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Biochemistry ; 56(36): 4871-4878, 2017 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-28809557

RESUMO

Short chain fatty acids (SCFAs) are postulated to modulate the immune development of neonates via epigenetic regulations such as histone deacetylase (HDAC) inhibition. In the context of atopic diseases, the inhibition of HDAC maintains T-cell homeostasis and induces naïve T-cell differentiation into adaptive Treg, which regulates the production of anti-inflammatory cytokines and suppression of Th2 immune responses. We investigated the structure-inhibition relationships of SCFAs with class I HDAC3 and class IIa HDAC7 using in silico docking simulation and the in vitro human recombinant HDAC inhibition assay. In silico docking simulation demonstrated that the lower binding energy of SCFAs toward HDACs was associated with the longer aliphatic chain length of SCFAs. Conversely, branching of SCFAs increased their binding energies toward both HDAC3 and HDAC7. The in vitro HDAC inhibition assay revealed that SCFAs more potently inhibit HDAC3 than HDAC7, with butyric acid being the most potent HDAC3 inhibitor among SCFAs (IC50 = 0.318 mM). In conclusion, our findings inform novel structural relationships between SCFAs and HDAC3 versus HDAC7. Future investigation of human disposition of SCFAs is important to establish their effects on innate versus adaptive immunity.


Assuntos
Ácidos Graxos Voláteis/química , Histona Desacetilases/metabolismo , Sítios de Ligação , Simulação por Computador , Inibidores de Histona Desacetilases , Histona Desacetilases/química , Humanos , Modelos Químicos , Ligação Proteica , Conformação Proteica
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