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HBO1-MLL interaction promotes AF4/ENL/P-TEFb-mediated leukemogenesis / HBO1とMLLは結合しAF4/ENL/P-TEFb複合体による白血化を促進するTakahashi, Satoshi 23 March 2022 (has links)
京都大学 / 新制・課程博士 / 博士(医学) / 甲第23803号 / 医博第4849号 / 新制||医||1058(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 村川 泰裕, 教授 滝田 順子, 教授 小川 誠司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Deciphering Substrate Promiscuity by Aminoglycoside Resistance Enzymes via a Biophysical Characterization and Dynamics of the Aminoglycoside Acetyltransferase-(3)-IIIb and the Aminoglycoside Phosphotransferase-(3′)-IIIaNorris, Adrianne Lee 01 May 2011 (has links)
Aminoglycoside antibiotics are losing their bactericidal efficacy due to the spread of enzymes that catalyze a covalent modification to them. A common property of many of these aminoglycoside modifying enzymes (AGMEs) is the capacity to modify multiple diverse aminoglycosides thus conferring resistance to these drugs among several pathogenic bacterial species. To gain a better understanding of the protein-antibiotic interactions responsible for resistance and the promiscuous nature of AGMEs, a variety of biophysical techniques including nuclear magnetic resonance (NMR), isothermal titration calorimetry (ITC), steady state kinetics, intrinsic tryptophan fluorescence, and computational modeling are employed in this work. Results and discussion presented herein are divided into two parts.
In Part I, a detailed thermodynamic and kinetic characterization of the association between the aminoglycoside acetyltransferase-(3)-IIIb (AAC) and several antibiotics and/or coenzyme(s) provides insight into the global properties of the protein. AAC is shown to have a broad substrate range where antibiotic interaction occurs with a favorable enthalpy and unfavorable entropy. When coenzyme A (the non-catalytic form of the acetyl donor, acetyl coenzyme A) is present, enthalpy becomes more favored, entropy more disfavored, and antibiotic affinity significantly increases. AAC shows preference for antibiotics with amine groups at the 2′ and 6′ positions and to those possessing four or more pseudo-saccharide rings. These and other data lay the foundation for understanding AAC and lead into the next discussion wherein the source of promiscuity of AGMEs is explored in Part II.
The aminoglycoside phosphotransferase-(3′)-IIIa (APH), a representative from the phosphotransferase family of AGMEs, has been well characterized previously. However, none of the data presented to date provides rationale for its promiscuity. In this work, NMR derived hydrogen-deuterium exchange experiments reveal that APH maneuvers its entire structure to accommodate diverse antibiotics. Furthermore, presence of an antibiotic creates a more stable APH conformation while coenzyme induces an antibiotic dependent increase in the flexibility of APH. For comparison, a computationally derived homology model of AAC predicts that its promiscuous nature may be due to a large flexible loop. Taken together, APH and AAC, two structurally and functionally diverse proteins, utilize different aspects of structural flexibility to facilitate a broad substrate repertoire that is key to bacterial survival.
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Further Investigation of Amantadine Disposition: Acetylation and SecretionFatani, Solafa 08 April 2010 (has links)
Amantadine is a cationic aliphatic primary amine eliminated by the kidneys, excreted predominantly unchanged into the urine, and undergoes limited metabolism. Renal tubule secretion has an important role in its elimination. We studied two aspects of amantadine disposition, firstly acetylation, by developing a model to induce the enzyme spermidine/spermine N1-acetyltransferase (SSAT1) with
N1, N11-diethylnorspermine (DENSPM) and alcohol (Alc) as representative agents reported to induce its activity, and secondly renal secretion, by studying the effect of intravenous bicarbonate infusion on its renal elimination. We drew two conclusions, firstly, longer exposure to Alc combined with DENSPM administration provided the greatest potentiation of SSAT1 enzyme activity than each agent alone, which indicates a high likelihood of synergy between Alc and DENSPM; and secondly, bicarbonate load administered to healthy male volunteers impairs amantadine renal secretion in the absence of a clinically important change in blood pH, serum creatinine concentration or urinary creatinine clearance.
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Further Investigation of Amantadine Disposition: Acetylation and SecretionFatani, Solafa 08 April 2010 (has links)
Amantadine is a cationic aliphatic primary amine eliminated by the kidneys, excreted predominantly unchanged into the urine, and undergoes limited metabolism. Renal tubule secretion has an important role in its elimination. We studied two aspects of amantadine disposition, firstly acetylation, by developing a model to induce the enzyme spermidine/spermine N1-acetyltransferase (SSAT1) with
N1, N11-diethylnorspermine (DENSPM) and alcohol (Alc) as representative agents reported to induce its activity, and secondly renal secretion, by studying the effect of intravenous bicarbonate infusion on its renal elimination. We drew two conclusions, firstly, longer exposure to Alc combined with DENSPM administration provided the greatest potentiation of SSAT1 enzyme activity than each agent alone, which indicates a high likelihood of synergy between Alc and DENSPM; and secondly, bicarbonate load administered to healthy male volunteers impairs amantadine renal secretion in the absence of a clinically important change in blood pH, serum creatinine concentration or urinary creatinine clearance.
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Synthese und biologische Evaluierung von Modulatoren der Histon-Acetylierung und Inhibitoren der Protein-Tyrosin-Dephosphorylierung als neue Wirkstoffe für die Krebstherapie /Heydel, Michael. Unknown Date (has links)
Leipzig, Universiẗat, Diss., 2007.
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Purification and properties of choline acetyltransferase from chicken brainMa, Kelvin January 1978 (has links)
Choline acetyltransferase (ChAc), the enzyme responsible for the synthesis of acetylcholine (ACh), has been extensively purified from chicken brains. Purification procedures included ammonium sulfate fractionation, DEAE-Sephadex (A-25), hydroxyapatite, Sephadex G-150 column chromatography, and affinity chromatography on agarose-hexane-Coenzyme A column. ChAc activity was measured radiochemically. Due to the instability of the enzyme in the course of purification, the most active fraction obtained after agarose-hexane-Coenzyme A chromatography
showed a specific activity of only 0.34 μmoles ACh formed/ min./mg protein which corresponded to a 773 fold purification from homogenate. However, on non-denaturing polyacrylamide gel electrophoresis
at pH 8.8, the highly purified ChAc preparation showed two distinct bands, and ChAc activity was recovered by slicing and assaying the gel. ChAc activity corresponded to the position of the faster moving band. The same preparation showed one major band and two minor bands on SDS gel electrophoresis. The estimated MW of chicken brain ChAc by gel filtration and SDS gel electrophoresis was 42,500 daltons and no subunit was observed. Two forms of chicken brain ChAc with different Km values for the substrates were eluted
from agarose-hexane-CoA column. The pH optimum was estimated to be
between pH 7.6-8.0. NaCl, KC1, Ca²⁺ and EDTA stimulated, while Cu²⁺,
N-ethylmaleimide and CoA inhibited the enzyme preparation. The apparent
Km values for acetyl-CoA and choline were, studied and were found to be similar to those of other mammalian species. The ChAc preparation
also showed species specificity by the Ouchterlony double immuno diffusion test. Effect and mechanisms of salt and EDTA activation of ChAc activity are discussed. / Medicine, Faculty of / Graduate
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Trimethyltin Increases Choline Acetyltransferase in Rat HippocampusCannon, Richard L., Hoover, Donald B., Woodruff, Michael L. 01 January 1991 (has links)
The environmental neurotoxin trimethyltin (TMT) destroys parts of the hippocampal formation as well as the entorhinal cortex but leaves the septal cholinergic projection to the hippocampus and dentate gyrus intact. In this study we measured choline acetyltransferase (ChAT) activity in micropunch samples of the dentate gyrus, the CA1 region of Ammon's horn, and the caudate-putamen as a measure of density of cholinergic innervation in control rats and rats exposed to 7 mg/kg TMT by means of gastric intubation. Three months after the rats were exposed to a single dose of TMT both the dentate gyrus and CA1 demonstrated significantly higher ChAT activity in TMT-exposed rats than in control rats. No differences were found between groups for the caudate-putamen samples. These results support the hypothesis that exposure to TMT causes reactive synaptogenesis in the cholinergic septohippocampal system.
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Investigating the Function and Therapeutic Potential of the GCN5b Bromodomain in Toxoplasma GondiiHanquier, Jocelyne Nicole 06 1900 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / The obligate intracellular protozoan parasite Toxoplasma gondii is a medically relevant pathogen that has infected a third of the world’s population. Toxoplasma is the causative agent of toxoplasmosis, which can have severe repercussions such as encephalitis and even death in immunocompromised patients. Current treatments for toxoplasmosis only target acute infection and can be toxic to patients, resulting in complications including allergy and bone marrow suppression. Thus, the identification of novel drug targets and therapies for toxoplasmosis is vital. Epigenetic modulators of lysine acetylation, including ‘writers,’ ‘erasers,’ and ‘readers,’ have been identified as promising drug targets for protozoan parasites. The lysine acetyltransferase (KAT) GCN5b appears to be an essential gene for Toxoplasma viability. The KAT domain of GCN5b is essential to GCN5b function and is targetable by small molecule inhibitors. While the acetyltransferase activity of this gene is well-characterized, the functionality of its C-terminal bromodomain (BRD) remains to be understood. Bromodomains are readers of lysine acetylation, and recently, bromodomain inhibitors have shown promise in a number of human diseases, as well as in protozoan parasites. We hypothesized that the GCN5b bromodomain is critical for Toxoplasma viability. The data reported herein suggest that the GCN5b bromodomain is important for tachyzoite viability and may serve as a novel therapeutic target in Toxoplasma.
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Lysine acetyltransferase and deacetylase in normal and abnormal brain developmentLi, Lin January 2018 (has links)
No description available.
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Effects of C-terminal truncations of the histone acetyltransferase p300 on the growth and gene expression patterns of human diffuse large B-cell lymphoma cell linesHaery, Leila M. 22 February 2016 (has links)
Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin’s B- cell lymphoma, accounting for about 30% of these lymphomas in the United States. Large-scale genome analyses of DLBCL have identified mutations in the related histone acetyltransferases (HATs) p300 and CBP in approximately 15% of patient samples and patient-derived cell lines. The research presented herein characterizes two human DLBCL cell lines, RC-K8 and SUDHL2, which express C-terminally truncated HAT domain-deficient p300 proteins, p300ΔC-1087 and p300 p300ΔC-820, respectively. It is shown that p300ΔC-820 localizes to sites of active transcription in the nucleus, interacts with NF-κB transcription factor REL, weakly enhances REL-dependent transactivation, and has a half-life similar to wild-type p300. Results demonstrate that knockdown of p300ΔC-820 in SUDHL2 cells reduces cell proliferation in vitro. In RC-K8 cells, p300ΔC-1087 suppresses expression of the NF-κB target genes A20 and IκBα, both of which are cytotoxic when overexpressed in RC-K8 cells. Microarray analysis of p300ΔC1087 knockdown compared to wild-type RC-K8 cells indicated that p300ΔC-1087 suppresses an NF-κB gene expression program and activates a MYC gene expression program in RC-K8 cells. Bioinformatic analysis demonstrated that cancer cell lines— regardless of tissue type—with truncating p300 mutations have altered expression of a MYC target gene set as compared to cancer cell lines with wild-type p300/CBP. Taken together, this research indicates that p300 truncations contribute to cell growth in DLBCL by modifying the transcriptional output of two lymphoid cell-specific oncoproteins, NF- κB and MYC, to optimal levels and suggests that p300 truncating mutations similarly modify the activity of oncogenic drivers in other cancer cell types. Based on this work, p300 truncation is proposed to represent a new class of oncogenic mutation that serves to optimize the activity of context-specific oncogenic transcription factors, and it is suggested that such oncogenic mutations be termed “cancer modifying” mutations. / 2017-09-30T00:00:00Z
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