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ACS Chemical Biology

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https://www.readbyqxmd.com/read/30427174/fluorescent-tracking-of-the-endoplasmic-reticulum-in-live-pathogenic-fungal-cells
#1
Raphael I Benhamou, Qais Z Jaber, Ido M Herzog, Yael Roichman, Micha Fridman
In fungal cells, the endoplasmic reticulum (ER) harbors several of the enzymes involved in the biosynthesis of ergosterol, an essential membrane component, making this organelle the site of action of antifungal azole drugs, used as first-line treatment for fungal infections. This highlights the need for specific fluorescent labeling of this organelle in cells of pathogenic fungi. Here we report on the development and evaluation of a collection of fluorescent ER trackers in a panel of Candida, considered as the most frequently encountered pathogen in fungal infections...
November 14, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30421914/hdac1-substrate-profiling-using-proteomics-based-substrate-trapping
#2
Dhanusha A Nalawansha, Yuchen Zhang, Kavinda Herath, Mary Kay H Pflum
Histone Deacetylase (HDAC) proteins are overexpressed in multiple diseases, including cancer, and have emerged as anticancer drug targets. HDAC proteins regulate cellular processes, such as cell cycle, apoptosis, and cell proliferation, by deacetylating histone and non-histone substrates. Although a plethora of acetylated proteins have been identified using large-scale proteomic approaches, the HDAC proteins responsible for their dynamic deacetylation are poorly studied. For example, few substrates of HDAC1 have been identified, which is mainly due to the scarcity of the substrate identification tools...
November 13, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30371052/structural-and-functional-studies-of-a-gem-dimethylating-methyltransferase-from-a-trans-acyltransferase-assembly-line
#3
Jessica L Meinke, M Rachel Mehaffey, Drew T Wagner, Ningze Sun, Zhicheng Zhang, Jennifer S Brodbelt, Adrian T Keatinge-Clay
The methyl substituents in products of trans-acyltransferase assembly lines are usually incorporated by S-adenosyl-methionine (SAM)-dependent methyltransferase (MT) domains. The gem-dimethyl moieties within the polyketide disorazol are installed through the iterative action of an MT in the third module of its assembly line. The 1.75-Å-resolution crystal structure of this MT helps elucidate how it catalyzes the addition of two methyl groups. Activity assays of point mutants on β-ketoacyl chains linked to an acyl carrier protein and N-acetylcysteamine provide additional insights into the roles of active site residues...
November 9, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30372610/a-local-allosteric-network-in-heat-shock-protein-70-hsp70-links-inhibitor-binding-to-enzyme-activity-and-distal-protein-protein-interactions
#4
Silvia Rinaldi, Victoria A Assimon, Zapporah T Young, Giulia Morra, Hao Shao, Isabelle R Taylor, Jason E Gestwicki, Giorgio Colombo
Allosteric inhibitors can be more difficult to optimize without an understanding of how their binding influences the conformational motions of the target. Here, we used an integrated computational and experimental approach to probe the molecular mechanism of an allosteric inhibitor of heat shock protein 70 (Hsp70). The anticancer compound, MKT-077, is known to bind a conserved site in members of the Hsp70 family, which favors the ADP-bound state and interferes with a protein-protein interaction (PPI) at long range...
November 8, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30346689/selective-usage-of-isozymes-for-stress-response
#5
Yugang Zhang, Zhewang Lin, Miao Wang, Hening Lin
Isozymes are enzymes with similar sequences that catalyze the same reaction in a given species. In Saccharomyces cerevisiae, most isozymes have major isoforms with high expression levels and minor isoforms with little expression under normal growth conditions. In a proteomic study aimed at identifying yeast protein regulated by rapamycin, we found an interesting phenomenon, that, for several metabolic enzymes, the major isozymes are downregulated while the minor isozymes are upregulated. Through enzymological and biochemical studies, we demonstrate that a rapamycin-upregulated enolase isozyme (ENO1) favors gluconeogenesis and a rapamycin-upregulated alcohol dehydrogenase isozyme (ALD4) promotes the reduction of NAD+ to NADH (instead of NADP+ to NADPH)...
November 8, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30296373/tunable-stability-of-imidazotetrazines-leads-to-a-potent-compound-for-glioblastoma
#6
Riley L Svec, Lucia Furiassi, Christine G Skibinski, Timothy M Fan, Gregory J Riggins, Paul J Hergenrother
Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), a small molecule DNA alkylating agent, remains the standard-of-care for glioblastoma (GBM). TMZ has an unusual mode-of-action, spontaneously converting to its active component via hydrolysis in vivo. While TMZ has been FDA approved for two decades, it provides little benefit to patients whose tumors express the resistance enzyme MGMT and gives rise to systemic toxicity through myelosuppression. TMZ was first synthesized in 1984, but certain key derivatives have been inaccessible due to the chemical sensitivity of TMZ, precluding broad exploration of the link between imidazotetrazine structure and biological activity...
November 8, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30404440/antagonists-for-constitutively-active-mutant-estrogen-receptors-insights-into-the-roles-of-antiestrogen-core-and-side-chain
#7
Abhishek Sharma, Weiyi Toy, Valeria Sanabria Guillen, Naina Sharma, Jian Min, Kathryn E Carlson, Christopher G Mayne, Shengjia Lin, Michael Sabio, Geoffrey Greene, Benita S Katzenellenbogen, Sarat Chandarlapaty, John A Katzenellenbogen
A major risk for patients having estrogen receptor α (ERα)-positive breast cancer is the recurrence of drug-resistant metastases after initial successful treatment with endocrine therapies. Recent studies have implicated a number of activating mutations in the ligand-binding domain of ERα that stabilize the agonist conformation as a prominent mechanism for this acquired resistance. There are several critical gaps in our knowledge regarding the specific pharmacophore requirements of an antagonist that could effectively inhibit all or most of the different mutant ERs...
November 7, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30403848/model-colibactins-exhibit-human-cell-genotoxicity-in-the-absence-of-host-bacteria
#8
Emilee E Shine, Mengzhao Xue, Jaymin R Patel, Alan R Healy, Yulia V Surovtseva, Seth B Herzon, Jason M Crawford
Colibactins are genotoxic secondary metabolites produced in select Enterobacteriaceae, which induce downstream DNA double-strand breaks (DSBs) in human cell lines and are thought to promote the formation of colorectal tumors. Although key structural and functional features of colibactins have been elucidated, the full molecular mechanisms regulating these phenotypes remain unknown. Here, we demonstrate that free model colibactins induce DSBs in human cell cultures and do not require delivery by host bacteria...
November 7, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30395437/bioorthogonal-profiling-of-a-cancer-cell-proteome-identifies-a-large-set-of-3-bromopyruvate-targets-beyond-glycolysis
#9
Narek Darabedian, Thomas C Chen, Henrik Molina, Matthew R Pratt, Axel H Schönthal
3-Bromopyruvate (3BP) is a potential anticancer agent viewed as a glycolytic inhibitor that preferentially kills cancer cells through inhibition of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), resulting in severe energy depletion. We previously identified four cysteine residues in GAPDH that are alkylated by 3BP, resulting in its inactivation. However, we also showed that addition of excess pyruvate, the final product of glycolysis, was unable to rescue cells from 3BP treatment. This result indicates that GAPDH may not be the only relevant target and is consistent with the chemical reactivity of 3BP that should result in the modification of cysteine residues in many different proteins...
November 7, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30398845/identification-and-molecular-characterization-of-ppar%C3%AE-as-a-novel-target-for-covalent-modification-by-15-deoxy-%C3%AE-12-14-prostaglandin-j-2
#10
Aravind T Reddy, Sowmya P Lakshmi, Asoka Banno, Raju C Reddy
PPARδ belongs to the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors. Upon activation by an agonist, PPARδ controls a variety of physiological processes via regulation of its target genes. 15-deoxy-Δ12,14 -PGJ2 (15d-PGJ2 ) is a cyclopentenone prostaglandin that features an electrophilic, α, β-unsaturated ketone (an enone) in the cyclopentenone ring. Many of 15d-PGJ2 's biological effects result from covalent interaction between C9 and the thiol group of a catalytic cysteine (Cys) in target proteins...
November 6, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30376293/structural-insights-into-the-substrate-promiscuity-of-a-laboratory-evolved-peroxygenase
#11
Mercedes Ramirez-Escudero, Patricia Molina-Espeja, Patricia Gomez de Santos, Martin Hofrichter, Julia Sanz-Aparicio, Miguel Alcalde
Due to their minimal requirements, substrate promiscuity and product selectivity, fungal peroxygenases are now considered to be the jewel in the crown of C-H oxyfunctionalization biocatalysts. In this work, the crystal structure of the first laboratory evolved peroxygenase expressed by yeast was solved at a resolution of 1.5 Å. Notable differences were detected between evolved and native peroxygenase from Agrocybe aegerita, including the presence of a full N-terminus and a broader heme access channel due to the mutations accumulated through directed evolution...
October 30, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30375843/precise-small-molecule-degradation-of-a-noncoding-rna-identifies-cellular-binding-sites-and-modulates-an-oncogenic-phenotype
#12
Yue Li, Matthew D Disney
Herein, we describe the precise cellular destruction of an oncogenic noncoding RNA with a small molecule-bleomycin A5 conjugate, affording reversal of phenotype and a facile method to map the cellular binding sites of a small molecule. In particular, bleomycin A5 was coupled to a small molecule that selectively binds the microRNA-96 hairpin precursor (pri-miR-96). By coupling of bleomycin A5's free amine to the RNA binder, its affinity for binding to pri-miR-96 is >100-fold stronger than to DNA and the compound selectively cleaves pri-miR-96 in triple negative breast cancer (TNBC) cells...
October 30, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30350943/exploring-fungal-polyketide-c-methylation-through-combinatorial-domain-swaps
#13
Philip A Storm, Paramita Pal, Callie R Huitt-Roehl, Craig A Townsend
Polyketide C-methylation occurs during a programmed sequence of dozens of reactions carried out by multidomain polyketide synthases (PKSs). Fungal PKSs perform these reactions iteratively, where a domain may be exposed to and act upon multiple enzyme-tethered intermediates during biosynthesis. We surveyed a collection of C-methyltransferase (CMeT) domains from nonreducing fungal PKSs to gain insight into how different methylation patterns are installed. Our in vitro results show that control of methylation resides primarily with the CMeT, and CMeTs can intercept and methylate intermediates from noncognate nonreducing PKS domains...
October 30, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30346688/structural-insight-into-a-novel-formyltransferase-and-evolution-to-a-nonribosomal-peptide-synthetase-tailoring-domain
#14
Janice M Reimer, Ingrid Harb, Olga G Ovchinnikova, Jessie Jiang, Chris Whitfield, T Martin Schmeing
Nonribosomal peptide synthetases (NRPSs) increase the chemical diversity of their products by acquiring tailoring domains. Linear gramicidin synthetase starts with a tailoring formylation (F) domain, which likely originated from a sugar formyltransferase (FT) gene. Here, we present studies on an Anoxybacillus kamchatkensis sugar FT representative of the prehorizontal gene transfer FT. Gene cluster analysis reveals that this FT acts on a UDP-sugar in a novel pathway for synthesis of a 7-formamido derivative of CMP-pseudaminic acid...
October 30, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30339758/hybrid-transcription-factor-engineering-activates-the-silent-secondary-metabolite-gene-cluster-for-asperlin-in-aspergillus-nidulans
#15
Michelle F Grau, Ruth Entwistle, Yi-Ming Chiang, Manmeet Ahuja, C Elizabeth Oakley, Tomohiro Akashi, Clay C C Wang, Richard B Todd, Berl R Oakley
Fungi are a major source of valuable bioactive secondary metabolites (SMs). These compounds are synthesized by enzymes encoded by genes that are clustered in the genome. The vast majority of SM biosynthetic gene clusters are not expressed under normal growth conditions, and their products are unknown. Developing methods for activation of these silent gene clusters offers the potential for discovering many valuable new fungal SMs. While a number of useful approaches have been developed, they each have limitations, and additional tools are needed...
October 29, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30272441/nitrosopyridine-probe-to-detect-polyketide-natural-products-with-conjugated-alkenes-discovery-of-novodaryamide-and-nocarditriene
#16
Gabriel Castro-Falcón, Natalie Millán-Aguiñaga, Catherine Roullier, Paul R Jensen, Chambers C Hughes
An optimized nitroso-based probe that facilitates the discovery of conjugated alkene-containing natural products in unprocessed extracts was developed. It chemoselectively reacts with conjugated olefins via a nitroso-Diels-Alder cyclization to yield derivatives with a distinct chromophore and an isotopically unique bromine atom that can be rapidly identified using liquid chromatography/mass spectrometry and a bioinformatics tool called MeHaloCoA (Marine Halogenated Compound Analysis). The probe is ideally employed when genome-mining techniques identify strains containing polyketide gene clusters with two or more repeating KS-AT-DH-KR-ACP domain sequences, which are required for the biosynthesis of conjugated alkenes...
October 26, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30359529/synthesis-of-a-self-adjuvanting-muc1-vaccine-via-diselenide-selenoester-ligation-deselenization
#17
David M McDonald, Cameron C Hanna, Anneliese S Ashhurst, Leo Corcilius, Scott N Byrne, Richard J Payne
Access to lipopeptide-based vaccines for immunological studies remains a significant challenge owing to the amphipathic nature of the molecules which makes them difficult to synthesize and purify to homogeneity. Here, we describe the application of a new peptide ligation technology - the diselenide-selenoester ligation (DSL) - to access self-adjuvanting glycolipopeptide vaccines. We show that rapid ligation of glycopeptides and lipopeptides is possible via DSL in mixed organic solvent-aqueous buffer and, when coupled with deselenization chemistry, affords rapid and efficient access to a vaccine candidate possessing a MUC1 glycopeptide epitope and the lipopeptide adjuvant Pam2Cys...
October 25, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30289689/fluorescent-benzothiazinone-analogues-efficiently-and-selectively-label-dpre1-in-mycobacteria-and-actinobacteria
#18
Raphael Sommer, João Neres, Jérémie Piton, Neeraj Dhar, Astrid van der Sar, Raju Mukherjee, Thierry Laroche, Paul J Dyson, John D McKinney, Wilbert Bitter, Vadim Makarov, Stewart T Cole
Benzothiazinones (BTZ) are highly potent bactericidal inhibitors of mycobacteria and the lead compound, BTZ043, and the optimized drug candidate, PBTZ169, have potential for the treatment of tuberculosis. Here, we exploited the tractability of the BTZ scaffold by attaching a range of fluorophores to the 2-substituent of the BTZ ring via short linkers. We show by means of fluorescence imaging that the most advanced derivative, JN108, is capable of efficiently labeling its target, the essential flavoenzyme DprE1, both in cell-free extracts and after purification as well as in growing cells of different actinobacterial species...
October 25, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30354045/de-novo-design-and-implementation-of-a-tandem-acyl-carrier-protein-domain-in-a-type-i-modular-polyketide-synthase
#19
Zilong Wang, Saket R Bagde, Gerardo Zavala, Tsutomu Matsui, Xi Chen, Chu-Young Kim
During polyketide and fatty acid biosynthesis, the growing acyl chain is attached to the acyl carrier protein via a thioester linkage. The acyl carrier protein interacts with other enzymes that perform chain elongation and chain modification on the bound acyl chain. Most type I polyketide synthases and fatty acid synthases contain only one acyl carrier protein. However, polyunsaturated fatty acid synthases from deep-sea bacteria contain anywhere from two to nine acyl carrier proteins. Recent studies have shown that this tandem acyl carrier protein feature is responsible for the unusually high fatty acid production rate of deep-sea bacteria...
October 24, 2018: ACS Chemical Biology
https://www.readbyqxmd.com/read/30286293/characterization-of-an-unusual-glycerate-esterification-process-in-vioprolide-biosynthesis
#20
David Auerbach, Fu Yan, Youming Zhang, Rolf Müller
Bacteria produce a large number of secondary metabolites with extraordinary chemical structures and bioactivities. Vioprolides are promising anticancer and antifungal lead compounds produced by the myxobacterium Cystobacter violaceus Cb vi35, which are initially synthesized as acylated precursors (previoprolides) by nonribosomal peptide synthetases (NRPS). Here, we describe and characterize an unprecedented glycerate esterification process in the biosynthesis of vioprolides. In vitro biochemical investigations revealed that the fatty acyl chain of previoprolides is adenylated by the starting fatty acyl-AMP ligase (FAAL) domain, while the glycerate moiety is incorporated by the FkbH domain...
October 22, 2018: ACS Chemical Biology
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