Search results for "Protein Biosynthesis"
showing 10 items of 220 documents
Targeting Nonsense: Optimization of 1,2,4-Oxadiazole TRIDs to Rescue CFTR Expression and Functionality in Cystic Fibrosis Cell Model Systems
2020
Cystic fibrosis (CF) patients develop a severe form of the disease when the cystic fibrosis transmembrane conductance regulator (CFTR) gene is affected by nonsense mutations. Nonsense mutations are responsible for the presence of a premature termination codon (PTC) in the mRNA, creating a lack of functional protein. In this context, translational readthrough-inducing drugs (TRIDs) represent a promising approach to correct the basic defect caused by PTCs. By using computational optimization and biological screening, we identified three new small molecules showing high readthrough activity. The activity of these compounds has been verified by evaluating CFTR expression and functionality after…
Modern diversification of the amino acid repertoire driven by oxygen
2017
All extant life employs the same 20 amino acids for protein biosynthesis. Studies on the number of amino acids necessary to produce a foldable and catalytically active polypeptide have shown that a basis set of 7-13 amino acids is sufficient to build major structural elements of modern proteins. Hence, the reasons for the evolutionary selection of the current 20 amino acids out of a much larger available pool have remained elusive. Here, we have analyzed the quantum chemistry of all proteinogenic and various prebiotic amino acids. We find that the energetic HOMO-LUMO gap, a correlate of chemical reactivity, becomes incrementally closer in modern amino acids, reaching the level of specialize…
Strategies against nonsense: oxadiazoles as translational readthrough-inducing drugs (TRIDs)
2019
This review focuses on the use of oxadiazoles as translational readthrough-inducing drugs (TRIDs) to rescue the functional full-length protein expression in mendelian genetic diseases caused by nonsense mutations. These mutations in specific genes generate premature termination codons (PTCs) responsible for the translation of truncated proteins. After a brief introduction on nonsense mutations and their pathological effects, the features of various classes of TRIDs will be described discussing differences or similarities in their mechanisms of action. Strategies to correct the PTCs will be presented, particularly focusing on a new class of Ataluren-like oxadiazole derivatives in comparison …
Ataluren for the Treatment of Usher Syndrome 2A Caused by Nonsense Mutations
2019
The identification of genetic defects that underlie inherited retinal diseases (IRDs) paves the way for the development of therapeutic strategies. Nonsense mutations caused approximately 12% of all IRD cases, resulting in a premature termination codon (PTC). Therefore, an approach that targets nonsense mutations could be a promising pharmacogenetic strategy for the treatment of IRDs. Small molecules (translational read-through inducing drugs
The Yeast eIF2 Kinase Gcn2 Facilitates H 2 O 2 -Mediated Feedback Inhibition of Both Protein Synthesis and Endoplasmic Reticulum Oxidative Folding du…
2021
Recombinant protein production is a known source of oxidative stress. However, knowledge of which reactive oxygen species are involved or the specific growth phase in which stress occurs remains lacking. Using modern, hypersensitive genetic H2O2-specific probes, microcultivation, and continuous measurements in batch culture, we observed H2O2 accumulation during and following the diauxic shift in engineered Saccharomyces cerevisiae, correlating with peak α-amylase production. In agreement with previous studies supporting a role of the translation initiation factor kinase Gcn2 in the response to H2O2, we find that Gcn2-dependent phosphorylation of eIF2α increases alongside translational atten…
Hepatitis B defective virus with rearrangements in the preS gene during chronic HBV infection.
1991
We have found a defective form of HBV2 in a HBsAg- and anti-HBe-positive patient with liver cancer. Viral deletions were identified in the preS coding region using PCR. The presence of deleted HBV forms was observed in serum, PBMC, and liver samples. After sequencing 12 clones were analyzed (subtype adr). In 9 out of 12 clones a 183-bp in-frame deletion was recorded in the preS1 region (2995 to 3177). Three out of 9 clones also yielded rearrangements of the preS2 N-terminal part. Four out of 9 showed numerous point mutations in the preS1 and preS2 sequence. In addition, 3 out of 12 clones, which did not show the 183-bp preS1 deletion were found to have small deletions and insertions in the …
Influence of nifedipine on the metabolism of gingival fibroblasts.
1994
Calcium antagonists are the gold standard in the therapy of coronary heart disease and hypertension. The prototype of these drugs is nifedipine which, as well as its therapeutic effects on the cells of the cardiovascular system, also has unpleasant side effects on other organ systems. One side effect can be a missive hyperplasia of the gingiva, the reason for which are unclear. In vitro experiments were designed to elucidate the influence of nifedipine on the growth of human gingival fibroblasts in short and long term (72 hours, 6 weeks) cell culture. The following cellular parameters were determined quantitatively: cell proliferation (cell count, [3H]thymidine incorporation), protein synth…
Stabilization of hsp70 mRNA on prolonged cell exposure to hypertonicity
2002
AbstractProlonged exposure of 3T3 cells to 0.5 osM hypertonic medium induced the accumulation of hsp70 mRNAs. This increase in mRNA levels required active protein synthesis. A weak and transient activation of heat shock factor 1 (HSF1) was noted, but it was temporally uncoupled to the accumulation of the hsp70 mRNAs. Nuclear run-on assay and transfection experiments showed that hsp70 gene transcription was not affected by hypertonicity. ActD chase experiments showed that during hypertonic treatment, degradation of hsp70 mRNAs was markedly reduced. This effect did not appear to be a general phenomenon since the increase in mRNA level of another gene induced by hypertonicity (ATA2 transporter…
Effect of nonprotein thiols on protein synthesis in isolated rat hepatocytes.
1996
The ability of nonprotein thiols to modulate rates of protein synthesis was investigated in isolated rat hepatocytes. Addition of cysteine stimulates protein labelling by [14C]Leucine. Glutathione depletion, induced by in vivo administration of L-buthionine sulfoximine and diethylmaleate, did not alter the effect of cysteine, although it decreased the rate of protein synthesis by 32%. The effect of cysteine on protein synthesis does not seem to be related to a perturbation of the redox state of the NAD+/NADH system or to changes in the rate of gluconeogenic pathway. The following observations indicate that cysteine may stimulate protein synthesis by increasing intracellular levels of aspart…
Proteomic evaluation of potentiated sulfa treatment on gilthead sea bream (Sparus aurata L.) liver
2013
Potentiated sulfa drugs are a combination of sulfonamide and pyrimidine potentiators. They are currently used against fish bacterial pathogens in Mediterranean marine fish farming. The present work aimed studying the potential hepatotoxicity of a combination of sulfadiazine (SDZ) and trimethoprim (TMP) in gilthead sea bream juveniles after oral administration, at the recommended ratio of 5: 1 (SDZ/TMP), equivalent to a dose of 30 mg kg(-1) fish day(-1), for 10 days at 19 degrees C temperature. Electrophoresis (DIGE) technology coupled with MS was used to identify possible markers of hepatotoxicity of this treatment. The results obtained show significant changes in the expression of 41 prote…