Inhibition of N8-acetylspermidine deacetylase by active-site-directed metal coordinating inhibitors
Abstract
A number of substrate analogues of N8-acetylspermidine (N8-AcSpd) (16) and chemical modifying agents containing metal coordinating ligands were assayed as inhibitors of the cytoplasmic enzyme N8-AcSpd deacetylase from rat liver. The enzyme is inhibited by metal chelators, several omega-amino-substituted carboxylic acids, and some thiol reagents. Inhibition by diisopropyl fluorophosphate was observed only at high concentrations. These results suggest that the catalytic mechanism of the enzyme requires a transition state metal and free sulfhydryl groups for activity. The most potent inhibitor synthesized 6-[(3-aminopropyl)amino]-N-hydroxyhexanamide (15), has an apparent Ki of 0.001 microM. It binds to the target enzyme 11,000 times tighter than the substrate (apparent Km = 11 microM). These compounds and a previously reported series of compounds (Dredar, S. A.; Blankenship, J. W.; Marchant, P. E.; Manneh, V. A.; Fries, D. S. J. Med. Chem. 1989, 32, 984-989) are useful in mapping the active site and determining the physiological function of N8-AcSpd deacetylase.
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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 [13]
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“Several appear to be metalloproteins, includingN8-acetylspermidine deacetylase from rat liver, an enzyme very effectively inhibited by metal-coordinating substrate analogs ( 12 ).”
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BackgroundKaur, N. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-95652-9.00019-3
- Authors
- Huang, T. L., Dredar, S. A., Manneh, V. A., Blankenship, J. W., & Fries, D. S.
- Affiliations
- University of the Pacific (US)
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1992-06
- Volume
- 35
- Issue
- 13
- Pages
- 2414-2418
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W1968332663
- Cited by
- 13
- References
- 0
- Citations by year
- 2023: 1 · 2022: 1 · 2021: 1 · 2017: 1 · 2013: 1
- FWCI
- 0.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Keywords
- enzyme inhibition, active-site-directed inhibitors, metal chelators, sulfhydryl reagents, diisopropylfluorophosphate, sulfhydryl groups, catalytic mechanism, substrate analogues, rat liver enzyme, polyamine metabolism
- MeSH terms
- Amidohydrolases, Animals, Binding Sites, Enzyme Inhibitors, Liver, Metals, Rats
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