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AMPK Activation via Modulation of De Novo Purine Biosynthesis with an Inhibitor of ATIC Homodimerization. 用ATIC同型二聚化抑制剂调节从头嘌呤生物合成激活AMPK。
Chemistry & biology Pub Date : 2015-07-23 Epub Date: 2015-07-02 DOI: 10.1016/j.chembiol.2015.06.008
Daniel J Asby, Francesco Cuda, Maxime Beyaert, Franchesca D Houghton, Felino R Cagampang, Ali Tavassoli
{"title":"AMPK Activation via Modulation of De Novo Purine Biosynthesis with an Inhibitor of ATIC Homodimerization.","authors":"Daniel J Asby,&nbsp;Francesco Cuda,&nbsp;Maxime Beyaert,&nbsp;Franchesca D Houghton,&nbsp;Felino R Cagampang,&nbsp;Ali Tavassoli","doi":"10.1016/j.chembiol.2015.06.008","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.008","url":null,"abstract":"<p><p>5-Aminoimidazole-4-carboxamide ribonucleotide (known as ZMP) is a metabolite produced in de novo purine biosynthesis and histidine biosynthesis, but only utilized in the cell by a homodimeric bifunctional enzyme (called ATIC) that catalyzes the last two steps of de novo purine biosynthesis. ZMP is known to act as an allosteric activator of the cellular energy sensor adenosine monophosphate-activated protein kinase (AMPK), when exogenously administered as the corresponding cell-permeable ribonucleoside. Here, we demonstrate that endogenous ZMP, produced by the aforementioned metabolic pathways, is also capable of activating AMPK. Using an inhibitor of ATIC homodimerization to block the ninth step of de novo purine biosynthesis, we demonstrate that the subsequent increase in endogenous ZMP activates AMPK and its downstream signaling pathways. We go on to illustrate the viability of using this approach to AMPK activation as a therapeutic strategy with an in vivo mouse model for metabolic disorders.</p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":" ","pages":"838-48"},"PeriodicalIF":0.0,"publicationDate":"2015-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33879615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 68
A 45-Amino-Acid Scaffold Mined from the PDB for High-Affinity Ligand Engineering. 从PDB中提取的45氨基酸支架用于高亲和力配体工程。
Chemistry & biology Pub Date : 2015-07-23 Epub Date: 2015-07-09 DOI: 10.1016/j.chembiol.2015.06.012
Max A Kruziki, Sumit Bhatnagar, Daniel R Woldring, Vandon T Duong, Benjamin J Hackel
{"title":"A 45-Amino-Acid Scaffold Mined from the PDB for High-Affinity Ligand Engineering.","authors":"Max A Kruziki,&nbsp;Sumit Bhatnagar,&nbsp;Daniel R Woldring,&nbsp;Vandon T Duong,&nbsp;Benjamin J Hackel","doi":"10.1016/j.chembiol.2015.06.012","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.012","url":null,"abstract":"<p><p>Small protein ligands can provide superior physiological distribution compared with antibodies, and improved stability, production, and specific conjugation. Systematic evaluation of the PDB identified a scaffold to push the limits of small size and robust evolution of stable, high-affinity ligands: 45-residue T7 phage gene 2 protein (Gp2) contains an α helix opposite a β sheet with two adjacent loops amenable to mutation. De novo ligand discovery from 10(8) mutants and directed evolution toward four targets yielded target-specific binders with affinities as strong as 200 ± 100 pM, Tms from 65 °C ± 3 °C to 80°C ± 1 °C, and retained activity after thermal denaturation. For cancer targeting, a Gp2 domain for epidermal growth factor receptor was evolved with 18 ± 8 nM affinity, receptor-specific binding, and high thermal stability with refolding. The efficiency of evolving new binding function and the size, affinity, specificity, and stability of evolved domains render Gp2 a uniquely effective ligand scaffold.</p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":" ","pages":"946-56"},"PeriodicalIF":0.0,"publicationDate":"2015-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34280753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 39
Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG. 乙烷活化的噻吩甲酰胺衍生物通过抑制CTP合成酶pyg杀死结核分枝杆菌。
Chemistry & biology Pub Date : 2015-07-23 DOI: 10.1016/j.chembiol.2015.05.016
Giorgia Mori, Laurent R Chiarelli, Marta Esposito, Vadim Makarov, Marco Bellinzoni, Ruben C Hartkoorn, Giulia Degiacomi, Francesca Boldrin, Sean Ekins, Ana Luisa de Jesus Lopes Ribeiro, Leonardo B Marino, Ivana Centárová, Zuzana Svetlíková, Jaroslav Blaško, Elena Kazakova, Alexander Lepioshkin, Nathalie Barilone, Giuseppe Zanoni, Alessio Porta, Marco Fondi, Renato Fani, Alain R Baulard, Katarína Mikušová, Pedro M Alzari, Riccardo Manganelli, Luiz Pedro S de Carvalho, Giovanna Riccardi, Stewart T Cole, Maria Rosalia Pasca
{"title":"Thiophenecarboxamide Derivatives Activated by EthA Kill Mycobacterium tuberculosis by Inhibiting the CTP Synthetase PyrG.","authors":"Giorgia Mori,&nbsp;Laurent R Chiarelli,&nbsp;Marta Esposito,&nbsp;Vadim Makarov,&nbsp;Marco Bellinzoni,&nbsp;Ruben C Hartkoorn,&nbsp;Giulia Degiacomi,&nbsp;Francesca Boldrin,&nbsp;Sean Ekins,&nbsp;Ana Luisa de Jesus Lopes Ribeiro,&nbsp;Leonardo B Marino,&nbsp;Ivana Centárová,&nbsp;Zuzana Svetlíková,&nbsp;Jaroslav Blaško,&nbsp;Elena Kazakova,&nbsp;Alexander Lepioshkin,&nbsp;Nathalie Barilone,&nbsp;Giuseppe Zanoni,&nbsp;Alessio Porta,&nbsp;Marco Fondi,&nbsp;Renato Fani,&nbsp;Alain R Baulard,&nbsp;Katarína Mikušová,&nbsp;Pedro M Alzari,&nbsp;Riccardo Manganelli,&nbsp;Luiz Pedro S de Carvalho,&nbsp;Giovanna Riccardi,&nbsp;Stewart T Cole,&nbsp;Maria Rosalia Pasca","doi":"10.1016/j.chembiol.2015.05.016","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.05.016","url":null,"abstract":"<p><p>To combat the emergence of drug-resistant strains of Mycobacterium tuberculosis, new antitubercular agents and novel drug targets are needed. Phenotypic screening of a library of 594 hit compounds uncovered two leads that were active against M. tuberculosis in its replicating, non-replicating, and intracellular states: compounds 7947882 (5-methyl-N-(4-nitrophenyl)thiophene-2-carboxamide) and 7904688 (3-phenyl-N-[(4-piperidin-1-ylphenyl)carbamothioyl]propanamide). Mutants resistant to both compounds harbored mutations in ethA (rv3854c), the gene encoding the monooxygenase EthA, and/or in pyrG (rv1699) coding for the CTP synthetase, PyrG. Biochemical investigations demonstrated that EthA is responsible for the activation of the compounds, and by mass spectrometry we identified the active metabolite of 7947882, which directly inhibits PyrG activity. Metabolomic studies revealed that pharmacological inhibition of PyrG strongly perturbs DNA and RNA biosynthesis, and other metabolic processes requiring nucleotides. Finally, the crystal structure of PyrG was solved, paving the way for rational drug design with this newly validated drug target. </p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":"22 7","pages":"917-27"},"PeriodicalIF":0.0,"publicationDate":"2015-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.05.016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10126323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 62
The Tetracycline Destructases: A Novel Family of Tetracycline-Inactivating Enzymes. 四环素破坏酶:一个新的四环素失活酶家族。
Chemistry & biology Pub Date : 2015-07-23 Epub Date: 2015-06-18 DOI: 10.1016/j.chembiol.2015.05.017
Kevin J Forsberg, Sanket Patel, Timothy A Wencewicz, Gautam Dantas
{"title":"The Tetracycline Destructases: A Novel Family of Tetracycline-Inactivating Enzymes.","authors":"Kevin J Forsberg,&nbsp;Sanket Patel,&nbsp;Timothy A Wencewicz,&nbsp;Gautam Dantas","doi":"10.1016/j.chembiol.2015.05.017","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.05.017","url":null,"abstract":"<p><p>Enzymes capable of inactivating tetracycline are paradoxically rare compared with enzymes that inactivate other natural-product antibiotics. We describe a family of flavoenzymes, previously unrecognizable as resistance genes, which are capable of degrading tetracycline antibiotics. From soil functional metagenomic selections, we discovered nine genes that confer high-level tetracycline resistance by enzymatic inactivation. We also demonstrate that a tenth enzyme, an uncharacterized homolog in the human pathogen Legionella longbeachae, similarly inactivates tetracycline. These enzymes catalyze the oxidation of tetracyclines in vitro both by known mechanisms and via previously undescribed activity. Tetracycline-inactivation genes were identified in diverse soil types, encompass substantial sequence diversity, and are adjacent to genes implicated in horizontal gene transfer. Because tetracycline inactivation is scarcely observed in hospitals, these enzymes may fill an empty niche in pathogenic organisms, and should therefore be monitored for their dissemination potential into the clinic.</p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":" ","pages":"888-97"},"PeriodicalIF":0.0,"publicationDate":"2015-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.05.017","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33408657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 130
Antibiotic Resistance in the Environment: Not the Usual Suspects. 环境中的抗生素耐药性:不是通常的怀疑。
Chemistry & biology Pub Date : 2015-07-23 DOI: 10.1016/j.chembiol.2015.07.001
David W Graham
{"title":"Antibiotic Resistance in the Environment: Not the Usual Suspects.","authors":"David W Graham","doi":"10.1016/j.chembiol.2015.07.001","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.07.001","url":null,"abstract":"<p><p>In this issue of Chemistry & Biology, Forsberg et al. (2015) show how metagenomics and biological chemistry can be combined to discover new classes of antibiotic resistance from soil metagenomes. The authors specifically reveal previously unseen resistance mechanisms and genes evident in soils, which will better inform both environmental and clinical studies on antibiotic resistance.</p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":" ","pages":"805-6"},"PeriodicalIF":0.0,"publicationDate":"2015-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.07.001","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33932343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 4
Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells. 新型EphA2激动剂的设计和特性,用于靶向递送化疗到癌细胞。
Chemistry & biology Pub Date : 2015-07-23 Epub Date: 2015-07-09 DOI: 10.1016/j.chembiol.2015.06.011
Bainan Wu, Si Wang, Surya K De, Elisa Barile, Bridget A Quinn, Irina Zharkikh, Angela Purves, John L Stebbins, Robert G Oshima, Paul B Fisher, Maurizio Pellecchia
{"title":"Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells.","authors":"Bainan Wu,&nbsp;Si Wang,&nbsp;Surya K De,&nbsp;Elisa Barile,&nbsp;Bridget A Quinn,&nbsp;Irina Zharkikh,&nbsp;Angela Purves,&nbsp;John L Stebbins,&nbsp;Robert G Oshima,&nbsp;Paul B Fisher,&nbsp;Maurizio Pellecchia","doi":"10.1016/j.chembiol.2015.06.011","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.011","url":null,"abstract":"<p><p>The development of novel, targeted delivery agents for anti-cancer therapies requires the design and optimization of potent and selective tumor-targeting agents that are stable and amenable to conjugation with chemotherapeutic drugs. While short peptides represent potentially an excellent platform for these purposes, they often get degraded and are eliminated too rapidly in vivo. In this study, we used a combination of nuclear magnetic resonance-guided structure-activity relationships along with biochemical and cellular studies to derive a novel tumor-homing agent, named 123B9, targeting the EphA2 tyrosine kinase receptor ligand-binding domain. Conjugating 123B9 to the chemotherapeutic drug paclitaxel (PTX) via a stable linker results in an agent that is significantly more effective than the unconjugated drug in both a pancreatic cancer xenograft model and a melanoma lung colonization and metastases model. Hence, 123B9 could represent a promising strategy for the development of novel targeted therapies for cancer.</p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":" ","pages":"876-887"},"PeriodicalIF":0.0,"publicationDate":"2015-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34280754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 28
Selective N-Hydroxyhydantoin Carbamate Inhibitors of Mammalian Serine Hydrolases. 哺乳动物丝氨酸水解酶的选择性n -羟基海因氨基甲酸酯抑制剂。
Chemistry & biology Pub Date : 2015-07-23 Epub Date: 2015-06-25 DOI: 10.1016/j.chembiol.2015.05.018
Armand B Cognetta, Micah J Niphakis, Hyeon-Cheol Lee, Michael L Martini, Jonathan J Hulce, Benjamin F Cravatt
{"title":"Selective N-Hydroxyhydantoin Carbamate Inhibitors of Mammalian Serine Hydrolases.","authors":"Armand B Cognetta,&nbsp;Micah J Niphakis,&nbsp;Hyeon-Cheol Lee,&nbsp;Michael L Martini,&nbsp;Jonathan J Hulce,&nbsp;Benjamin F Cravatt","doi":"10.1016/j.chembiol.2015.05.018","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.05.018","url":null,"abstract":"<p><p>Serine hydrolase inhibitors, which facilitate enzyme function assignment and are used to treat a range of human disorders, often act by an irreversible mechanism that involves covalent modification of the serine hydrolase catalytic nucleophile. The portion of mammalian serine hydrolases for which selective inhibitors have been developed, however, remains small. Here, we show that N-hydroxyhydantoin (NHH) carbamates are a versatile class of irreversible serine hydrolase inhibitors that can be modified on both the staying (carbamylating) and leaving (NHH) groups to optimize potency and selectivity. Synthesis of a small library of NHH carbamates and screening by competitive activity-based protein profiling furnished selective, in vivo-active inhibitors and tailored activity-based probes for multiple mammalian serine hydrolases, including palmitoyl protein thioesterase 1, mutations of which cause the human disease infantile neuronal ceroid lipofuscinosis.</p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":" ","pages":"928-37"},"PeriodicalIF":0.0,"publicationDate":"2015-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.05.018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33426735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 45
Structural Basis for β-Carboline Alkaloid Production by the Microbial Homodimeric Enzyme McbB. 微生物同型二聚体酶McbB生产β-碳碱生物碱的结构基础
Chemistry & biology Pub Date : 2015-07-23 Epub Date: 2015-06-25 DOI: 10.1016/j.chembiol.2015.06.006
Takahiro Mori, Shotaro Hoshino, Shusaku Sahashi, Toshiyuki Wakimoto, Takashi Matsui, Hiroyuki Morita, Ikuro Abe
{"title":"Structural Basis for β-Carboline Alkaloid Production by the Microbial Homodimeric Enzyme McbB.","authors":"Takahiro Mori,&nbsp;Shotaro Hoshino,&nbsp;Shusaku Sahashi,&nbsp;Toshiyuki Wakimoto,&nbsp;Takashi Matsui,&nbsp;Hiroyuki Morita,&nbsp;Ikuro Abe","doi":"10.1016/j.chembiol.2015.06.006","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.06.006","url":null,"abstract":"<p><p>The β-carboline (βC) alkaloids occur throughout nature and exhibit diverse biological activities. In contrast to βC alkaloid synthesis in plants, the biosynthesis in microorganisms remains poorly understood. The recently reported McbB from Marinactinospora thermotolerans is a novel enzyme proposed to catalyze the Pictet-Spengler (PS) reaction of L-tryptophan and oxaloacetaldehyde to produce the βC scaffold of marinacarbolines. In this study, we solved the crystal structure of McbB complexed with L-tryptophan at 2.48 Å resolution, which revealed the novel protein folding of McbB and the totally different structure from those of other PS condensation catalyzing enzymes, such as strictosidine synthase and norcoclaurine synthase from plants. Structural analysis and site-directed mutagenesis confirmed that the previously proposed catalytic Glu97 at the active-site center functions as an acid and base catalyst. Remarkably, the structure-based mutants R72A and H87A, with expanded active-site cavities, newly accepted bulky phenylglyoxal as the aldehyde substrate, to produce 1-benzoyl-3-carboxy-β-carboline.</p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":" ","pages":"898-906"},"PeriodicalIF":0.0,"publicationDate":"2015-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.06.006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33426736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 33
Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP Competitive Inhibitor. ATP竞争性抑制剂特异性抑制tRNA合成酶的结构基础。
Chemistry & biology Pub Date : 2015-06-18 Epub Date: 2015-06-11 DOI: 10.1016/j.chembiol.2015.05.007
Pengfei Fang, Hongyan Han, Jing Wang, Kaige Chen, Xin Chen, Min Guo
{"title":"Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP Competitive Inhibitor.","authors":"Pengfei Fang,&nbsp;Hongyan Han,&nbsp;Jing Wang,&nbsp;Kaige Chen,&nbsp;Xin Chen,&nbsp;Min Guo","doi":"10.1016/j.chembiol.2015.05.007","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.05.007","url":null,"abstract":"<p><p>Pharmaceutical inhibitors of aminoacyl-tRNA synthetases demand high species and family specificity. The antimalarial ATP-mimetic cladosporin selectively inhibits Plasmodium falciparum LysRS (PfLysRS). How the binding to a universal ATP site achieves the specificity is unknown. Here we report three crystal structures of cladosporin with human LysRS, PfLysRS, and a Pf-like human LysRS mutant. In all three structures, cladosporin occupies the class defining ATP-binding pocket, replacing the adenosine portion of ATP. Three residues holding the methyltetrahydropyran moiety of cladosporin are critical for the specificity of cladosporin against LysRS over other class II tRNA synthetase families. The species-exclusive inhibition of PfLysRS is linked to a structural divergence beyond the active site that mounts a lysine-specific stabilizing response to binding cladosporin. These analyses reveal that inherent divergence of tRNA synthetase structural assembly may allow for highly specific inhibition even through the otherwise universal substrate binding pocket and highlight the potential for structure-driven drug development. </p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":"22 6","pages":"734-44"},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.05.007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33386599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 34
Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus. 一氧化氮合酶作为耐甲氧西林金黄色葡萄球菌的靶点。
Chemistry & biology Pub Date : 2015-06-18 DOI: 10.1016/j.chembiol.2015.05.013
Jeffrey K Holden, Soosung Kang, Federico C Beasley, Maris A Cinelli, Huiying Li, Saurabh G Roy, Dillon Dejam, Aimee L Edinger, Victor Nizet, Richard B Silverman, Thomas L Poulos
{"title":"Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus.","authors":"Jeffrey K Holden,&nbsp;Soosung Kang,&nbsp;Federico C Beasley,&nbsp;Maris A Cinelli,&nbsp;Huiying Li,&nbsp;Saurabh G Roy,&nbsp;Dillon Dejam,&nbsp;Aimee L Edinger,&nbsp;Victor Nizet,&nbsp;Richard B Silverman,&nbsp;Thomas L Poulos","doi":"10.1016/j.chembiol.2015.05.013","DOIUrl":"https://doi.org/10.1016/j.chembiol.2015.05.013","url":null,"abstract":"<p><p>Bacterial infections associated with methicillin-resistant Staphylococcus aureus (MRSA) are a major economic burden to hospitals, and confer high rates of morbidity and mortality among those infected. Exploitation of novel therapeutic targets is thus necessary to combat this dangerous pathogen. Here, we report on the identification and characterization, including crystal structures, of two nitric oxide synthase (NOS) inhibitors that function as antimicrobials against MRSA. These data provide the first evidence that bacterial NOS (bNOS) inhibitors can work synergistically with oxidative stress to enhance MRSA killing. Crystal structures show that each inhibitor contacts an active site Ile residue in bNOS that is Val in the mammalian NOS isoforms. Mutagenesis studies show that the additional nonpolar contacts provided by the Ile in bNOS contribute to tighter binding toward the bacterial enzyme. </p>","PeriodicalId":9772,"journal":{"name":"Chemistry & biology","volume":"22 6","pages":"785-92"},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.chembiol.2015.05.013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33283256","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 17
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