Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mithramycin (MTR) is an anticancer drug that blocks macromolecular biosynthesis via reversible interaction with DNA in the presence of bivalent cation such as Mg2+. Mithramycin forms two types of complexes with Mg2+: complex I (1:1 in terms of MTR:Mg2+) and complex II (2:1 in terms of MTR:Mg2+). In vivo antibiotic would interact with chromatin, a protein-DNA complex. For the first time we have demonstrated and characterized the association of both complexes of MTR with chromatin and nucleosome core. From an evaluation and comparison of the binding and thermodynamic parameters and CD spectra of bound complexes, we have shown the following. Histone(s) stand in the say of the access of the ligand(s) to chromosomal DNA. Chromatin and core particle interact differentially with the same ligand. Mode of interaction of the two complexes, I and II, with the same system is different. Significance of these results to understand the transcription inhibitory property of the drug in eukaryotic chromosome is discussed.
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PMID:Interaction of antitumor drug, mithramycin, with chromatin. 1116 79

Mithramycin and chromomycin A(3) are two anticancer antibiotics, which inhibit protein biosynthesis via transcription inhibition. They bind reversibly to DNA with (G.C) base specificity. At and above physiological pH in the absence of DNA, they form two types of complexes with Mg(2+), complex I (1:1 in terms of antibiotic: Mg(2+)) and complex II (2:1 in terms of antibiotic: Mg(2+)). These are the DNA binding ligands. In vivo, the antibiotics interact with chromatin, a protein-DNA complex. In order to understand the mode of action of these antibiotics at molecular level, we have carried out spectroscopic, gel electrophoretic and UV melting studies of complex I of these antibiotics with rat liver chromatin, nucleosome core particle and DNA stripped of all chromosomal proteins. Analysis of the results has led us to propose that the antibiotic: Mg(2+) complex binds to both nucleosomal and linker DNA in native chromatin. Histone proteins reduce the binding potential and accessibility of the complexes to the minor groove of (G.C) rich regions of chromosomal DNA. The antibiotic: Mg(2+) complex stabilizes DNA duplex and histone- DNA contacts in chromatin fiber. It also leads to the aggregation of chromatin fibers. From a comparison of the association of the antibiotic: Mg(2+) complexes with different levels of chromatin structure and their effects upon the structure, we suggest that the sugar moieties of the antibiotics play a role in the binding process. Significance of these results to understand the molecular basis of the transcription inhibition potential of the antibiotics in eukaryotes is discussed.
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PMID:Association of chromatin with anticancer antibiotics, mithramycin and chromomycin A3. 1278 53

Histone acetylation is important in regulating DNA accessibility. Multifunctional Sin3 proteins bind histone deacetylases (HDACs) to assemble silencing complexes that selectively target chromatin. We show that, in fission yeast, an essential HDAC, Clr6, exists in two distinct Sin3 core complexes. Complex I contains an essential Sin3 homolog, Pst1, and other factors, and predominantly targets gene promoters. Complex II contains a nonessential Sin3 homolog, Pst2, and several conserved proteins. It preferentially targets transcribed chromosomal regions and centromere cores. Defects in complex II abrogate global protective functions of chromatin, causing increased accessibility of DNA to genotoxic agents and widespread antisense transcripts that are processed by the exosome. Notably, the two Clr6 complexes differentially repress forward and reverse centromeric repeat transcripts, suggesting that these complexes regulate transcription in heterochromatin and euchromatin in similar manners, including suppression of spurious transcripts from cryptic start sites.
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PMID:Distinct roles of HDAC complexes in promoter silencing, antisense suppression and DNA damage protection. 1747 77

Mitochondrial dysfunction is critical for neurodegeneration in movement disorders. Neurotoxicological models recapitulating movement disorder involve mitochondrial damage including inhibition of mitochondrial complexes. Previously, we demonstrated that neurotoxic models of Parkinson's disease and Manganism showed distinct morphological, electrophysiological and molecular profile indicating disease-specific characteristics. In a recent study, we demonstrated that the transcriptomic changes triggered by the neurotoxic mitochondrial complex II inhibitor 3-nitropropionic acid (3-NPA), was significantly different from the profile induced by the neurotoxic mitochondrial complex I inhibitor 1-methyl-4- phenylpyridinium (MPP+) and mitochondrial toxin Manganese (Mn). Among the plausible pathways, we surmised that epigenetic mechanisms could contribute to 3-NPA specific transcriptomic profile. To address this, we assessed global and individual lys-specific acetylation profile of Histone H3 and H4 in the 3-NPA neuronal cell model. Our data revealed histone acetylation profile unique to the 3-NPA model that was not noted in the MPP+ and Mn models. Among the individual lys, Histone H3K56 showed robust dose and time-dependent hyperacetylation in the 3-NPA model. Chromatin Immunoprecipitation-sequencing (ChIP-seq) revealed that acetylated H3K56 was associated with 13072 chromatin sites, which showed increased occupancy in the transcription start site-promoter site. Acetylated histone H3K56 was associated with 1747 up-regulated and 263 down-regulated genes in the 3-NPA model, which included many up-regulated autophagy and mitophagy genes. Western analysis validated the involvement of PINK1-Parkin dependent mitophagy in the 3-NPA model. We propose that 3-NPA specific chromatin dynamics could contribute to the unique transcriptomic profile with implications for movement disorders.
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PMID:Exposure to the neurotoxin 3-nitropropionic acid in neuronal cells induces unique histone acetylation pattern: Implications for neurodegeneration. 3292 24

Recurrent somatic mutations in ETNK1 (Ethanolamine-Kinase-1) were identified in several myeloid malignancies and are responsible for a reduced enzymatic activity. Here, we demonstrate in primary leukemic cells and in cell lines that mutated ETNK1 causes a significant increase in mitochondrial activity, ROS production, and Histone H2AX phosphorylation, ultimately driving the increased accumulation of new mutations. We also show that phosphoethanolamine, the metabolic product of ETNK1, negatively controls mitochondrial activity through a direct competition with succinate at mitochondrial complex II. Hence, reduced intracellular phosphoethanolamine causes mitochondria hyperactivation, ROS production, and DNA damage. Treatment with phosphoethanolamine is able to counteract complex II hyperactivation and to restore a normal phenotype.
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PMID:ETNK1 mutations induce a mutator phenotype that can be reverted with phosphoethanolamine. 3323 96