Efficient Demyristoylase Activity of SIRT2 Revealed by Kinetic and Structural Studies
Open accessAbstract
Sirtuins are a class of enzymes originally identified as nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacetylases. Among the seven mammalian sirtuins, SIRT1-7, only SIRT1-3 possess efficient deacetylase activity in vitro, whereas SIRT4-7 possess very weak in vitro deacetylase activity. Several sirtuins that exhibit weak deacetylase activity have recently been shown to possess more efficient activity for the removal other acyl lysine modifications, such as succinyl lysine and palmitoyl lysine. Here, we demonstrate that even the well-known deacetylase SIRT2 possesses efficient activity for the removal of long-chain fatty acyl groups. The catalytic efficiency (kcat/Km) for the removal of a myristoyl group is slightly higher than that for the removal of an acetyl group. The crystal structure of SIRT2 in complex with a thiomyristoyl peptide reveals that SIRT2 possesses a large hydrophobic pocket that can accommodate the myristoyl group. Comparison of the SIRT2 acyl pocket to those of SIRT1, SIRT3 and SIRT6 reveals that the acyl pockets of SIRT1-3 are highly similar and to a lesser degree, similar to that of SIRT6. The efficient in vitro demyristoylase activity of SIRT2 suggests that this activity may be physiologically relevant and warrants future investigative studies.
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This is the first report of a zinc-dependent HDAC with defatty-acylation activity.
“While some of the sirtuins, the NAD+-dependent HDACs, have been recognized as protein defatty-acylases,12,16,17 this is the first report of a zinc-dependent HDAC possessing this enzymatic activity.”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [17]
Several NAD+-dependent deacetylases, SIRT1, SIRT2, SIRT3 and SIRT6, have been previously reported to possess lysine defatty-acylation activities.
“Several NAD+-dependent deacetylase, SIRT1, SIRT2, SIRT3 and SIRT6, have been previously reported to possess lysine defatty-acylation activities.15-17”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [17]
SIRT1, 2, 3 and SIRT6 are capable of hydrolyzing long chain fatty acyl groups from lysine residues.
“and SIRT1, 2, 3 and SIRT6 are capable of hydrolyzing long chain fatty acyl groups from lysine residues.15-17”
From HDAC8 catalyzes the hydrolysis of long chain fatty acyl lysine (2016) · cites this paper as [17]
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- Authors
- Teng, Y.-B., Jing, H., Aramsangtienchai, P., He, B., Khan, S., Hu, J., Lin, H., & Hao, Q.
- Affiliations
- Cornell University (US)
- Corresponding author
- Lin, Hening
- Hao, Quan
- Venue
- Scientific Reports
- Published
- 2015-02-23
- Volume
- 5
- Issue
- 1
- Pages
- 8529-8529
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4894398
- OpenAlex
- W2087497962
- Cited by
- 184
- References
- 36
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 16 · 2023: 12 · 2022: 13 · 2021: 17 · 2020: 16 · 2019: 13 · 2018: 27 · 2017: 14 · 2016: 27 · 2015: 7
- FWCI
- 12.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion, cc-by-nc-nd)
- Funders
- National Science Foundation
- National Institutes of Health
- National Cancer Institute (R01CA152870)
- National Institute of General Medical Sciences (P41GM103485)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- SIRT2, NAD+-dependent deacetylase, catalytic efficiency, SIRT1, SIRT3, SIRT6
- MeSH terms
- Binding Sites, Chromatography, High Pressure Liquid, Fatty Acids, Monounsaturated, Histones, Humans, Crystallography, X-Ray, Catalytic Domain, Lipopeptides, Molecular Dynamics Simulation, Sirtuin 2
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