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507 records returned

Sequential reactions of surface- tethered glycolytic enzymes.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The development of complex hybrid organic-inorganic devices faces several challenges, including how they can generate energy. Cells face similar challenges regarding local energy production. Mammalian sperm solve this problem by generating ATP down the flagellar principal piece by means of glycolytic enzymes, several of which are tethered to a cytoskeletal support via germ-cell-specific targeting domains. Inspired by this design, we have produced recombinant hexokinase type 1 and glucose-6-phosphate isomerase capable of oriented immobilization on a nickel-nitrilotriacetic acid modified surface. Specific activities of e...
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Mukai C, Bergkvist M, Nelson JL, Travis AJ Tags: Chem Biol Source Type: journals

Direct measurement of cathepsin B activity in the cytosol of apoptotic cells by an activity-based probe.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We report here the development of an activity-based probe that, under optimized conditions, reports on cathepsin B activity only in apoptotic cells by reading out the release of cathepsin B from the lysosomes. Biochemical characterization of apoptosis in cells from cathepsin B null mice shows delayed and suboptimal activation of caspases. Our data further supports a role for cathepsin B in the cytosol as a positive regulator of a cell death feed-forward loop and provides a chemical tool for future investigations. PMID: 19778728 [PubMed - in process]
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Pratt MR, Sekedat MD, Chiang KP, Muir TW Tags: Chem Biol Source Type: journals

The platelet integrin alphaIIbbeta3 binds to the RGD and AGD motifs in fibrinogen.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Fibrinogen (Fbg) mediates platelet aggregation by binding the alphaIIbbeta3 integrin receptor, but the interaction of the receptor with peptide motifs of Fbg remains unresolved. This paper describes the use of self-assembled monolayers (SAMs) to study the adhesion of alphaIIbbeta3-transfected CHO cells to the GRGDS and HHLGGAKQAGDV motifs within Fbg. Cells adhered to and spread on monolayers presenting either peptide. Cell adhesion could be inhibited by either soluble peptide, demonstrating that the peptides bind competitively to the integrin. A peptide array was used to show that AGD was the minimal binding sequence i...
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Sánchez-Cortés J, Mrksich M Tags: Chem Biol Source Type: journals

Chemical probes identify a role for histone deacetylase 3 in Friedreich's ataxia gene silencing.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We recently identified a class of pimelic diphenylamide histone deacetylase (HDAC) inhibitors that show promise as therapeutics in the neurodegenerative diseases Friedreich's ataxia (FRDA) and Huntington's disease. Here, we describe chemical approaches to identify the HDAC enzyme target of these inhibitors. Incubation of a trifunctional activity-based probe with a panel of class I and class II recombinant HDAC enzymes, followed by click chemistry addition of a fluorescent dye and gel electrophoresis, identifies HDAC3 as a unique high-affinity target of the probe. Photoaffinity labeling in a nuclear extract prepared fro...
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Xu C, Soragni E, Chou CJ, Herman D, Plasterer HL, Rusche JR, Gottesfeld JM Tags: Chem Biol Source Type: journals

Ribocation transition state capture and rebound in human purine nucleoside phosphorylase.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Purine nucleoside phosphorylase (PNP) catalyzes the phosphorolysis of 6-oxy-purine nucleosides to the corresponding purine base and alpha-D-ribose 1-phosphate. Its genetic loss causes a lethal T cell deficiency. The highly reactive ribocation transition state of human PNP is protected from solvent by hydrophobic residues that sequester the catalytic site. The catalytic site was enlarged by replacing individual catalytic site amino acids with glycine. Reactivity of the ribocation transition state was tested for capture by water and other nucleophiles. In the absence of phosphate, inosine is hydrolyzed by native, Y88G, F...
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Ghanem M, Murkin AS, Schramm VL Tags: Chem Biol Source Type: journals

Molecular basis for the recognition of structurally distinct autoinducer mimics by the Pseudomonas aeruginosa LasR quorum-sensing signaling receptor.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The human pathogen Pseudomonas aeruginosa coordinates the expression of virulence factors using quorum sensing, a signaling cascade triggered by the activation of signal receptors by small-molecule autoinducers. These homoserine lactone autoinducers stabilize their cognate receptors and activate their functions as transcription factors. Because quorum sensing regulates the progression of infection and host immune resistance, significant efforts have been devoted toward the identification of small molecules that disrupt this process. Screening efforts have identified a class of triphenyl compounds that are structurally ...
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Zou Y, Nair SK Tags: Chem Biol Source Type: journals

Analysis of two additional signaling molecules in Streptomyces coelicolor and the development of a butyrolactone-specific reporter system.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
gamma-Butyrolactone bacterial hormones regulate antibiotic production and morphological differentiation in Streptomyces species. One gamma-butyrolactone, SCB1, has been previously characterized in Streptomyces coelicolor. Here we report the characterization of two additional gamma-butyrolactones, named SCB2 (2-[1'-hydroxyoctyl]-3-hydroxymethylbutanolide) and SCB3 (2-[1'-hydroxy-6'-methyloctyl]-3-hydroxymethylbutanolide), possessing an antibiotic stimulatory activity. To elucidate the specificity determinants of these ligands for the receptor protein, ScbR, 30 chemically synthesized gamma-butyrolactone analogs were test...
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Hsiao NH, Nakayama S, Merlo ME, de Vries M, Bunet R, Kitani S, Nihira T, Takano E Tags: Chem Biol Source Type: journals

A peptidomimetic approach to targeting pre-amyloidogenic states in type II diabetes.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Protein fiber formation is associated with diseases ranging from Alzheimer's to type II diabetes. For many systems, including islet amyloid polypeptide (IAPP) from type II diabetes, fibrillogenesis can be catalyzed by lipid bilayers. Paradoxically, amyloid fibers are beta sheet rich while membrane-stabilized states are alpha-helical. Here, a small molecule alpha helix mimetic, IS5, is shown to inhibit bilayer catalysis of fibrillogenesis and to rescue IAPP-induced toxicity in cell culture. Importantly, IAPP:IS5 interactions localize to the putative alpha-helical region of IAPP, revealing that alpha-helical states are o...
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Hebda JA, Saraogi I, Magzoub M, Hamilton AD, Miranker AD Tags: Chem Biol Source Type: journals

Inorganic mercury detection and controlled release of chelating agents from ion-responsive liposomes.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
A liposome system that can detect and detoxify mercury in aqueous solution is demonstrated. The system consists of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine and 20% PEG-PE (PEG MW 2000 Da) that forms liposome, which encapsulates self-quenching fluorescein for detection, and chelating agent meso-2,3-dimercaptosuccinic acid (meso-DMSA) for chelating detoxification through Hg(2+)-responsive release of fluorescein and meso-DMSA. This system can detect mercury levels as low as 10 nM with high selectivity. In particular, the release profile of meso-DMSA by the local concentration of Hg can be modulated, so that more chel...
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Yigit MV, Mishra A, Tong R, Cheng J, Wong GC, Lu Y Tags: Chem Biol Source Type: journals

The alpha,alpha-difluorinated phosphonate L-pSer-analogue: an accessible chemical tool for studying kinase-dependent signal transduction.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This overview focuses on the (alpha,alpha-difluoromethylene)phosphonate mimic of phosphoserine (pCF(2)Ser) and its application to the study of kinase-mediated signal transduction-pathways of great interest to drug development. The most versatile modes of access to these chemical biological tools are discussed, organized by method of PCF(2)-C bond formation. The pCF(2)-Ser mimic may be site-specifically incorporated into peptides (SPPS) and proteins (expressed protein ligation). This isopolar, dianionic pSer mimic results in a "constitutive phosphorylation" phenotype and is seen to support native protein-protein interac...
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Panigrahi K, Eggen M, Maeng JH, Shen Q, Berkowitz DB Tags: Chem Biol Source Type: journals

High-throughput screening and chemical biology: new approaches for understanding circadian clock mechanisms.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Most organisms exhibit daily changes in physiology and metabolism under the control of a cell-autonomous circadian clock. In the core clock mechanism, clock genes form a transcription factor network to generate circadian rhythms of gene expression. Clock protein phosphorylation and histone modifications are also important for the clock regulation. Pharmacological approaches have been making significant contributions to the clock research, for example, in characterizing the roles of protein kinases CKIdelta, CKIepsilon, CK2, and GSK-3beta. Recently, high-throughput circadian functional assays have been established. Chem...
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Hirota T, Kay SA Tags: Chem Biol Source Type: journals

Making strides in peptide-based therapeutics.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In a recent report published in PNAS, Gellman and coworkers describe the design, characterization, and potent activity of alpha/beta-peptides that mimic a long alpha helix involved in HIV viral entry. PMID: 19778718 [PubMed - in process]
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Guarracino DA, Arora PS Tags: Chem Biol Source Type: journals

Reassembling biological machinery in vitro.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Inspired by the specialized glycolytic system of flagella of mammalian sperm, Mukai et al. (2009) describe the controlled immobilization of two enzymes constituting the first steps in the glycolytic pathway. Extension of this work may provide "power converters" for bionanodevices, which transduce chemical energy from glucose to ATP. PMID: 19778717 [PubMed - in process]
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Hess H Tags: Chem Biol Source Type: journals

Punching holes in an enzyme.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Schramm and coworkers have punched holes into human purine nucleoside phosphorylase by substitution of glycine for aromatic amino acid residues at a protein lid. The results of studies on the enzymes with holes illuminate hidden chemistry that occurs at the enzyme active site. PMID: 19778716 [PubMed - in process]
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Richard JP Tags: Chem Biol Source Type: journals

Mastering the chemical language of bacteria.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The publication of the crystal structures of a bacterial quorum sensing receptor complexed with a variety of ligands (Zou and Nair, 2009) provides a much-needed molecular rationale for the modulation of this intercellular signaling process, which may facilitate the development of new therapeutic agents. PMID: 19778715 [PubMed - in process]
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Galloway WR, Hodgkinson JT, Welch M, Spring DR Tags: Chem Biol Source Type: journals

Aileron staples peptides.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19778714 [PubMed - in process]
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Wolfson W Tags: Chem Biol Source Type: journals

Something old, something new.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19778713 [PubMed - in process]
Source: Chemistry & Biology - September 25, 2009 Category: Chemistry Authors: Crews C, Famulok M, Shokat K, Wohlleben W, Kostic M Tags: Chem Biol Source Type: journals

Hoiamide a, a sodium channel activator of unusual architecture from a consortium of two papua new Guinea cyanobacteria.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Hoiamide A, a novel bioactive cyclic depsipeptide, was isolated from an environmental assemblage of the marine cyanobacteria Lyngbya majuscula and Phormidium gracile collected in Papua New Guinea. This stereochemically complex metabolite possesses a highly unusual structure, which likely derives from a mixed peptide-polyketide biogenetic origin, and includes a peptidic section featuring an acetate extended and S-adenosyl methionine modified isoleucine moiety, a triheterocyclic fragment bearing two alpha-methylated thiazolines and one thiazole, and a highly oxygenated and methylated C15-polyketide substructure. Pure hoi...
Source: Chemistry & Biology - August 28, 2009 Category: Chemistry Authors: Pereira A, Cao Z, Murray TF, Gerwick WH Tags: Chem Biol Source Type: journals

A small molecule that blocks fat synthesis by inhibiting the activation of SREBP.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Sterol regulatory element binding proteins (SREBPs) are transcription factors that activate transcription of the genes involved in cholesterol and fatty acid biosynthesis. In the present study, we show that a small synthetic molecule we previously discovered to block adipogenesis is an inhibitor of the SREBP activation. The diarylthiazole derivative, now called fatostatin, impairs the activation process of SREBPs, thereby decreasing the transcription of lipogenic genes in cells. Our analysis suggests that fatostatin inhibits the ER-Golgi translocation of SREBPs through binding to their escort protein, the SREBP cleavag...
Source: Chemistry & Biology - August 28, 2009 Category: Chemistry Authors: Kamisuki S, Mao Q, Abu-Elheiga L, Gu Z, Kugimiya A, Kwon Y, Shinohara T, Kawazoe Y, Sato S, Asakura K, Choo HY, Sakai J, Wakil SJ, Uesugi M Tags: Chem Biol Source Type: journals

Noninflammatory gluten peptide analogs as biomarkers for celiac sprue.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
New tools are needed for managing celiac sprue, a lifelong immune disease of the small intestine. Ongoing drug trials are also prompting a search for noninvasive biomarkers of gluten-induced intestinal change. We have synthesized and characterized noninflammatory gluten peptide analogs in which key Gln residues are replaced by Asn or His. Like their proinflammatory counterparts, these biomarkers are resistant to gastrointestinal proteases, susceptible to glutenases, and permeable across enterocyte barriers. Unlike gluten peptides, however, they are not appreciably recognized by transglutaminase, HLA-DQ2, or disease-spe...
Source: Chemistry & Biology - August 28, 2009 Category: Chemistry Authors: Bethune MT, Crespo-Bosque M, Bergseng E, Mazumdar K, Doyle L, Sestak K, Sollid LM, Khosla C Tags: Chem Biol Source Type: journals

Prototyping nanorod control: A DNA double helix sheathed within a DNA six-helix bundle.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The control of the structure of matter is a key goal of nanoscience. DNA is an exciting molecule for control because it forms programmable intermolecular interactions. Stiff DNA structures, such as the double crossover motif, the tensegrity triangle, and the six-helix bundle (6HB) have been used to produce periodic arrays of DNA components. The 6HB motif consists of six DNA double helices flanking an inner cavity whose diameter is similar to that of a double helix. This motif appears to be an excellent candidate to sheathe and control nanorods by inserting them into the cavity, and then to control the placement and ori...
Source: Chemistry & Biology - August 28, 2009 Category: Chemistry Authors: Wang R, Liu W, Seeman NC Tags: Chem Biol Source Type: journals

Targeting NAD biosynthesis in bacterial pathogens: Structure-based development of inhibitors of nicotinate mononucleotide adenylyltransferase NadD.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The emergence of multidrug-resistant pathogens necessitates the search for new antibiotics acting on previously unexplored targets. Nicotinate mononucleotide adenylyltransferase of the NadD family, an essential enzyme of NAD biosynthesis in most bacteria, was selected as a target for structure-based inhibitor development. Using iterative in silico and in vitro screens, we identified small molecule compounds that efficiently inhibited target enzymes from Escherichia coli (ecNadD) and Bacillus anthracis (baNadD) but had no effect on functionally equivalent human enzymes. On-target antibacterial activity was demonstrated ...
Source: Chemistry & Biology - August 28, 2009 Category: Chemistry Authors: Sorci L, Pan Y, Eyobo Y, Rodionova I, Huang N, Kurnasov O, Zhong S, MacKerell AD, Zhang H, Osterman AL Tags: Chem Biol Source Type: journals

Chemical genetic identification of peptidoglycan inhibitors potentiating carbapenem activity against methicillin-resistant Staphylococcus aureus.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial and community-acquired pathogen for which few existing antibiotics are efficacious. Here we describe two structurally related synthetic compounds that potentiate beta-lactam activity against MRSA. Genetic studies indicate that these agents target SAV1754 based on the following observations: (i) it has a unique chemical hypersensitivity profile, (ii) overexpression or point mutations are sufficient to confer resistance, and (iii) genetic inactivation phenocopies the potentiating effect of these agents in combination with beta-lactams. Further, we d...
Source: Chemistry & Biology - August 28, 2009 Category: Chemistry Authors: Huber J, Donald RG, Lee SH, Jarantow LW, Salvatore MJ, Meng X, Painter R, Onishi RH, Occi J, Dorso K, Young K, Park YW, Skwish S, Szymonifka MJ, Waddell TS, Miesel L, Phillips JW, Roemer T Tags: Chem Biol Source Type: journals

A Staphylococcus aureus fitness test platform for mechanism-based profiling of antibacterial compounds.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The emergence of drug-resistant bacteria coupled with the limited discovery of novel chemical scaffolds and druggable targets inspires new approaches to antibiotic development. Here we describe a chemical genomics strategy based on 245 Staphylococcus aureus antisense RNA strains, each engineered for reduced expression of target genes essential for S. aureus growth. Attenuation of gene expression can sensitize cells to compounds that inhibit the activity of a gene product or associated process. Pools of strains grown competitively in the presence of bioactive compounds generate characteristic profiles of strain sensitiv...
Source: Chemistry & Biology - August 28, 2009 Category: Chemistry Authors: Donald RG, Skwish S, Forsyth RA, Anderson JW, Zhong T, Burns C, Lee S, Meng X, LoCastro L, Jarantow LW, Martin J, Lee SH, Taylor I, Robbins D, Malone C, Wang L, Zamudio CS, Youngman PJ, Phillips JW Tags: Chem Biol Source Type: journals

A promiscuous ribozyme promotes nucleotide synthesis in addition to ribose chemistry.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Here we report the in vitro selection of an unusual ribozyme that efficiently performs nucleotide synthesis even though it was selected to perform a distinctly different sugar chemistry. This ribozyme, called pR1, when derivatized with ribose 5-phosphate (PR) at its 3' terminus and incubated with 6-thioguanine, produces two interconverting thiol-containing products corresponding to a Schiff base and its Amadori rearranged product. Consistent with this hypothesis, removing the 2-hydroxyl from the PR substrate results in only a single product. Surprisingly, as this was not selected for, switching the tethered PR substrat...
Source: Chemistry & Biology - August 28, 2009 Category: Chemistry Authors: Lau MW, Unrau PJ Tags: Chem Biol Source Type: journals

Context-specific target definition in influenza a virus hemagglutinin-glycan receptor interactions.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We present here a representative example of such an interaction: the binding of influenza A hemagglutinin (HA) to specific sialylated glycans on the cell surface of human upper airway epithelial cells, which initiates the infection cycle. We detail a generalizable strategy to understand the nature of protein-glycan interactions both structurally and biochemically, using HA as a model system. This strategy combines a top-down approach using available structural information to define important contacts between glycans and HA, with a bottom-up approach using data-mining and informatics approaches to identify the common motifs...
Source: Chemistry & Biology - August 28, 2009 Category: Chemistry Authors: Shriver Z, Raman R, Viswanathan K, Sasisekharan R Tags: Chem Biol Source Type: journals

Fatty acid synthesis and PPARalpha hand in hand.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
How can an ex-orphan be adopted? Is it possible to do so by attributing to it a key endogenous ligand that regulates its central functions? In the recent issue of Cell, Chakravarthy et al. attempted to answer this question by characterizing a new physiologically relevant ligand for the ex-orphan receptor peroxisome proliferator activated receptor alpha (PPARalpha). PMID: 19716470 [PubMed - in process]
Source: Chemistry & Biology - August 28, 2009 Category: Chemistry Authors: Rotman N, Wahli W Tags: Chem Biol Source Type: journals

Putative fat fighter hits the middle man.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this issue, Kamisuki and colleagues characterize fatostatin. This compound inhibits the activity of SREBPs, the master transcription factors of lipid homeostasis. This useful laboratory tool also improved the lipid profile of obese mice; does this have clinical implications? PMID: 19716469 [PubMed - in process]
Source: Chemistry & Biology - August 28, 2009 Category: Chemistry Authors: Krycer JR, Brown AJ Tags: Chem Biol Source Type: journals

Evolution of ribozymes in an RNA world.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Ribozymes (catalytic RNAs) were the center of a presumed RNA world in the early origin of life. In this issue, Lau and Unrau show evidence that an RNA world could have used a similar evolutionary pathway as most proteins do. PMID: 19716468 [PubMed - in process]
Source: Chemistry & Biology - August 28, 2009 Category: Chemistry Authors: Müller UF Tags: Chem Biol Source Type: journals

Order up! The custom enzyme shop is open for business.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19716467 [PubMed - in process]
Source: Chemistry & Biology - August 28, 2009 Category: Chemistry Authors: McCarthy A Tags: Chem Biol Source Type: journals

Pandemic paradox: new flu virus keeps researchers and health officials guessing.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
PMID: 19635405 [PubMed - in process]
Source: Chemistry & Biology - July 30, 2009 Category: Chemistry Authors: Shekhar C Tags: Chem Biol Source Type: journals

Self-Assembling, Dynamic alphaPNAs.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In the recent report published in Science, Ghadiri and coworkers describe dynamic tPNAs, alphaPNA derivatives with a nucleobase attached via a thioester bond that are a step forward toward self-repairing and replicating molecules. PMID: 19635406 [PubMed - in process]
Source: Chemistry & Biology - July 30, 2009 Category: Chemistry Authors: Nielsen PE Tags: Chem Biol Source Type: journals

Perturbation of Estrogen Receptor alpha Localization with Synthetic Nona-Arginine LXXLL-Peptide Coactivator Binding Inhibitors.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The interaction of estrogen receptor alpha (ERalpha) with the consensus LXXLL motifs of transcriptional coactivators provides an entry for functional ERalpha inhibition. Here, synthetic cell-permeable LXXLL peptide probes are brought forward that allow evaluation of the interaction of specific recognition motifs with ERalpha in the context of the cell. The probes feature a nona-arginine tag that facilitates cellular entry and induces probe localization in nucleoli. The nucleoli localization provides an explicit tool for evaluating the LXXLL motif interaction with ERalpha. The probes compete with coactivators, bind ERal...
Source: Chemistry & Biology - July 30, 2009 Category: Chemistry Authors: Carraz M, Zwart W, Phan T, Michalides R, Brunsveld L Tags: Chem Biol Source Type: journals

Kinetic cell-based morphological screening: prediction of mechanism of compound action and off-target effects.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We describe a cell-based kinetic profiling approach using impedance readout for monitoring the effect of small molecule compounds. This noninvasive readout allows continuous sampling of cellular responses to biologically active compounds and the ensuing kinetic profile provides information regarding the temporal interaction of compounds with cells. The utility of this approach was tested by screening a library containing FDA approved drugs, experimental compounds, and nature compounds. Compounds with similar activity produced similar impedance-based time-dependent cell response profiles (TCRPs). The compounds were clustere...
Source: Chemistry & Biology - July 30, 2009 Category: Chemistry Authors: Abassi YA, Xi B, Zhang W, Ye P, Kirstein SL, Gaylord MR, Feinstein SC, Wang X, Xu X Tags: Chem Biol Source Type: journals

Single Bead Labeling Method for Combining Confocal Fluorescence On-Bead Screening and Solution Validation of Tagged One-Bead One-Compound Libraries.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Screening of one-bead one-compound libraries by incubating beads with fluorescently labeled target protein requires isolation and structure elucidation of a large number of primary hit beads. However, the potency of the identified ligands is only revealed after time consuming and expensive larger scale resynthesis and testing in solution. Often, many of the resynthesized compounds turn out to be weak target binders in solution due to large differences between surface and solution binding affinities. For an industry style high-throughput screening (HTS) process a high false positive rate is detrimental. We have therefor...
Source: Chemistry & Biology - July 30, 2009 Category: Chemistry Authors: Hintersteiner M, Kimmerlin T, Kalthoff F, Stoeckli M, Garavel G, Seifert JM, Meisner NC, Uhl V, Buehler C, Weidemann T, Auer M Tags: Chem Biol Source Type: journals

Cloning and heterologous expression of the cyclooctatin biosynthetic gene cluster afford a diterpene cyclase and two p450 hydroxylases.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Cyclooctatin, a diterpene characterized by a 5-8-5 fused ring system, is a potent inhibitor of lysophospholipase. Here we report the cloning and characterization of a complete cyclooctatin biosynthetic gene cluster from Streptomyces melanosporofaciens MI614-43F2 and heterologous production of cyclooctatin in S. albus. Sequence analysis coupled with subcloning and gene deletion revealed that the minimal cyclooctatin biosynthetic gene cluster consists of four genes, cotB1 to cotB4, encoding geranylgeranyl diphosphate (GGDP) synthase, terpene cyclase (CotB2), and two cytochromes P450, respectively. Incubation of the recom...
Source: Chemistry & Biology - July 30, 2009 Category: Chemistry Authors: Kim SY, Zhao P, Igarashi M, Sawa R, Tomita T, Nishiyama M, Kuzuyama T Tags: Chem Biol Source Type: journals

Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Monoacylglycerol lipase (MAGL) is a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). We recently reported a piperidine carbamate, JZL184, that inhibits MAGL with high potency and selectivity. Here, we describe a comprehensive mechanistic characterization of JZL184. We provide evidence that JZL184 irreversibly inhibits MAGL via carbamoylation of the enzyme's serine nucleophile. Functional proteomic analysis of mice treated with JZL184 revealed that this inhibitor maintains good selectivity for MAGL across a wide range of central and peripheral tissues. Interestingly, MAGL blockade prod...
Source: Chemistry & Biology - July 30, 2009 Category: Chemistry Authors: Long JZ, Nomura DK, Cravatt BF Tags: Chem Biol Source Type: journals

pHLIP-Mediated Translocation of Membrane-Impermeable Molecules into Cells.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Our goal is to define the properties of cell-impermeable cargo molecules that can be delivered into cells by pH (Low) Insertion Peptide (pHLIP), which can selectively target tumors in vivo based on their acidity. Using biophysical methods and fluorescence microscopy, we show that pHLIP can successfully deliver polar and membrane-impermeable cyclic peptides linked to its C terminus through the membranes of lipid vesicles and cancer cells. Our results also indicate that the translocation of these cargo molecules is pH dependent and mediated by transmembrane helix formation. Since a broad range of cell-impermeable molecul...
Source: Chemistry & Biology - July 30, 2009 Category: Chemistry Authors: Thévenin D, An M, Engelman DM Tags: Chem Biol Source Type: journals

Useful tools for biomolecule isolation, detection, and identification: acylhydrazone-based cleavable linkers.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Proteomic searches using affinity-based chromatography (e.g., biotin-[strept]avidin) have been severely hampered by low protein recovery yields, protein destruction and denaturation, and the release of background proteins from the support. These limitations confound protein identification. A new acylhydrazone-based cleavable linker was developed to permit the efficient isolation of proteins with a traceable tag allowing detection and identification under mild conditions. The utility of the acylhydrazone linker was validated in a proteomic search wherein aldehyde dehydrogenase-1 was selectively captured and isolated fro...
Source: Chemistry & Biology - July 30, 2009 Category: Chemistry Authors: Park KD, Liu R, Kohn H Tags: Chem Biol Source Type: journals

A Dumbbell-Shaped Small Molecule that Promotes Cell Adhesion and Growth.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
During an image-based phenotype screening of our chemical library, we noted a small molecule that boosts the adhesion and growth of human cells. Chemical and cell biological experiments suggest that the diaryldispirotripiperazine derivative (adhesamine) targets selective cell-surface glycosaminoglycans, especially heparan sulfate, for increasing cell adhesion and growth. The addition of adhesamine to the culture medium enables the adhesion of even floating lymphocytes to cell culture plates and the microinjection into them. Unlike poly-L-lysine, adhesamine induces apparently normal cell adhesion accompanied by organize...
Source: Chemistry & Biology - July 30, 2009 Category: Chemistry Authors: Yamazoe S, Shimogawa H, Sato S, Esko JD, Uesugi M Tags: Chem Biol Source Type: journals

Development of an IL-6 Inhibitor Based on the Functional Analysis of Murine IL-6Ralpha(1).Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Dysregulated cytokine production contributes to inflammatory and proliferative diseases. Therefore, inhibition of proinflammatory mediators such as TNF, IL-1, and IL-6 is of great clinical relevance. Actual strategies are aimed at preventing receptor activation through sequestration of the ligand. Here we describe the development of an inhibitor of murine IL-6 based on fused receptor fragments. Molecular modeling-guided analysis of the murine IL-6Ralpha revealed that mutations in the Ig-like domain D1 severely affect protein function, although D1 is not directly involved in the ligand-binding interface. The resulting s...
Source: Chemistry & Biology - July 30, 2009 Category: Chemistry Authors: Wiesinger MY, Haan S, Wüller S, Kauffmann ME, Recker T, Küster A, Heinrich PC, Müller-Newen G Tags: Chem Biol Source Type: journals

A Semaphorin 3A Inhibitor Blocks Axonal Chemorepulsion and Enhances Axon Regeneration.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Secreted semaphorins are a large group of extracellular proteins involved in a variety of processes during development, including neuronal migration and axon guidance. We screened a peptoid combinatorial library to search for semaphorin 3A inhibitors, and identified a peptoid (SICHI: semaphorin Induced chemorepulsion inhibitor) that blocks semaphorin 3A-chemorepulsion and growth-cone collapse in axons at millimolar concentrations. SICHI inhibits the binding of semaphorin 3A to its receptor complex (neuropilin 1/plexin A1) and semaphorin 3A-induced phosphorylation of GSK3. Chemorepulsion induced by semaphorin 3F or netr...
Source: Chemistry & Biology - July 15, 2009 Category: Chemistry Authors: Montolio M, Messeguer J, Masip I, Guijarro P, Gavin R, Antonio Del Río J, Messeguer A, Soriano E Tags: Chem Biol Source Type: journals

Chimeric glycosyltransferases for the generation of hybrid glycopeptides.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Glycodiversification, an invaluable tool for generating biochemical diversity, can be catalyzed by glycosyltransferases, which attach activated sugar "donors" onto "acceptor" molecules. However, many glycosyltransferases can tolerate only minor modifications to their native substrates, thus making them unsuitable tools for current glycodiversification strategies. Here we report the production of functional chimeric glycosyltransferases by mixing and matching the N- and C-terminal domains of glycopeptide glycosyltransferases. Using this method we have generated hybrid glycopeptides and have demonstrated that domain swap...
Source: Chemistry & Biology - June 26, 2009 Category: Chemistry Authors: Truman AW, Dias MV, Wu S, Blundell TL, Huang F, Spencer JB Tags: Chem Biol Source Type: journals

Structural basis for different specificities of acyltransferases associated with the human cytosolic and mitochondrial fatty acid synthases.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Animals employ two systems for the de novo biosynthesis of fatty acids: a megasynthase complex in the cytosol (type I) that produces mainly palmitate, and an ensemble of freestanding enzymes in the mitochondria (type II) that produces mainly octanoyl moieties. The acyltransferases responsible for initiation of fatty acid biosynthesis in the two compartments are distinguished by their different substrate specificities: the type I enzyme transfers both the acetyl primer and the malonyl chain extender, whereas the type II enzyme is responsible for translocation of only the malonyl substrate. Crystal structures for the typ...
Source: Chemistry & Biology - June 26, 2009 Category: Chemistry Authors: Bunkoczi G, Misquitta S, Wu X, Lee WH, Rojkova A, Kochan G, Kavanagh KL, Oppermann U, Smith S Tags: Chem Biol Source Type: journals

A cell active chemical GEF inhibitor selectively targets the Trio/RhoG/Rac1 signaling pathway.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study introduces a selective cell active inhibitor of the Trio/RhoG/Rac1 pathway and validates RhoGEFs as druggable targets. PMID: 19549603 [PubMed - in process]
Source: Chemistry & Biology - June 26, 2009 Category: Chemistry Authors: Bouquier N, Vignal E, Charrasse S, Weill M, Schmidt S, Léonetti JP, Blangy A, Fort P Tags: Chem Biol Source Type: journals

Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We report here that amitriptyline, an antidepressant drug, directly binds TrkA and TrkB and triggers their dimerization and activation. Amitriptyline, but not any other tricyclic or selective serotonin reuptake inhibitor antidepressants, promotes TrkA autophosphorylation in primary neurons and induces neurite outgrowth in PC12 cells. Amitriptyline binds the extracellular domain of both TrkA and TrkB and promotes TrkA-TrkB receptor heterodimerization. Truncation of amitriptyline binding motif on TrkA abrogates the receptor dimerization by amitriptyline. Administration of amitriptyline to mice activates both receptors and si...
Source: Chemistry & Biology - June 26, 2009 Category: Chemistry Authors: Jang SW, Liu X, Chan CB, Weinshenker D, Hall RA, Xiao G, Ye K Tags: Chem Biol Source Type: journals

Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Human kallikrein-related peptidase 4 (KLK4/prostase), a trypsin-like serine protease, is a potential target for prostate cancer treatment because of its proteolytic ability to activate many tumorigenic and metastatic pathways including the protease activated receptors (PARs). Currently there are no KLK4-specific small-molecule inhibitors available for therapeutic development. Here we re-engineer the naturally occurring sunflower trypsin inhibitor to selectively block the proteolytic activity of KLK4 and prevent stimulation of PAR activity in a cell-based system. The re-engineered inhibitor was designed using a combinat...
Source: Chemistry & Biology - June 26, 2009 Category: Chemistry Authors: Swedberg JE, Nigon LV, Reid JC, de Veer SJ, Walpole CM, Stephens CR, Walsh TP, Takayama TK, Hooper JD, Clements JA, Buckle AM, Harris JM Tags: Chem Biol Source Type: journals

Physically discrete beta-lactamase-type thioesterase catalyzes product release in atrochrysone synthesis by iterative type I polyketide synthase.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
ATEG_08451 in Aspergillus terreus, here named atrochrysone carboxylic acid synthase (ACAS), is a nonreducing, iterative type I polyketide synthase that contains no thioesterase domain. In vitro, reactions of ACAS with malonyl-CoA yielded a polyketide intermediate, probably attached to its acyl carrier protein (ACP). The addition of ATEG_08450, here named atrochrysone carboxyl ACP thioesterase (ACTE), to the reaction resulted in the release of products derived from atrochrysone carboxylic acid, such as atrochrysone and endocrocin. ACTE, belonging to the beta-lactamase superfamily, thus appears to be a novel type of thio...
Source: Chemistry & Biology - June 26, 2009 Category: Chemistry Authors: Awakawa T, Yokota K, Funa N, Doi F, Mori N, Watanabe H, Horinouchi S Tags: Chem Biol Source Type: journals

Polypeptide translocation by the AAA+ ClpXP protease machine.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In the AAA+ ClpXP protease, ClpX uses repeated cycles of ATP hydrolysis to pull native proteins apart and to translocate the denatured polypeptide into ClpP for degradation. Here, we probe polypeptide features important for translocation. ClpXP degrades diverse synthetic peptide substrates despite major differences in side-chain chirality, size, and polarity. Moreover, translocation occurs without a peptide -NH and with 10 methylenes between successive peptide bonds. Pulling on homopolymeric tracts of glycine, proline, and lysine also allows efficient ClpXP degradation of a stably folded protein. Thus, minimal chemical...
Source: Chemistry & Biology - June 26, 2009 Category: Chemistry Authors: Barkow SR, Levchenko I, Baker TA, Sauer RT Tags: Chem Biol Source Type: journals

Chemical inhibition of a subset of Arabidopsis thaliana GSK3-like kinases activates brassinosteroid signaling.Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Glycogen synthase kinase 3 (GSK3) is a key regulator in signaling pathways in both animals and plants. Three Arabidopsis thaliana GSK3s are shown to be related to brassinosteroid (BR) signaling. In a phenotype-based compound screen we identified bikinin, a small molecule that activates BR signaling downstream of the BR receptor. Bikinin directly binds the GSK3 BIN2 and acts as an ATP competitor. Furthermore, bikinin inhibits the activity of six other Arabidopsis GSK3s. Genome-wide transcript analyses demonstrate that simultaneous inhibition of seven GSK3s is sufficient to activate BR responses. Our data suggest that GS...
Source: Chemistry & Biology - June 26, 2009 Category: Chemistry Authors: De Rybel B, Audenaert D, Vert G, Rozhon W, Mayerhofer J, Peelman F, Coutuer S, Denayer T, Jansen L, Nguyen L, Vanhoutte I, Beemster GT, Vleminckx K, Jonak C, Chory J, Inzé D, Russinova E, Beeckman T Tags: Chem Biol Source Type: journals

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