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20S proteasome

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https://www.readbyqxmd.com/read/28193903/structural-analysis-of-mycobacterium-tuberculosis-homologues-of-the-eukaryotic-proteasome-assembly-chaperone-2-pac2
#1
Lin Bai, Jordan B Jastrab, Marta Isasa, Kuan Hu, Hongjun Yu, Steven P Gygi, K Heran Darwin, Huilin Li
A previous bioinformatics analysis identified the Mycobacterium tuberculosis (M. tuberculosis) proteins Rv2125 and Rv2714 as orthologs of the eukaryotic proteasome assembly chaperone 2 (PAC2). We set out to investigate whether Rv2125 or Rv2714 could function in proteasome assembly. We solved the crystal structure of Rv2125 at 3.0 Å resolution, which showed an overall fold similar to that of the PAC2 family proteins that include the archaeal PbaB and the yeast Pba1. However, Rv2125 and Rv2714 formed trimers, whereas PbaB forms tetramers and Pba1 dimerizes with Pba2...
February 13, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/28183185/rational-design-of-selective-and-bioactive-inhibitors-of-the-mycobacterium-tuberculosis-proteasome
#2
Kyle A Totaro, Dominik Barthelme, Peter T Simpson, Xiuju Jiang, Gang Lin, Carl F Nathan, Robert T Sauer, Jason K Sello
The 20S core particle of the proteasome in Mycobacterium tuberculosis (Mtb) is a promising, yet unconventional, drug target. This multimeric peptidase is not essential, yet degrades proteins that have become damaged and toxic via reactions with nitric oxide (and/or the associated reactive nitrogen intermediates) produced during the host immune response. Proteasome inhibitors could render Mtb susceptible to the immune system, but they would only be therapeutically viable if they do not inhibit the essential 20S counterpart in humans...
February 10, 2017: ACS Infectious Diseases
https://www.readbyqxmd.com/read/28182990/design-synthesis-and-biological-evaluation-of-novel-non-peptide-boronic-acid-derivatives-as-proteasome-inhibitors
#3
Ying Ge, Aibo Li, Jianwei Wu, Haiwei Feng, Letian Wang, Hongwu Liu, Yungen Xu, Qingxiang Xu, Li Zhao, Yuyan Li
A novel series of non-peptide proteasome inhibitors bearing the 1, 4-naphthoquinone scaffold and boronic acid warhead was developed. In the biological evaluation on the chymotrypsin-like activity of human 20S proteasome, five compounds showed IC50 values in the nanomolar range. Docking experiments into the yeast 20S proteasome rationalized their biological activities and allowed further optimization of this interesting class of inhibitors. Within the cellular proliferation inhibition assay and western blot analysis, compound 3e demonstrated excellent anti-proliferative activity against solid tumor cells and clear accumulation of ubiquitinated cellular proteins...
January 23, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28177129/role-of-parp-activity-in-lung-cancer-induced-cachexia-effects-on-muscle-oxidative-stress-proteolysis-anabolic-markers-and-phenotype
#4
Alba Chacon-Cabrera, Mercè Mateu-Jimenez, Klaus Langohr, Clara Fermoselle, Elena García-Arumí, Antoni L Andreu, Jose Yelamos, Esther Barreiro
Strategies to treat cachexia are still at its infancy. Enhanced muscle protein breakdown and ubiquitin-proteasome system are common features of cachexia associated with chronic conditions including lung cancer (LC). Poly(ADP-ribose) polymerases (PARP), which play a major role in chromatin structure regulation, also underlie maintenance of muscle metabolism and body composition. We hypothesized that protein catabolism, proteolytic markers, muscle fiber phenotype, and muscle anabolism may improve in respiratory and limb muscles of LC-cachectic Parp-1-deficient (Parp-1(-/-) ) and Parp-2(-/-) mice...
February 8, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28165654/identification-of-proteasomal-catalytic-subunit-psma6-as-a-therapeutic-target-for-lung-cancer
#5
Tomohiko Kakumu, Mitsuo Sato, Daiki Goto, Toshio Kato, Naoyuki Yogo, Tetsunari Hase, Masahiro Morise, Takayuki Fukui, Kohei Yokoi, Yoshitaka Sekido, Luc Girard, John D Minna, Lauren A Byers, John V Heymach, Kevin R Coombes, Masashi Kondo, Yoshinori Hasegawa
To identify potential therapeutic targets for lung cancer, we performed semi-genome-wide shRNA screening combined with the utilisation of genome-wide expression and copy number data. shRNA screening targeting 5,043 genes in NCI-H460 identified 51 genes as candidates. Pathway analysis revealed that the 51 genes were enriched for the five pathways, including ribosome, proteasome, RNA polymerase, pyrimidine metabolism and spliceosome pathways. We focused on the proteasome pathway that involved six candidate genes because its activation has been demonstrated in diverse human malignancies, including lung cancer...
February 6, 2017: Cancer Science
https://www.readbyqxmd.com/read/28159760/nad-p-h-quinone-oxidoreductase-1-nqo1-competes-with-20s-proteasome-for-binding-with-c-ebp%C3%AE-leading-to-its-stabilization-and-protection-against-radiation-induced-myeloproliferative-disease
#6
https://www.readbyqxmd.com/read/28157553/immunoproteasome-subunit-deficiency-has-no-influence-on-the-canonical-pathway-of-nf-%C3%AE%C2%BAb-activation
#7
Annegret Bitzer, Michael Basler, Daniel Krappmann, Marcus Groettrup
Activation of the pro-inflammatory transcription factor NF-κB requires signal-induced proteasomal degradation of the inhibitor of NF-κB (IκB) in order to allow nuclear translocation. Most cell types are capable of expressing two types of 20S proteasome core particles, the constitutive proteasome and immunoproteasome. Inducible under inflammatory conditions, the immunoproteasome is mainly characterized through an altered cleavage specificity compared to the constitutive proteasome. However, the question whether immunoproteasome subunits affect NF-κB signal transduction differently from constitutive subunits is still up for debate...
March 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28137628/effect-of-ionizing-radiation-exposure-on-trypanosoma-cruzi-ubiquitin-proteasome-system
#8
Paula G Cerqueira, Danielle G Passos-Silva, João P Vieira-da-Rocha, Isabela Cecilia Mendes, Karla A de Oliveira, Camila F B Oliveira, Liza F F Vilela, Ronaldo A P Nagem, Joseane Cardoso, Sheila C Nardelli, Marco A Krieger, Glória R Franco, Andrea M Macedo, Sérgio D J Pena, Sérgio Schenkman, Dawidson A Gomes, Renata Guerra-Sá, Carlos R Machado
In recent years, proteasome involvement in the damage response induced by ionizing radiation (IR) became evident. However, whether proteasome plays a direct or indirect role in IR-induced damage response still unclear. Trypanosoma cruzi is a human parasite capable of remarkable high tolerance to IR, suggesting a highly efficient damage response system. Here, we investigate the role of T. cruzi proteasome in the damage response induced by IR. We exposed epimastigotes to high doses of gamma ray and we analyzed the expression and subcellular localization of several components of the ubiquitin-proteasome system...
January 27, 2017: Molecular and Biochemical Parasitology
https://www.readbyqxmd.com/read/28106073/high-resolution-cryo-em-structure-of-the-proteasome-in-complex-with-adp-alfx
#9
Zhanyu Ding, Zhenglin Fu, Cong Xu, Yifan Wang, Yanxing Wang, Junrui Li, Liangliang Kong, Jinhuan Chen, Na Li, Rongguang Zhang, Yao Cong
The 26S proteasome is an ATP-dependent dynamic 2.5 MDa protease that regulates numerous essential cellular functions through degradation of ubiquitinated substrates. Here we present a near-atomic-resolution cryo-EM map of the S. cerevisiae 26S proteasome in complex with ADP-AlFx. Our biochemical and structural data reveal that the proteasome-ADP-AlFx is in an activated state, displaying a distinct conformational configuration especially in the AAA-ATPase motor region. Noteworthy, this map demonstrates an asymmetric nucleotide binding pattern with four consecutive AAA-ATPase subunits bound with nucleotide...
January 20, 2017: Cell Research
https://www.readbyqxmd.com/read/28104457/genetic-deletion-of-soluble-epoxide-hydrolase-provides-cardioprotective-responses-following-myocardial-infarction-in-aged-mice
#10
REVIEW
K Lockhart Jamieson, Victor Samokhvalov, Maria Akhnokh, Kyra Lee, Woo Jung Cho, Abhijit Takawale, Xiuhua Wang, Zamaneh Kassiri, John M Seubert
BACKGROUND: Pathophysiological responses, including cardiovascular complications, often alter with age. Cardioprotective effects of epoxyeicosatrienoic acids (EETs) toward acute myocardial ischemia-reperfusion injury have been well documented. However, biological relevance of EET-evoked cardioprotection in the ageing myocardium remains unknown. EETs are metabolized to less active metabolites by the enzyme soluble epoxide hydrolase (sEH). This study uses permanent occlusion of the left anterior descending artery (LAD) in young and aged sEH null and WT mice to compare cardiac and mitochondrial function following ischemic injury...
January 16, 2017: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/28065760/establishment-of-a-suite-of-assays-that-support-the-discovery-of-proteasome-stimulators
#11
Darci J Trader, Scott Simanski, Paige Dickson, Thomas Kodadek
BACKGROUND: The proteasome catalyzes the degradation of many mis-folded proteins, which are otherwise cytotoxic. There is interest in the discovery of proteasome agonists, but previous efforts to do so have been disappointing. METHODS: The cleavage of small fluorogenic peptides is used routinely as an assay to screen for proteasome modulators. We have developed follow-on assays that employ more physiologically relevant substrates. RESULTS: To demonstrate the efficacy of this workflow, the NIH Clinical Collection (NCC) was screened...
January 5, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28060342/examining-proteasome-assembly-with-recombinant-archaeal-proteasomes-and-nondenaturing-page-the-case-for-a-combined-approach
#12
Dilrajkaur Panfair, Andrew R Kusmierczyk
Proteasomes are found in all domains of life. They provide the major route of intracellular protein degradation in eukaryotes, though their assembly is not completely understood. All proteasomes contain a structurally conserved core particle (CP), or 20S proteasome, containing two heptameric β subunit rings sandwiched between two heptameric α subunit rings. Archaeal 20S proteasomes are compositionally simpler compared to their eukaryotic counterparts, yet they both share a common assembly mechanism. Consequently, archaeal 20S proteasomes continue to be important models for eukaryotic proteasome assembly...
December 17, 2016: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28028152/pharmacologic-inhibition-of-hsp90-to-prevent-glt-1-degradation-as-an-effective-therapy-for-epilepsy
#13
Longze Sha, Xueqin Wang, Jing Li, Xinze Shi, Liwen Wu, Yan Shen, Qi Xu
The glutamate transporter GLT-1 is critical for the maintenance of low interstitial glutamate concentrations. Loss of GLT-1 is commonly observed in neurological disorders, including temporal lobe epilepsy (TLE). Despite the hypothesis that targeting the mechanisms of GLT-1 deficiency may be a novel strategy for treating drug-resistant epilepsy, the underlying molecular cascade remains largely unknown. Here, we show that Hsp90β is up-regulated in reactive astrocytes of the epileptic hippocampus in patients with TLE and mouse models of epilepsy...
February 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/28027531/exploration-of-novel-piperazine-or-piperidine-constructed-non-covalent-peptidyl-derivatives-as-proteasome-inhibitors
#14
Rangxiao Zhuang, Lixin Gao, Xiaoqing Lv, Jianjun Xi, Li Sheng, Yanmei Zhao, Ruoyu He, Xiaobei Hu, Yidan Shao, Xuwang Pan, Shourong Liu, Weiwei Huang, Yubo Zhou, Jia Li, Jiankang Zhang
A series of novel piperazine or piperidine-containing non-covalent peptidyl derivatives possessing a neopentyl-asparagine residue were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were screened for their 20S proteasome chymotrypsin-like inhibitory activities, and 15 ones displayed more potent activities than carfilzomib with IC50 values lower than 10 nM. Subsequently, the most potent 10 analogues were tested for their cytotoxic activities against two multiple myeloma (MM) cell lines RPMI-8226 and MM-1S...
December 18, 2016: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27982755/cytotoxicity-and-proteasome-inhibition-by-alkaloid-extract-from-murraya-koenigii-leaves-in-breast-cancer-cells-molecular-docking-studies
#15
Ayesha Ismail, Bindu Noolu, Ramesh Gogulothu, Shyam Perugu, Ajumeera Rajanna, Suresh K Babu
Murraya koenigii (curry tree) leaves are rich in bioactive compounds such as flavonoids, alkaloids, and coumarins. Alkaloids from M. koenigii leaves have antianalgesic, antiulcerogenic, antiobesity, and antitumor activities. In this study, we tested the cytotoxic and proteasome-inhibitory potential of a total alkaloid extract (TAE) from M. koenigii leaves in the breast cancer cell line MDA-MB-231. The TAE decreased cell viability with an IC50 of 14.4 μg/mL and altered growth kinetics of breast cancer cells...
December 2016: Journal of Medicinal Food
https://www.readbyqxmd.com/read/27976853/structural-basis-for-the-species-selective-binding-of-n-c-capped-dipeptides-to-the-mycobacterium-tuberculosis-proteasome
#16
Hao-Chi Hsu, Pradeep K Singh, Hao Fan, Rong Wang, George Sukenick, Carl Nathan, Gang Lin, Huilin Li
The Mycobacterium tuberculosis (Mtb) 20S proteasome is vital for the pathogen to survive under nitrosative stress in vitro and to persist in mice. To qualify for drug development, inhibitors targeting Mtb 20S must spare both the human constitutive proteasome (c-20S) and immunoproteasome (i-20S). We recently reported members of a family of noncovalently binding dipeptide proteasome inhibitors that are highly potent and selective for Mtb 20S over human c-20S and i-20S. To understand the structural basis of their potency and selectivity, we have studied the structure-activity relationship of six derivatives and solved their cocrystal structures with Mtb 20S...
December 27, 2016: Biochemistry
https://www.readbyqxmd.com/read/27966496/recent-excitements-in-protein-nmr-large-proteins-and-biologically-relevant-dynamics
#17
Sai Chaitanya Chiliveri, Mandar V Deshmukh
The advent of Transverse Relaxation Optimized SpectroscopY (TROSY) and perdeuteration allowed biomolecular NMR spectroscopists to overcome the size limitation barrier (approx. 20 kDa) in de novo structure determination of proteins. The utility of these techniques was immediately demonstrated on large proteins and protein complexes (e.g. GroELGroES, ClpP protease, Hsp90-p53, 20S proteasome, etc.). Further, recent methodological developments such as Residual Dipolar Couplings and Paramagnetic Relaxation Enhancement allowed accurate measurement of long-range structural restraints...
December 2016: Journal of Biosciences
https://www.readbyqxmd.com/read/27956634/brief-treatment-with-a-highly-selective-immunoproteasome-inhibitor-promotes-long-term-cardiac-allograft-acceptance-in-mice
#18
Esilida Sula Karreci, Hao Fan, Mayuko Uehara, Albana B Mihali, Pradeep K Singh, Ahmed T Kurdi, Zhabiz Solhjou, Leonardo V Riella, Irene Ghobrial, Teresina Laragione, Sujit Routray, Jean Pierre Assaker, Rong Wang, George Sukenick, Lei Shi, Franck J Barrat, Carl F Nathan, Gang Lin, Jamil Azzi
Constitutive proteasomes (c-20S) are ubiquitously expressed cellular proteases that degrade polyubiquitinated proteins and regulate cell functions. An isoform of proteasome, the immunoproteasome (i-20S), is highly expressed in human T cells, dendritic cells (DCs), and B cells, suggesting that it could be a potential target for inflammatory diseases, including those involving autoimmunity and alloimmunity. Here, we describe DPLG3, a rationally designed, noncovalent inhibitor of the immunoproteasome chymotryptic subunit β5i that has thousands-fold selectivity over constitutive β5c...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27921229/an-extracellular-proteasome-releases-endostatin-from-human-collagen-xviii
#19
Maria L V Reiss-Pistilli, Detlef Schuppan, Madalena M S Barroso, Iranaia Assunção-Miranda, Shirley Farias, Letícia Lery, Michael Bauer, Luiz Juliano, Maria A Juliano, Tatiana Coelho-Sampaio
Endostatin is a potent anti-angiogenic and anti-tumor protein capable of regressing tumors without inducing acquired resistance. Since it is a fragment of the parental molecule, collagen XVIII, its endogenous production depends on the activity of a specific proteolytic enzyme. While such an enzyme has been described in mice, a human counterpart has not been identified so far. Here, we searched for this enzyme by using a fluorescence resonance energy transfer peptide containing the cleavage site of human collagen XVIII...
December 5, 2016: Angiogenesis
https://www.readbyqxmd.com/read/27917682/the-preclinical-discovery-and-development-of-bortezomib-for-the-treatment-of-mantle-cell-lymphoma
#20
Richard Arkwright, Tri Minh Pham, Jeffrey A Zonder, Q Ping Dou
Mantle cell lymphoma (MCL) is an incurable, often aggressive B-cell malignancy. Bortezomib (BTZ), the 20S proteasome inhibitor was originally developed and approved for treatment of relapsed refractory multiple myeloma, and subsequently approved for treatment of MCL. BTZ's single-agent activity induces clinical responses in approximately one-third of relapsed MCL patients. BTZ-containing combination therapies have further improved the quality and duration of clinical responses compared to standard chemotherapies in previously untreated MCL patients...
December 20, 2016: Expert Opinion on Drug Discovery
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