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4 results on '"FAD, flavine adenine dinucleotide"'

1. Thioredoxin reductase: An emerging pharmacologic target for radiosensitization of cancer

Author

Raghavendra S. Patwardhan, Deepak Sharma, and Santosh K. Sandur

Subjects
Cancer Research, TrxR, thioredoxin reductase, PDI, protein disulfide isomerase, MSR, methionine sulfoxide reductase, PMA, phorbol-12-myristic acid, ARE, antioxidant response element, Review, SAPK, stress activated protein kinase, CypD, cyclophilin D, ROS, reactive oxygen species, G.R., glutathione reductase, NSCLC, non-small cell lung cancer, HNSCC, head & neck squamous cell carcinoma, Nrf2, nuclear factor erythroid 2 related factor 2, Trx, thioredoxin, MnSOD, manganese superoxide dismutase, Con A, concanavalin A, Thioredoxin, RC254-282, PEG, polyethylene glycol, PTEN, Phosphatase and Tensin Homolog, TNF, tumor necrosis factor, Radiation, APE1, apurinic/apyrimidinic endonuclease 1, N.F.-κB, nuclear factor kappa B, Hif1α, hypoxia inducible factor 1 α, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, BSO, buthionine sulfoximine, Ref-1, redox factor 1, RNR, ribonucleotide reductase, IQ9, indolequinone 9, NADPH, nicotinamide adenine dinucleotide phosphate, Thioredoxin reductase, PRX, peroxiredoxin, SLNB, solid lipid nanoparticles of baicalein, Oncology, Sec, selenocysteine, FAD, flavine adenine dinucleotide, IR, ionizing radiation, LPS, lipopolysaccharide, GNP, gold nanoparticle, LLC, Lewis lung carcinoma, ASK1, apoptosis signaling kinase, Grx2, glutaredoxin 2, AIF, apoptosis inducing factor, Redox homeostasis
Abstract

Highlights • Thioredoxin reductase (TrxR), a seleno enzyme, regulates cellular redox. • Several human cancers are known to overexpress TrxR. • Inhibitors of TrxR have enhanced radiation induced cytotoxicity in multiple cancers. • TrxR could be a potential target during radiotherapy of cancer patients., Novel agents are required to increase the radiosensitivity of cancer and improve the outcome of radiotherapy. Thioredoxin (Trx) and thioredoxin reductase (TrxR) reduce the oxidized cysteine thiols in several proteins, which regulate cellular redox, survival, proliferation, DNA synthesis, transcription factor activity and apoptosis. TrxR is essential for maintaining a conducive redox state for tumor growth, survival and resistance to therapy. Therefore, it is an appealing pharmacological target for the radiosensitization of tumors. Ionizing radiation (IR) is known to cause cytotoxicity through ROS, oxidative stress and DNA damage. Inhibition of thioredoxin system augments IR induced oxidative stress and potentiates cytotoxic effects. However, TrxR also regulates several critical cellular processes in normal cells. Here, we highlight the pre-clinical research and pharmacological studies to surmise possible utility of different TrxR inhibitors for radiosensitization. This review provides a succinct perspective on the role of TrxR inhibitors during the radiotherapy of cancer., Graphical abstract Image, graphical abstract

Published
2022

2. Identification and cloning of two forms of liver peroxisomal fatty Acyl CoA Oxidase from the koala (Phascolarctos cinereus)

Author

Ngo, Suong Ngoc Thi, McKinnon, Ross Allan, and Stupans, Ieva

Subjects
*REVERSE transcriptase
Abstract

In the present study, the cloning, expression and characterization of the rate-limiting enzyme of the peroxisomal β-oxidation spiral, acyl CoA oxidase (AOX), from koala (Phascolarctos cinereus) liver is described. It has been previously reported that peroxisomal cyanide-insensitive palmitoyl-CoA oxidation activity was absent in koala liver [Comp. Biochem. Physiol. (C) 127 (2000) 327]. This activity is a measure of the overall peroxisomal β-oxidation minus the final step catalysed by thiolase. Two 2039 bp koala liver AOX cDNAs, designated AOX1 and AOX2, were cloned by reverse transcription–polymerase chain reaction and rapid amplification of cDNA ends. The koala AOX cDNAs encode proteins of 662 amino acids. Transfection of the koala AOX cDNAs into Cos-7 cells resulted in the expression of proteins with palmitoyl-CoA oxidase activity. The apparent Km values for AOX1 and AOX2 cDNA-expressed enzymes were 28 and 38 μM, respectively, which are within the range of order of magnitude reported for rat and human purified AOX enzymes (approximately 10 μM). Northern analysis, utilizing the koala AOX1 cDNA as probe, detected a more intense AOX mRNA band in the koala liver as compared to rats and humans. Southern blot analysis of liver genomic DNA samples revealed a single AOX gene fragment of less than 14 kb in koalas, rat and humans, suggesting a single AOX gene. Collectively, the results of this study suggest that the absence of peroxisomal cyanide-insensitive palmitoyl-CoA oxidation activity in the koala liver is possibly due to deficiencies of one or more enzymes downstream of acyl-CoA oxidase and/or deficiencies of mitochondrial β-oxidation enzymes. [Copyright &y& Elsevier]

Published
2003
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3. Estradiol increases rat aorta endothelium-derived relaxing factor (EDRF) activity without changes in endothelial NO synthase gene expression: possible role of decreased endothelium-derived superoxide anion production.

Author

Barbacanne, M.A, Rami, J, Michel, J.B, Souchard, J.P, Philippe, M, Besombes, J.P, Bayard, F, and Arnal, J.F

Abstract

Objectives: Estradiol is known to exert a protective effect against atherosclerosis, but the mechanism(s) whereby this protection is mediated is/are unclear. However, estradiol-treated castrated animals exhibit increased activity of endothelium-derived relaxing factor (EDRF), which could contribute to vasculoprotection. In the present work, we investigated the molecular mechanism(s) of the enhancement of EDRF activity in the thoracic aorta of oophorectomized female rats given 17β-estradiol (E2, 2 or 40 μg/kg/day) compared to those given a placebo. Methods and Results: The abundance in the thoracic aorta of NO synthase I, II and III mRNA (using RT-PCR) and of NO synthase I, II and III immunoreactive protein (using Western blotting) was unaltered by E2. NO synthase activity (based on arginine/citrulline conversion) in thoracic aorta homogenates did not differ significantly among the three groups, suggesting that NO production was not enhanced by E2. In contrast, lucigenin-enhanced chemiluminescence of aorta from the E2 group was decreased compared to that of the placebo group. Desendothelialization and exogenously added superoxide dismutase suggested that this difference was due to a decrease in extracellular endothelium-derived production of superoxide anion (O2−⋅). Experiments in cultured bovine aortic endothelial cells confirmed a decreased extracellular production of O2−⋅ in response to ethinylestradiol (1 nM) using both lucigenin-enhanced chemiluminescence and ESR spectroscopy. Luminol-enhanced chemiluminescence revealed that ethinylestradiol-treated cultured endothelial cells generated less peroxynitrite (the byproduct of NO⋅ and O2−⋅ interaction) than control cells. Conclusion: Estradiol increases rat aorta EDRF activity in the absence of changes in endothelial NO synthase gene expression. The decreased endothelium-derived generation of O2−⋅ in response to estrogens could account for enhanced EDRF–NO bioactivity and decreased peroxynitrite release. All of these effects could contribute to the vascular protective properties of estrogens. [ABSTRACT FROM PUBLISHER]

Published
1999
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4. From the similarity analysis of protein cavities to the functional classification of protein families using cavbase

Author

Nils Weskamp, Eyke Hüllermeier, Daniel Kuhn, Gerhard Klebe, and Stefan Schmitt

Subjects
cluster analysis of protein binding pockets, Protein family, TGEV, transmissible gastroenteritis virus, Coronavirus M Proteins, Nearest neighbor search, medicine.medical_treatment, CoV, coronavirus, EC, enzyme classification, Sequence (biology), SAM, S-adenosyl-methionine, Computational biology, Plasma protein binding, CDKs, cyclin-dependent protein kinases, Biology, Article, Viral Matrix Proteins, HB, hydrogen bond, UPGMA, unweighted pair group method with arithmetic mean, Structural Biology, Similarity analysis, medicine, Cluster Analysis, CML, chronic myelogenous leukemia, SARS, severe acute respiratory syndrome, Binding site, Molecular Biology, Carbonic Anhydrases, protein kinases, Protease, Binding Sites, Chemistry, Physical, SARS protease, MAP, mitogen-activated protein kinases, Computational Biology, Proteins, Reproducibility of Results, Enzymes, Enzyme binding, classification of protein binding pockets, Biochemistry, protein binding pockets, Structural Homology, Protein, CA, carbonic anhydrase, FAD, flavine adenine dinucleotide, Algorithms, NADP, RMSD, root-mean-square deviations
Abstract

In this contribution, the classification of protein binding sites using the physicochemical properties exposed to their pockets is presented. We recently introduced Cavbase, a method for describing and comparing protein binding pockets on the basis of the geometrical and physicochemical properties of their active sites. Here, we present algorithmic and methodological enhancements in the Cavbase property description and in the cavity comparison step. We give examples of the Cavbase similarity analysis detecting pronounced similarities in the binding sites of proteins unrelated in sequence. A similarity search using SARS M(pro) protease subpockets as queries retrieved ligands and ligand fragments accommodated in a physicochemical environment similar to that of the query. This allowed the characterization of the protease recognition pockets and the identification of molecular building blocks that can be incorporated into novel antiviral compounds. A cluster analysis procedure for the functional classification of binding pockets was implemented and calibrated using a diverse set of enzyme binding sites. Two relevant protein families, the alpha-carbonic anhydrases and the protein kinases, are used to demonstrate the scope of our cluster approach. We propose a relevant classification of both protein families, on the basis of the binding motifs in their active sites. The classification provides a new perspective on functional properties across a protein family and is able to highlight features important for potency and selectivity. Furthermore, this information can be used to identify possible cross-reactivities among proteins due to similarities in their binding sites.

Published
2006

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