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Trichostatin A (TSA) is an organic compound that serves as an antifungal antibiotic and selectively inhibits the class I and II mammalian histone deacetylase (HDAC) families of enzymes, but not class III HDACs (i.e., sirtuins). However, there are recent reports of the interactions of this molecule with Sirt 6 protein. TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage. TSA can be used to alter gene expression by interfering with the removal of acetyl groups from histones (histone deacetylases, HDAC) and therefore altering the ability of DNA transcription factors to access the DNA molecules inside chromatin. It is a member of a larger class of histone deacetylase inhibitors (HDIs or HDACIs) that have a broad spectrum of epigenetic activities. Thus, TSA has some potential as an anti-cancer drug. One suggested mechanism is that TSA promotes the expression of apoptosis-related genes, leading to cancerous cells surviving at lower rates, thus slowing the progression of cancer. Other mechanisms may include the activity of HDIs to induce cell differentiation, thus acting to "mature" some of the de-differentiated cells found in tumors. HDIs have multiple effects on non-histone effector molecules, so the anti-cancer mechanisms are truly not understood at this time.
TSA inhibits HDACs 1, 3, 4, 6 and 10 with IC50 values around 20 nM.
TSA represses IL (interleukin)-1β/LPS (lipopolysaccharide)/IFNγ (interferon γ)-induced nitric oxide synthase 2 (NOS2) expression in murine macrophage-like cells but increases LPS-stimulated NOS2 expression in murine N9 and primary rat microglial cells.
Vorinostat is structurally related to trichostatin A and used to treat cutaneous T cell lymphoma. |
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InChI=1S/C17H22N2O3/c1- 12(5- 10- 16(20) 18- 22) 11- 13(2) 17(21) 14- 6- 8- 15(9- 7- 14) 19(3) 4/h5- 11,13,22H,1- 4H3,(H,18,20) /b10- 5+,12- 11+/t13- /m1/s1 |
RTKIYFITIVXBLE-QEQCGCAPSA-N |
C[C@@H](C(=O)c1ccc(cc1)N(C)C)\C=C(C)\C=C\C(=O)NO |
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Streptomyces hygroscopicus
(NCBI:txid1912)
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See:
PubMed
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bacterial metabolite
Any prokaryotic metabolite produced during a metabolic reaction in bacteria.
EC 3.5.1.98 (histone deacetylase) inhibitor
An EC 3.5.1.* (non-peptide linear amide C-N hydrolase) inhibitor that interferes with the function of histone deacetylase (EC 3.5.1.98).
antifungal agent
An antimicrobial agent that destroys fungi by suppressing their ability to grow or reproduce.
(via antibiotic antifungal agent )
antimicrobial agent
A substance that kills or slows the growth of microorganisms, including bacteria, viruses, fungi and protozoans.
(via carbocyclic antibiotic )
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geroprotector
Any compound that supports healthy aging, slows the biological aging process, or extends lifespan.
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View more via ChEBI Ontology
(2E,4E,6R)- 7- [4- (dimethylamino)phenyl]- N- hydroxy- 4,6- dimethyl- 7- oxohepta- 2,4- dienamide
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(2E,4E,6R)- 7- (4- (dimethylamino)phenyl)- N- hydroxy- 4,6- dimethyl- 7- oxo- 2,4- heptadienamide
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ChemIDplus
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TRICHOSTATIN A
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PDBeChem
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TSA
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ChemIDplus
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5291761
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Beilstein Registry Number
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Beilstein
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58880-19-6
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CAS Registry Number
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ChemIDplus
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Haritwal T, Goyal N, Gupta N, Parvez S, Agrawala PK (2021) Trichostatin A mitigates radiation-induced teratogenesis in C57Bl/6 mice. Mutagenesis 36, 303-309 [PubMed:34086940] [show Abstract] Radiation exposure in utero is known to lead to serious concerns to both the mother and children, including developmental anomalies in the children. In the recent past, trichostatin A, an HDAC (histone deacetylase) inhibitor and epigenetic modifier, has been shown to mitigate radiation-induced anomalies in the male reproductive system of C57BL/6 mice. Therefore, the current study was undertaken to evaluate the mitigating effects of trichostatin A (TSA) against radiation-induced developmental anomalies in mice. Foetuses of in utero whole-body gamma-irradiated mice during the active organogenesis period were examined for developmental anomalies at 8.5 and 18.5 days of gestation. In utero radiation exposure caused developmental anomalies like microcephaly, microphthalmia, gastroschisis and kinky tail besides prenatal mortality. TSA administration post-irradiation was observed to reduce 50% of prenatal mortality at E18.5 by reducing congenital and developmental anomalies. Observation of such results could be corroborated with the HDAC inhibitory potential of TSA knowing that developmental anomalies may have epigenetic origin. TSA, therefore, can be considered as a potential radiomitigator. | Peng C, Lv Z, Hai T, Dai X, Zhou Q (2021) Differential effects of trichostatin A on mouse embryogenesis and development. Reproduction (Cambridge, England) 162, 83-94 [PubMed:33983895] [show Abstract] Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, can significantly improve the reprogramming efficiency of somatic cells. However, whether TSA has a detrimental effect on other kinds of embryos is largely unknown because of the lack of integrated analysis of the TSA effect on natural fertilized embryos. To investigate the effect of TSA on mouse embryo development, we analyzed preimplantation and post-implantation development of in vivo, in vitro fertilized, and parthenogenetic embryos treated with TSA at different concentrations and durations. In vivo fertilized embryos appeared to be the most sensitive to TSA treatment among the three groups, and the blastocyst formation rate decreased sharply as TSA concentration and treatment time increased. TSA treatment also reduced the livebirth rate for in vivo fertilized embryos from 56.59 to 38.33% but did not significantly affect postnatal biological functions such as the pups' reproductive performance and their ability for spatial learning and memory. Further analysis indicated that the acetylation level of H3K9 and H4K5 was enhanced by TSA treatment at low concentrations, while DNA methylation appeared to be also disturbed by TSA treatment only at high concentration. Thus, our data indicates that TSA has different effects on preimplantation embryonic development depending on the nature of the embryo's reproductive origin, the TSA concentration and treatment time, whereas the effect of TSA at the indicated concentration on postnatal function was minor. | Osko JD, Christianson DW (2020) Binding of inhibitors to active-site mutants of CD1, the enigmatic catalytic domain of histone deacetylase 6. Acta crystallographica. Section F, Structural biology communications 76, 428-437 [PubMed:32880591] [show Abstract] The zinc hydrolase histone deacetylase 6 (HDAC6) is unique among vertebrate deacetylases in that it contains two catalytic domains, designated CD1 and CD2. Both domains are fully functional as lysine deacetylases in vitro. However, the in vivo function of only the CD2 domain is well defined, whereas that of the CD1 domain is more enigmatic. Three X-ray crystal structures of HDAC6 CD1-inhibitor complexes are now reported to broaden the understanding of affinity determinants in the active site. Notably, cocrystallization with inhibitors was facilitated by using active-site mutants of zebrafish HDAC6 CD1. The first mutant studied, H82F/F202Y HDAC6 CD1, was designed to mimic the active site of human HDAC6 CD1. The structure of its complex with trichostatin A was generally identical to that with the wild-type zebrafish enzyme. The second mutant studied, K330L HDAC6 CD1, was prepared to mimic the active site of HDAC6 CD2. It has previously been demonstrated that this substitution does not perturb inhibitor binding conformations in HDAC6 CD1; here, this mutant facilitated cocrystallization with derivatives of the cancer chemotherapy drug suberoylanilide hydroxamic acid (SAHA). These crystal structures allow the mapping of inhibitor-binding regions in the outer active-site cleft, where one HDAC isozyme typically differs from another. It is expected that these structures will help to guide the structure-based design of inhibitors with selectivity against HDAC6 CD1, which in turn will enable new chemical biology approaches to probe its cellular function. | Osko JD, Christianson DW (2019) Structural Basis of Catalysis and Inhibition of HDAC6 CD1, the Enigmatic Catalytic Domain of Histone Deacetylase 6. Biochemistry 58, 4912-4924 [PubMed:31755702] [show Abstract] Histone deacetylase 6 (HDAC6) is emerging as a target for inhibition in therapeutic strategies aimed at treating cancer, neurodegenerative disease, and other disorders. Among the metal-dependent HDAC isozymes, HDAC6 is unique in that it contains two catalytic domains, CD1 and CD2. CD2 is a tubulin deacetylase and a tau deacetylase, and the development of HDAC6-selective inhibitors has focused exclusively on this domain. In contrast, there is a dearth of structural and functional information regarding CD1, which exhibits much narrower substrate specificity in comparison with CD2. As the first step in addressing the CD1 information gap, we now present X-ray crystal structures of seven inhibitor complexes with wild-type, Y363F, and K330L HDAC6 CD1. These structures broaden our understanding of molecular features that are important for catalysis and inhibitor binding. The active site of HDAC6 CD1 is wider than that of CD2, which is unexpected in view of the narrow substrate specificity of CD1. Amino acid substitutions between HDAC6 CD1 and CD2, as well as conformational differences in conserved residues, define striking differences in active site contours. Catalytic activity measurements with HDAC6 CD1 confirm the preference for peptide substrates containing C-terminal acetyllysine residues. However, these measurements also show that CD1 exhibits weak activity for peptide substrates bearing certain small amino acids on the carboxyl side of the scissile acetyllysine residue. Taken together, these results establish a foundation for understanding the structural basis of HDAC6 CD1 catalysis and inhibition, pointing to possible avenues for the development of HDAC6 CD1-selective inhibitors. | You W, Steegborn C (2018) Structural Basis of Sirtuin 6 Inhibition by the Hydroxamate Trichostatin A: Implications for Protein Deacylase Drug Development. Journal of medicinal chemistry 61, 10922-10928 [PubMed:30395713] [show Abstract] Protein lysine deacylases comprise three zinc-dependent families and the NAD+-dependent sirtuins Sirt1-7, which contribute to aging-related diseases. Few Sirt6-specific inhibitors are available. Trichostatin A, which belongs to the potent, zinc-chelating hydroxamate inhibitors of zinc-dependent deacylases, was recently found to potently and isoform-specifically inhibit Sirt6. We solved a crystal structure of a Sirt6/ADP-ribose/trichostatin A complex, which reveals nicotinamide pocket and acyl channel as binding site and provides interaction details supporting the development of improved deacylase inhibitors. | Miyake Y, Keusch JJ, Wang L, Saito M, Hess D, Wang X, Melancon BJ, Helquist P, Gut H, Matthias P (2016) Structural insights into HDAC6 tubulin deacetylation and its selective inhibition. Nature chemical biology 12, 748-754 [PubMed:27454931] [show Abstract] We report crystal structures of zebrafish histone deacetylase 6 (HDAC6) catalytic domains in tandem or as single domains in complex with the (R) and (S) enantiomers of trichostatin A (TSA) or with the HDAC6-specific inhibitor nexturastat A. The tandem domains formed, together with the inter-domain linker, an ellipsoid-shaped complex with pseudo-twofold symmetry. We identified important active site differences between both catalytic domains and revealed the binding mode of HDAC6 selective inhibitors. HDAC inhibition assays with (R)- and (S)-TSA showed that (R)-TSA was a broad-range inhibitor, whereas (S)-TSA had moderate selectivity for HDAC6. We identified a uniquely positioned α-helix and a flexible tryptophan residue in the loop joining α-helices H20 to H21 as critical for deacetylation of the physiologic substrate tubulin. Using single-molecule measurements and biochemical assays we demonstrated that HDAC6 catalytic domain 2 deacetylated α-tubulin lysine 40 in the lumen of microtubules, but that its preferred substrate was unpolymerized tubulin. | Decroos C, Bowman CM, Moser JA, Christianson KE, Deardorff MA, Christianson DW (2014) Compromised structure and function of HDAC8 mutants identified in Cornelia de Lange Syndrome spectrum disorders. ACS chemical biology 9, 2157-2164 [PubMed:25075551] [show Abstract] Cornelia de Lange Syndrome (CdLS) is a multiple congenital anomaly disorder resulting from mutations in genes that encode the core components of the cohesin complex, SMC1A, SMC3, and RAD21, or two of its regulatory proteins, NIPBL and HDAC8. HDAC8 is the human SMC3 lysine deacetylase required for cohesin recycling in the cell cycle. To date, 16 different missense mutations in HDAC8 have recently been identified in children diagnosed with CdLS. To understand the molecular effects of these mutations in causing CdLS and overlapping phenotypes, we have fully characterized the structure and function of five HDAC8 mutants: C153F, A188T, I243N, T311M, and H334R. X-ray crystal structures reveal that each mutation causes local structural changes that compromise catalysis and/or thermostability. For example, the C153F mutation triggers conformational changes that block acetate product release channels, resulting in only 2% residual catalytic activity. In contrast, the H334R mutation causes structural changes in a polypeptide loop distant from the active site and results in 91% residual activity, but the thermostability of this mutant is significantly compromised. Strikingly, the catalytic activity of these mutants can be partially or fully rescued in vitro by the HDAC8 activator N-(phenylcarbamothioyl)benzamide. These results suggest that HDAC8 activators might be useful leads in the search for new therapeutic strategies in managing CdLS. | Park JW, Park SR, Han AR, Ban YH, Yoo YJ, Kim EJ, Kim E, Yoon YJ (2011) Microbial transformation of trichostatin A to 2,3-dihydrotrichostatin A. Journal of natural products 74, 1272-1274 [PubMed:21504214] [show Abstract] A new reduced hydroxamate, 2,3-dihydrotrichostatin A, was created from trichostatin A by employing a recombinant strain of Streptomyces venezuelae as a microbial catalyst. Compared with trichostatin A, 2,3-dihydrotrichostatin A showed similar antifungal activity against Saccharomyces cerevisiae, but, interestingly, approximately twice the cytostatic activity against human small-cell lung cancer cells. The production of 2,3-dihydrotrichostatin A via microbial biotransformation demonstrates that the regiospecific and substrate-flexible hydrogenation by S. venezuelae provides a new approach for creating natural product analogues with improved bioactive properties. | Noh EJ, Lim DS, Jeong G, Lee JS (2009) An HDAC inhibitor, trichostatin A, induces a delay at G2/M transition, slippage of spindle checkpoint, and cell death in a transcription-dependent manner. Biochemical and biophysical research communications 378, 326-331 [PubMed:19038231] [show Abstract] Histone deacetylases (HDACs), a promising target for cancer therapy, play a role in regulating cell-cycle progression. The mechanisms for HDAC inhibition-induced regulation of G(2)/M transition and mitotic progression remain to be elucidated. Herein, we report that trichostatin A (TSA), an HDAC inhibitor, induces a delay at the G(2)/M transition, chromosome missegregation and multi-nucleation, and thereby leads to cell death by promoting exit from aberrant mitosis without spindle checkpoint. These results are associated with a transcriptional modulation of key regulator genes of the cell cycle, including CyclinB1, Plk1, Survivin, and p21(WAF1/Cip1). Actinomycin D, a transcriptional inhibitor, abrogated the TSA-induced delay of G(2)/M transition and transcriptional modulation of cell-cycle regulator genes, indicating that the impact of TSA in this manner is transcription dependent. Overall, our findings indicate that TSA provides a barrier to cell-cycle progression for antiproliferation and promotes escape from mitotic catastrophe and cell death, by inhibiting an HDAC-mediated transcriptional action. | Schuetz A, Min J, Allali-Hassani A, Schapira M, Shuen M, Loppnau P, Mazitschek R, Kwiatkowski NP, Lewis TA, Maglathin RL, McLean TH, Bochkarev A, Plotnikov AN, Vedadi M, Arrowsmith CH (2008) Human HDAC7 harbors a class IIa histone deacetylase-specific zinc binding motif and cryptic deacetylase activity. The Journal of biological chemistry 283, 11355-11363 [PubMed:18285338] [show Abstract] Histone deacetylases (HDACs) are protein deacetylases that play a role in repression of gene transcription and are emerging targets in cancer therapy. Here, we characterize the structure and enzymatic activity of the catalytic domain of human HDAC7 (cdHDAC7). Although HDAC7 normally exists as part of a multiprotein complex, we show that cdHDAC7 has a low level of deacetylase activity which can be inhibited by known HDAC inhibitors. The crystal structures of human cdHDAC7 and its complexes with two hydroxamate inhibitors are the first structures of the catalytic domain of class IIa HDACs and demonstrate significant differences with previously reported class I and class IIb-like HDAC structures. We show that cdHDAC7 has an additional class IIa HDAC-specific zinc binding motif adjacent to the active site which is likely to participate in substrate recognition and protein-protein interaction and may provide a site for modulation of activity. Furthermore, a different active site topology results in modified catalytic properties and in an enlarged active site pocket. Our studies provide mechanistic insights into class IIa HDACs and facilitate the design of specific modulators. | Choi YH (2005) Induction of apoptosis by trichostatin A, a histone deacetylase inhibitor, is associated with inhibition of cyclooxygenase-2 activity in human non-small cell lung cancer cells. International journal of oncology 27, 473-479 [PubMed:16010430] [show Abstract] Although histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in malignancy, how they exert their effect on human non-small cell lung cancer cells is as yet unclear. This study was undertaken to investigate the underlying mechanism of an HDAC inhibitor, Trichostatin A (TSA), -induced apoptosis in a human lung carcinoma cell line A549. The effects of this compound were also tested on cyclooxygenase (COX) activity. Treatment of A549 cells to TSA resulted in the inhibition of viability and the induction of apoptosis in a concentration-dependent manner, which could be proved by trypan blue counts, DAPI staining, agarose gel electrophoresis and flow cytometry analysis. Apoptosis of A549 cells by TSA was associated with a down-regulation of anti-apoptotic Bcl-2 protein and an up-regulation of pro-apoptotic Bax protein. TSA treatment induced the proteolytic activation of caspase-3 and caspase-9, and a concomitant degradation of poly(ADP-ribose)-polymerase protein. Furthermore, TSA decreased the levels of COX-2 mRNA and protein expression without significant changes in the levels of COX-1, which was correlated with an inhibition in prostaglandin E2 synthesis. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of TSA. | Tao D, Lu J, Sun H, Zhao YM, Yuan ZG, Li XX, Huang BQ (2004) Trichostatin A extends the lifespan of Drosophila melanogaster by elevating hsp22 expression. Acta biochimica et biophysica Sinica 36, 618-622 [PubMed:15346199] [show Abstract] The level of acetylation of histones in nucleosomes is related to the longevity of yeast and animals. However, the mechanisms by which acetylation and deacetylation affect longevity remain unclear. In present study, we investigated the influence of histone acetylation modification on the expression of hsp22 gene and the lifespan in Drosophila melanogaster using histone deacetylase (HDAC) inhibitor Trichostatin A (TSA). The results showed that TSA could extend the lifespan of Drosophila melanogaster. Furthermore, TSA significantly promoted the hsp22 gene transcription, and affected the chromatin morphology at the locus of hsp22 gene along the polytene chromosome. Present data implicate that TSA may affect the lifespan of Drosophila through changing the level of histone acetylation and influencing the expression of hsp22 gene that is related to aging. | Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, Breslow R, Pavletich NP (1999) Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 401, 188-193 [PubMed:10490031] [show Abstract] Histone deacetylases (HDACs) mediate changes in nucleosome conformation and are important in the regulation of gene expression. HDACs are involved in cell-cycle progression and differentiation, and their deregulation is associated with several cancers. HDAC inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have anti-tumour effects, as they can inhibit cell growth, induce terminal differentiation and prevent the formation of tumours in mice models, and they are effective in the treatment of promyelocytic leukemia. Here we describe the structure of the histone deacetylase catalytic core, as revealed by the crystal structure of a homologue from the hyperthermophilic bacterium Aquifex aeolicus, that shares 35.2% identity with human HDAC1 over 375 residues, deacetylates histones in vitro and is inhibited by TSA and SAHA. The deacetylase, deacetylase-TSA and deacetylase-SAHA structures reveal an active site consisting of a tubular pocket, a zinc-binding site and two Asp-His charge-relay systems, and establish the mechanism of HDAC inhibition. The residues that make up the active site and contact the inhibitors are conserved across the HDAC family. These structures also suggest a mechanism for the deacetylation reaction and provide a framework for the further development of HDAC inhibitors as antitumour agents. |
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