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