SIRT3 substrate specificity determined by peptide arrays and machine learning
Open accessAbstract
Accumulating evidence suggests that reversible protein acetylation may be a major regulatory mechanism that rivals phosphorylation. With the recent cataloging of thousands of acetylation sites on hundreds of proteins comes the challenge of identifying the acetyltransferases and deacetylases that regulate acetylation levels. Sirtuins are a conserved family of NAD(+)-dependent protein deacetylases that are implicated in genome maintenance, metabolism, cell survival, and lifespan. SIRT3 is the dominant protein deacetylase in mitochondria, and emerging evidence suggests that SIRT3 may control major pathways by deacetylation of central metabolic enzymes. Here, to identify potential SIRT3 substrates, we have developed an unbiased screening strategy that involves a novel acetyl-lysine analogue (thiotrifluoroacetyl-lysine), SPOT-peptide libraries, machine learning, and kinetic validation. SPOT peptide libraries based on known and potential mitochondrial acetyl-lysine sites were screened for SIRT3 binding and then analyzed using machine learning to establish binding trends. These trends were then applied to the mitochondrial proteome as a whole to predict binding affinity of all lysine sites within human mitochondria. Machine learning prediction of SIRT3 binding correlated with steady-state kinetic k(cat)/K(m) values for 24 acetyl-lysine peptides that possessed a broad range of predicted binding. Thus, SPOT peptide-binding screens and machine learning prediction provides an accurate and efficient method to evaluate sirtuin substrate specificity from a relatively small learning set. These analyses suggest potential SIRT3 substrates involved in several metabolic pathways such as the urea cycle, ATP synthesis, and fatty acid oxidation.
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Sirtuins favor unstructured regions, and SIRT3 favors beta sheets.
“past studies have shown that sirtuins favor either unstructured regions (Khan and Lewis 2005, Smith et al. 2011) or, in the case of SIRT3, beta sheets (Smith et al. 2011).”
From The Mitochondrial Acylome Emerges: Proteomics, Regulation by Sirtuins, and Metabolic and Disease Implications (2018) · cites this paper as Smith et al. 2011
SIRT5 has a major role in controlling lysine succinylation, similar to SIRT3's principal role in mitochondrial lysine acetylation.
“Our data are consistent with a major role for SIRT5 in regulating Ksucc levels, which is analogous to the principal role of SIRT3 in regulating mitochondrial Lys acetylation (Hebert et al., 2013; Lombard et al., 2007; Smith et al., 2011).”
From SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways (2013) · cites this paper as Smith et al., 2011
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SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways
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- Authors
- Smith, B. C., Settles, B., Hallows, W. C., Craven, M. W., & Denu, J. M.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Denu, John M.
- Venue
- ACS Chemical Biology
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-11-01
- Volume
- 6
- Issue
- 2
- Pages
- 146-157
- ISSN
- 1554-8929 (ISSN-L)
- 1554-8937
- PMC
- PMC3042044
- OpenAlex
- W2132373747
- Cited by
- 80
- References
- 75
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 5 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 7 · 2017: 6 · 2016: 15 · 2015: 7 · 2014: 1 · 2013: 7 · 2012: 11
- FWCI
- 2.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Human Genome Research Institute (T32HG002760)
- National Institute of General Medical Sciences (GM-065386, R01GM065386, R37GM059785)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- SIRT3, protein deacetylation, NAD+-dependent deacetylase, mitochondrial proteome, binding kinetics, urea cycle, ATP production, fatty acid oxidation, metabolic enzymes
- MeSH terms
- Acetylation, Amino Acid Sequence, Artificial Intelligence, Computer Simulation, Histone Deacetylases, Humans, Kinetics, Mitochondria, Molecular Sequence Data, NAD, Peptides, Protein Binding, Substrate Specificity, Protein Array Analysis, Sirtuin 3
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