Design, Synthesis, and Evaluation of Polyamine Deacetylase Inhibitors, and High-Resolution Crystal Structures of Their Complexes with Acetylpolyamine Amidohydrolase
Open accessAbstract
Polyamines are essential aliphatic polycations that bind to nucleic acids and accordingly are involved in a variety of cellular processes. Polyamine function can be regulated by acetylation and deacetylation, just as histone function can be regulated by lysine acetylation and deacetylation. Acetylpolyamine amidohydrolase (APAH) from Mycoplana ramosa is a zinc-dependent polyamine deacetylase that shares approximately 20% amino acid sequence identity with human histone deacetylases. We now report the X-ray crystal structures of APAH-inhibitor complexes in a new and superior crystal form that diffracts to very high resolution (1.1-1.4 Å). Inhibitors include previously synthesized analogues of N(8)-acetylspermidine bearing trifluoromethylketone, thiol, and hydroxamate zinc-binding groups [Decroos, C., Bowman, C. M., and Christianson, D. W. (2013) Bioorg. Med. Chem. 21, 4530], and newly synthesized hydroxamate analogues of shorter, monoacetylated diamines, the most potent of which is the hydroxamate analogue of N-acetylcadaverine (IC50 = 68 nM). The high-resolution crystal structures of APAH-inhibitor complexes provide key inferences about the inhibition and catalytic mechanism of zinc-dependent deacetylases. For example, the trifluoromethylketone analogue of N(8)-acetylspermidine binds as a tetrahedral gem-diol that mimics the tetrahedral intermediate and its flanking transition states in catalysis. Surprisingly, this compound is also a potent inhibitor of human histone deacetylase 8 with an IC50 of 260 nM. Crystal structures of APAH-inhibitor complexes are determined at the highest resolution of any currently existing zinc deacetylase structure and thus represent the most accurate reference points for understanding structure-mechanism and structure-inhibition relationships in this critically important enzyme family.
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The AAT binding mode in HDAC10 is similar to that observed in APAH-AAT and zHDAC6 CD2-AAT complexes.
“This binding mode was similar to that observed in the APAH–AAT and zHDAC6 CD2–AAT complexes1729.”
From Histone deacetylase 10 structure and molecular function as a polyamine deacetylase (2017) · cites this paper as [29]
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Histone deacetylase 10 structure and molecular function as a polyamine deacetylase
Hai, Y., Shinsky, S. A., Porter, N. J., & Christianson, D. W. (2017) · Nature Communications · doi:10.1038/ncomms15368 · Cited by 200 · see citing works
Self-citationStrategies To Design Selective Histone Deacetylase Inhibitors
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- Authors
- Decroos, C., & Christianson, D. W.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Christianson, David W.
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-07-22
- Volume
- 54
- Issue
- 30
- Pages
- 4692-4703
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- PMC
- PMC4526345
- OpenAlex
- W2263423519
- Cited by
- 12
- References
- 57
- Citations by year
- 2024: 1 · 2023: 2 · 2021: 1 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 1
- FWCI
- 0.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- National Institute of General Medical Sciences (GM49758)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Keywords
- hydroxamate inhibitors, catalytic mechanism, enzyme-inhibitor complex, structure-activity relationship
- MeSH terms
- Amidohydrolases, Aminohydrolases, Bacterial Proteins, Enzyme Inhibitors, Humans, Zinc, Protein Structure, Tertiary, Crystallography, X-Ray, Brucellaceae
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