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Conservation of mechanism in flavoprotein-catalyzed amine oxidation.
Arch Biochem Biophys
November 2024
Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX, 78229, USA. Electronic address:
Article Synopsis
- The presentation aims to clarify how flavoproteins perform amine oxidation and explore if monoamine oxidase can cause carbon-carbon bond oxidation.
- The focus will be on the protonation state of the amine substrate, highlighting that flavoproteins prefer the uncharged form of nitrogen during the oxidation process.
- The discussion includes insights on L-6-hydroxynicotine oxidase, showing it actually catalyzes carbon-nitrogen bond oxidation rather than carbon-carbon, with key residue analysis aiding in understanding substrate binding.
Biochemical and biophysical approaches to characterization of the aromatic amino acid hydroxylases.
Methods Enzymol
September 2024
Department of Biochemistry and Structural Biology, UT Health San Antonio, San Antonio, TX, United States.
The aromatic amino acid hydroxylases phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase utilize a non-heme iron to catalyze the hydroxylation of the aromatic rings of their amino acid substrates, with a tetrahydropterin serving as the source of the electrons necessary for the monooxygenation reaction. These enzymes have been subjected to a variety of biochemical and biophysical approaches, resulting in a detailed understanding of their structures and mechanism. We summarize here the experimental approaches that have led to this understanding.
View Article and Find Full Text PDFA novel in vitro high-content imaging assay for the prediction of drug-induced lung toxicity.
Arch Toxicol
September 2024
Safety Sciences, Clinical Pharmacology and Safety Sciences, R and D, AstraZeneca, Gothenburg, Sweden.
The development of inhaled drugs for respiratory diseases is frequently impacted by lung pathology in non-clinical safety studies. To enable design of novel candidate drugs with the right safety profile, predictive in vitro lung toxicity assays are required that can be applied during drug discovery for early hazard identification and mitigation. Here, we describe a novel high-content imaging-based screening assay that allows for quantification of the tight junction protein occludin in A549 cells, as a model for lung epithelial barrier integrity.
View Article and Find Full Text PDFMechanistic safety assessment via multi-omic characterisation of systemic pathway perturbations following in vivo MAT2A inhibition.
Arch Toxicol
August 2024
Oncology Safety, Safety Sciences, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge, UK.
The tumour suppressor p16/CDKN2A and the metabolic gene, methyl-thio-adenosine phosphorylase (MTAP), are frequently co-deleted in some of the most aggressive and currently untreatable cancers. Cells with MTAP deletion are vulnerable to inhibition of the metabolic enzyme, methionine-adenosyl transferase 2A (MAT2A), and the protein arginine methyl transferase (PRMT5). This synthetic lethality has paved the way for the rapid development of drugs targeting the MAT2A/PRMT5 axis.
View Article and Find Full Text PDFPublic and patient involvement: a survey on knowledge, experience and opinions among researchers within a precision oncology European project.
BMC Cancer
August 2023
Palliative Care, Pain Therapy and Rehabilitation Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Article Synopsis
- A survey was done to find out how much clinicians and researchers know about Patient and Public Involvement (PPI) in clinical research on cancer.
- Out of 101 people who answered, most knew about PPI, but only about half had worked with it in the last five years, and many wanted practical training on the topic.
- The survey showed that more experienced professionals knew more about PPI, and opinions on PPI varied depending on whether people had experience with it or not.
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