Histone acetyltransferase inhibitors: An overview in synthesis, structure-activity relationship and molecular mechanism

Huang, Mengyuan; Huang, Jiangkun; Zheng, Y. George; Sun, Qiu

doi:10.1016/j.ejmech.2019.05.078

Cited by 52 publications

(36 citation statements)

References 203 publications

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“…On the basis of the subcellular localization, HATs can be divided into type A and type B, of which type A HATs are located in nuclear and type B HATs are located in the cytoplasm. Moreover, HATs can be divided into three main families by homology sequences and functional similarities: Gcn5 related HAT (GNAT) family, MYST family, and P300/ CBP family [56]. In humans, there are 18 highly conserved HDAC enzymes.…”

Section: Mechanisms Of Histone Modification In Keloidmentioning

confidence: 99%

Epigenetic modification mechanisms involved in keloid: current status and prospect

Ren

Hou

et al. 2020

Clin Epigenet

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Keloid, a common dermal fibroproliferative disorder, is benign skin tumors characterized by the aggressive fibroblasts proliferation and excessive accumulation of extracellular matrix. However, common therapeutic approaches of keloid have limited effectiveness, emphasizing the momentousness of developing innovative mechanisms and therapeutic strategies. Epigenetics, representing the potential link of complex interactions between genetics and external risk factors, is currently under intense scrutiny. Accumulating evidence has demonstrated that multiple diverse and reversible epigenetic modifications, represented by DNA methylation, histone modification, and non-coding RNAs (ncRNAs), play a critical role in gene regulation and downstream fibroblastic function in keloid. Importantly, abnormal epigenetic modification manipulates multiple behaviors of keloid-derived fibroblasts, which served as the main cellular components in keloid skin tissue, including proliferation, migration, apoptosis, and differentiation. Here, we have reviewed and summarized the present available clinical and experimental studies to deeply investigate the expression profiles and clarify the mechanisms of epigenetic modification in the progression of keloid, mainly including DNA methylation, histone modification, and ncRNAs (miRNA, lncRNA, and circRNA). Besides, we also provide the challenges and future perspectives associated with epigenetics modification in keloid. Deciphering the complicated epigenetic modification in keloid is hopeful to bring novel insights into the pathogenesis etiology and diagnostic/therapeutic targets in keloid, laying a foundation for optimal keloid ending.

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Section: Mechanisms Of Histone Modification In Keloidmentioning

confidence: 99%

Epigenetic modification mechanisms involved in keloid: current status and prospect

Ren

Hou

et al. 2020

Clin Epigenet

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“…Due to their indisputable importance in tuning gene expression, not surprisingly many KATs have been found overexpressed and/or dysregulated in several human pathologies, such as cancer, inflammation, and neurodegenerative disorders 25 – 28 . In the past decade, several inhibitors targeting this biomedically important family of epigenetic enzymes have been developed, many of them lacking inter and intra families selectivity as well as displaying poor activity 29 , 30 . Given the challenges encountered in the development of KATs inhibitors, a better understanding of the substrate scope for KAT catalysis is of great biomolecular and medicinal interest.…”

Section: Introductionmentioning

confidence: 99%

Effect of lysine side chain length on histone lysine acetyltransferase catalysis

Proietti

Wang

Rainone

et al. 2020

Sci Rep

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Histone lysine acetyltransferase (KAT)-catalyzed acetylation of lysine residues in histone tails plays a key role in regulating gene expression in eukaryotes. Here, we examined the role of lysine side chain length in the catalytic activity of human KATs by incorporating shorter and longer lysine analogs into synthetic histone H3 and H4 peptides. The enzymatic activity of MOF, PCAF and GCN5 acetyltransferases towards histone peptides bearing lysine analogs was evaluated using MALDI-TOF MS assays. Our results demonstrate that human KAT enzymes have an ability to catalyze an efficient acetylation of longer lysine analogs, whereas shorter lysine analogs are not substrates for KATs. Kinetics analyses showed that lysine is a superior KAT substrate to its analogs with altered chain length, implying that lysine has an optimal chain length for KAT-catalyzed acetylation reaction.

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“…Our approach circumvents this failure by targeting Gna1, a GNAT-family enzyme with no isoforms. Inhibitors targeting other GNAT family members are known in the literature (57,58) with bisubstrate inhibitors, molecules incorporating tethered mimics of both substrate and cofactor, offering improved selectivity profiles compared with alternative approaches but harboring nonideal pharmacokinetic properties (59 -63). However, such an approach is unlikely to offer robust selectivity in the case of Gna1 because of the high structural homology between fungal and human enzyme.…”

Section: Discussionmentioning

confidence: 99%

Targeting a critical step in fungal hexosamine biosynthesis

Stanley

Raimi

Robinson

et al. 2020

Journal of Biological Chemistry

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Aspergillus fumigatus is a human opportunistic fungal pathogen whose cell wall protects it from the extracellular environment including host defenses. Chitin, an essential component of the fungal cell wall, is synthesized from UDP-GlcNAc produced in the hexosamine biosynthetic pathway. As this pathway is critical for fungal cell wall integrity, the hexosamine biosynthesis enzymes represent potential targets of antifungal drugs. Here, we provide genetic and chemical evidence that glucosamine 6-phosphate N-acetyltransferase (Gna1), a key enzyme in this pathway, is an exploitable antifungal drug target. GNA1 deletion resulted in loss of fungal viability and disruption of the cell wall, phenotypes that could be rescued by exogenous GlcNAc, the product of the Gna1 enzyme. In a murine model of aspergillosis, the Δgna1 mutant strain exhibited attenuated virulence. Using a fragment-based approach, we discovered a small heterocyclic scaffold that binds proximal to the Gna1 active site and can be optimized to a selective submicromolar binder. Taken together, we have provided genetic, structural, and chemical evidence that Gna1 is an antifungal target in A. fumigatus.

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Histone acetyltransferase inhibitors: An overview in synthesis, structure-activity relationship and molecular mechanism

Cited by 52 publications

References 203 publications

Epigenetic modification mechanisms involved in keloid: current status and prospect

Epigenetic modification mechanisms involved in keloid: current status and prospect

Effect of lysine side chain length on histone lysine acetyltransferase catalysis

Targeting a critical step in fungal hexosamine biosynthesis

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