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bioRxiv · 10.1101/415364

Regulation of Histone Deacetylase 3 by Metal Cations and 10-Hydroxy-2E-Decenoic Acid: Possible Molecular Epigenetic Mechanisms of Queen-Worker Bee Differentiation

Polsinelli, G. A.·Yu, H. D.
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Abstract

Histone deacetylases (HDACs) catalyze the hydrolysis of {varepsilon}-acetyl-lysine residues of histones. Removal of acetyl groups results in condensation of chromatin structure and repression of gene expression. Human class I, II, and IV HDACs are said to be zinc-dependent in that they require divalent zinc ions to catalyze the deacetylase reaction. HDACs are considered potential targets for the treatment of cancer due to their role in regulating transcription. They are also thought to play important roles in the development of organisms such as honey bees. The fatty acid, 10-hydroxy-2E-decenoic acid (10-HDA), which can account for up to 5% of royal jelly composition has been reported as an HDAC inhibitor. The crystal structure of the HDAC3:SMRT complex possesses two monovalent cations (MVCs) labeled as potassium with one MVC binding site near the active site Zn(II) and the second MVC binding site [≥]20 [A] from the active site Zn(II). We report here the inhibitory effects of excess Zn(II) on the catalytic activity of histone deacetylase 3 (HDAC3) bound to the deacetylase activating domain of nuclear receptor corepressor 2 (NCOR2). We also report the effects of varying concentrations of potassium ions where [K+] up to 10 mM increase HDAC3 activity with a maximum kcat/KM of approximately 80,000 M-1s-1 while [K+] above 10 mM inhibit HDAC3 activity. The inhibition constant (Ki) of 10-HDA was determined to be 5.32 mM. The regulatory effects of zinc, potassium, and 10-HDA concentration on HDAC3 activity suggest a strong correlation between these chemical species and epigenetic control over Apis mellifera caste differentiation among other control mechanisms.

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Polsinelli, G. A., Yu, H. D.. 2018-09-12. Regulation of Histone Deacetylase 3 by Metal Cations and 10-Hydroxy-2E-Decenoic Acid: Possible Molecular Epigenetic Mechanisms of Queen-Worker Bee Differentiation. https://doi.org/10.1101/415364

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