A selective inhibitor of N8-acetylspermidine deacetylation in mice and hela cells without effects on histone deacetylation
Abstract
The inhibitory effects of 7-[N-(3-aminopropyl)amino]heptan-2-one (APAH) on N8-acetylspermidine deacetylation were studied. In in vitro studies, APAH produced inhibition (apparent Ki of 0.18 microM) of N8-acetylspermidine deacetylation by the 100,000g supernatant fraction of rat liver. This apparent Ki was 60-fold less than the apparent Km (11 microM) for deacetylation of the substrate, N8-acetylspermidine, suggesting that APAH could be a potent, effective inhibitor in vivo. APAH was administered to mice by intraperitoneal injection at a dose of 200 mg/kg, and polyamine and acetylpolyamine levels in liver and spleen were measured. In tissues of control mice, N8-acetylspermidine was not detectable but increased to detectable levels 30-360 min after APAH treatment. These data are consistent with inhibition of the deacetylase by APAH. Increases in putrescine and N1-acetylspermidine levels occurred in liver after APAH treatment with increases in N1-acetylspermidine levels observed in spleen. In HeLa cells, a significant increase in N8-acetylspermidine was observed following 24 h exposure to 10 microM APAH while no change occurred in the acetylation level of HeLa cell histones. In contrast, 24 h exposure to 10 mM sodium butyrate produced no change in N8-acetylspermidine levels and an increase in the acetylation level of histones H4 and H2B. These results suggest that APAH has a relatively selective inhibitory effect on N8-acetylspermidine but not histone deacetylation. This is the first report of significant levels of N8-acetylspermidine in animal tissues and of the effects of in vivo inhibition of N8-acetylspermidine deacetylase.
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Substrate specificity trends observed for zHDAC10 and hHDAC10 matched those of previously reported mammalian N8-acetylspermidine deacetylase activity.
“Substrate specificity trends observed for zHDAC10 and hHDAC10 matched those of the previously reported mammalian N8-acetylspermidine deacetylase activity91011.”
From Histone deacetylase 10 structure and molecular function as a polyamine deacetylase (2017) · cites this paper as [11]
Selective inhibition of PDAC activity in HeLa cells increases N8-acetylspermidine levels but not acetylated histone levels, so PDAC activity is distinct from HDAC activity.
“Selective inhibition of PDAC activity in HeLa cells increases N8-acetylspermidine levels but not acetylated histone levels, so PDAC activity is distinct from HDAC activity11.”
From Histone deacetylase 10 structure and molecular function as a polyamine deacetylase (2017) · cites this paper as [11]
Selective inhibitors have been developed that block mammalian PDAC activity.
“However, selective inhibitors have been developed that block mammalian PDAC activity111213.”
From Histone deacetylase 10 structure and molecular function as a polyamine deacetylase (2017) · cites this paper as [11]
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- Authors
- Marchant, P., Dredar, S., Manneh, V., Alshabanah, O., Matthews, H., Fries, D., & Blankenship, J.
- Affiliations
- University of the Pacific (US)
- University of California, Davis (US)
- Corresponding author
- Blankenship, Jim
- Venue
- Archives of Biochemistry and Biophysics
- Publisher
- Elsevier BV
- Published
- 1989-08
- Volume
- 273
- Issue
- 1
- Pages
- 128-136
- ISSN
- 0003-9861 (ISSN-L)
- OpenAlex
- W2093019130
- Cited by
- 23
- References
- 22
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2013: 1
- FWCI
- 0.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Biochemistry and Biophysics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- ApaH, polyamines, histone deacetylation, putrescine, N1-acetylspermidine, sodium butyrate, HeLa cells, rat liver
- MeSH terms
- Acetylation, Amidohydrolases, Animals, Chromatography, High Pressure Liquid, Densitometry, Diamines, HeLa Cells, Histones, Humans, Liver, Male, Putrescine, Spermidine, Spleen, Mice
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