Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.3.1 (citrate synthase)
 4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, it became clear that aminoglycoside antibiotics affect protein-protein interactions involving protein disulfide isomerase as well as protein synthesis in the endoplasmic reticulum. In this study, we used affinity column chromatography to screen gentamicin-binding proteins in microsomes derived from bovine kidney in order to learn about the possible mechanisms of gentamicin-associated nephrotoxicity. One of the gentamicin-binding proteins was identified as calreticulin (CRT) by N-terminal amino acid sequence analysis. Interestingly, gentamicin inhibited the chaperone and oxidative refolding activities of CRT when N-glycosylated substrates such as alpha1-antitrypsin and alpha-mannosidase were used as substrates, but it did not inhibit the chaperone activity of CRT when unglycosylated citrate synthase was used. Moreover, CRT suppressed the aggregation of deglycosylated and denatured alpha-mannosidase, but gentamicin did not inhibit its chaperone activity. Experiments with domain mutants suggest that the lectin site of CRT is the main target for gentamicin binding and that binding of gentamicin to this site inhibits the chaperone activity of CRT.
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PMID:Gentamicin binds to the lectin site of calreticulin and inhibits its chaperone activity. 1535 34

Cytochrome c oxidase (COX) is the terminal enzyme of the electron transport chain composed of 13 subunits; three are mitochondria-encoded, and 10 are nucleus-inscribed on nine different chromosomes within the mammalian genome. The transcriptional regulation of such a multisubunit, multichromosomal, and bigenomic enzyme is mechanistically challenging. Transcription factories have been proposed as one mechanism by which genes from different genomic loci congregate to transcribe functionally related genes, and chromosome conformation capture (3C) is a means by which such interactions can be revealed. Thus far, however, only loci from the same chromosome or at most two chromosomes have been co-localized by 3C. The present study used 3C to test our hypothesis that not only the 10 genomic loci from nine chromosomes encoding the 10 nuclear subunits of COX, but also genes from three chromosomes encoding mitochondrial transcription factors A and B (Tfam, Tfb1m, and Tfb2m) critical for the transcription of the three mitochondria-encoded COX subunit genes all occupy common intranuclear sites in the murine neuronal nuclei. The pairing of various COX subunit genes and Tf genes indicates that interactions are present among all of them. On the other hand, genes for a non-mitochondrial protein (calreticulin) as well as a mitochondrial enzyme (citrate synthase) did not interact with COX genes. Furthermore, interactions between COX subunit and Tf genes were up-regulated by depolarizing stimulation and down-regulated by impulse blockade in primary neurons. Thus, a viable mechanism is in place for a synchronized, coordinated transcriptional regulation of this multisubunit, bigenomic COX enzyme in neurons.
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PMID:Chromosome conformation capture of all 13 genomic Loci in the transcriptional regulation of the multisubunit bigenomic cytochrome C oxidase in neurons. 1943 16

Calreticulin (CALR), a multifunctional protein thoroughly researched in mammals, comprises N-, P-, and C-domain and has roles in calcium homeostasis, chaperoning, clearance of apoptotic cells, cell adhesion, and also angiogenesis. In this study, the spatial and temporal expression patterns of the Opisthorchis viverrini CALR gene were analyzed, and calcium-binding and chaperoning properties of recombinant O. viverrini CALR (OvCALR) investigated. OvCALR mRNA was detected from the newly excysted juvenile to the mature parasite by RT-PCR while specific antibodies showed a wide distribution of the protein. OvCALR was localized in tegumental cell bodies, testes, ovary, eggs, Mehlis' gland, prostate gland, and vitelline cells of the mature parasite. Recombinant OvCALR showed an in vitro suppressive effect on the thermal aggregation of citrate synthase. The recombinant OvCALR C-domain showed a mobility shift in native gel electrophoresis in the presence of calcium. The results imply that OvCALR has comparable function to the mammalian homolog as a calcium-binding molecular chaperone. Inferred from the observed strong immunostaining of the reproductive tissues, OvCALR should be important for reproduction and might be an interesting target to disrupt parasite fecundity. Transacetylase activity of OvCALR as reported for calreticulin of Haemonchus contortus could not be observed.
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PMID:Molecular and Biochemical Characterization of Opisthorchis viverrini Calreticulin. 2932 Aug 19