating hSIRT1 at these positions altered substrate specificity, reducing activity towards Metazoa-specific p53 acetylation.
  • Enzyme activity on conserved histone substrates remained unaffected.

Conclusions:

  • SIRT1 multispecificity is influenced by specific amino acid substitutions.
  • Ancestral sirtuins likely possessed multispecificity, indicating it is an ancient trait.
  • The multispecificity of metazoan sirtuins, like hSIRT1, may be a conserved, ancient characteristic.