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• The biology of time across different scales.

  Authors: Dean V Buonomano

  Nature chemical biology. 3(10):594-7.

• Pamela Silver.

  Authors: Catherine Goodman

  Nature chemical biology. 3(10):603.

• A carbohydrate vaccine exceeds the sum of its parts.

  Authors: David R Bundle

  Nature chemical biology. 3(10):605-6.

• A proton-controlled check valve for sodium ion transport.

  Authors: Benoît Roux

  Nature chemical biology. 3(10):609-10.

• Prolyl cis-trans isomerization as a molecular timer.

  Authors: Kun Ping Lu, Greg Finn, Tae Ho Lee, Linda K Nicholson

  Nature chemical biology. 3(10):619-29.

  Proline is unique in the realm of amino acids in its ability to adopt completely distinct cis and trans conformations, which allows it to act as a backbone switch that is controlled by prolylProline is unique in the realm of amino acids in its ability to adopt completely distinct cis and trans conformations, which allows it to act as a backbone switch that is controlled by prolyl cis-trans isomerization. This intrinsically slow interconversion can be catalyzed by the evolutionarily conserved group of peptidyl prolyl cis-trans isomerase enzymes. These enzymes include cyclophilins and FK506-binding proteins, which are well known for their isomerization-independent role as cellular targets for immunosuppressive drugs. The significance of enzyme-catalyzed prolyl cis-trans isomerization as an important regulatory mechanism in human physiology and pathology was not recognized until the discovery of the phosphorylation-specific prolyl isomerase Pin1. Recent studies indicate that both phosphorylation-dependent and phosphorylation-independent prolyl cis-trans isomerization can act as a novel molecular timer to help control the amplitude and duration of a cellular process, and prolyl cis-trans isomerization might be a new target for therapeutic interventions.

• Telomere length, stem cells and aging.

  Authors: Maria A Blasco

  Nature chemical biology. 3(10):640-9.

  Telomere shortening occurs concomitant with organismal aging, and it is accelerated in the context of human diseases associated with mutations in telomerase, such as some cases of dyskeratosisTelomere shortening occurs concomitant with organismal aging, and it is accelerated in the context of human diseases associated with mutations in telomerase, such as some cases of dyskeratosis congenita, idiopathic pulmonary fibrosis and aplastic anemia. People with these diseases, as well as Terc-deficient mice, show decreased lifespan coincidental with a premature loss of tissue renewal, which suggests that telomerase is rate-limiting for tissue homeostasis and organismal survival. These findings have gained special relevance as they suggest that telomerase activity and telomere length can directly affect the ability of stem cells to regenerate tissues. If this is true, stem cell dysfunction provoked by telomere shortening may be one of the mechanisms responsible for organismal aging in both humans and mice. Here, we will review the current evidence linking telomere shortening to aging and stem cell dysfunction.

• Expanding the promiscuity of a natural-product glycosyltransferase by directed evolution.

  Authors: Gavin J Williams, Changsheng Zhang, Jon S Thorson

  Nature chemical biology. 3(10):657-62.

  Natural products, many of which are decorated with essential sugar residues, continue to serve as a key platform for drug development. Adding or changing sugars attached to such natural products canNatural products, many of which are decorated with essential sugar residues, continue to serve as a key platform for drug development. Adding or changing sugars attached to such natural products can improve the parent compound's pharmacological properties, specificity at multiple levels, and/or even the molecular mechanism of action. Though some natural-product glycosyltransferases (GTs) are sufficiently promiscuous for use in altering these glycosylation patterns, the stringent specificity of others remains a limiting factor in natural-product diversification and highlights a need for general GT engineering and evolution platforms. Herein we report the use of a simple high-throughput screen based on a fluorescent surrogate acceptor substrate to expand the promiscuity of a natural-product GT via directed evolution. Cumulatively, this study presents variant GTs for the glycorandomization of a range of therapeutically important acceptors, including aminocoumarins, flavonoids and macrolides, and a potential template for engineering other natural-product GTs.

• Robust immune responses elicited by a fully synthetic three-component vaccine.

  Authors: Sampat Ingale, Margreet A Wolfert, Jidnyasa Gaekwad, Therese Buskas, Geert-Jan Boons

  Nature chemical biology. 3(10):663-7.

  The overexpression of saccharides such as Globo-H, Lewis(Y) and Tn antigen is a common feature of oncogenic transformed cells. Endeavors to exploit this aberrant glycosylation for cancer vaccineThe overexpression of saccharides such as Globo-H, Lewis(Y) and Tn antigen is a common feature of oncogenic transformed cells. Endeavors to exploit this aberrant glycosylation for cancer vaccine development have been complicated by difficulties in eliciting high titers of IgG antibodies against classical conjugates of tumor-associated carbohydrates to carrier proteins. We have designed, chemically synthesized and immunologically evaluated a number of fully synthetic vaccine candidates to establish strategies to overcome the poor immunogenicity of tumor-associated carbohydrates and glycopeptides. We have found that a three-component vaccine composed of a TLR2 agonist, a promiscuous peptide T-helper epitope and a tumor-associated glycopeptide can elicit in mice exceptionally high titers of IgG antibodies that can recognize cancer cells expressing the tumor-associated carbohydrate. The superior properties of the vaccine candidate are attributed to the local production of cytokines, upregulation of co-stimulatory proteins, enhanced uptake by macrophages and dendritic cells and avoidance of epitope suppression.

• Light-controlled gene silencing in zebrafish embryos.

  Authors: Ilya A Shestopalov, Surajit Sinha, James K Chen

  Nature chemical biology. 3(10):650-1.

  Functional genomic studies in zebrafish frequently use synthetic oligonucleotides called morpholinos that block RNA splicing or translation. However, the constitutive activity of these reagentsFunctional genomic studies in zebrafish frequently use synthetic oligonucleotides called morpholinos that block RNA splicing or translation. However, the constitutive activity of these reagents limits their experimental utility. We report here the synthesis of a photoactivatable morpholino targeting the no tail (ntl) gene. This caged reagent permits spatiotemporal gene regulation in vivo and the photochemical generation of functionally mosaic organisms.

• Memorizing spatiotemporal patterns.

  Authors: Atsushi Miyawaki, Satoshi Karasawa

  Nature chemical biology. 3(10):598-601.

• Enzymatic glycosynthesis GeTs better.

  Authors: Benjamin G Davis

  Nature chemical biology. 3(10):604-5.

• Sensing nutrient levels in bacteria.

  Authors: Thomas Ferenci

  Nature chemical biology. 3(10):607-8.

• Conserved mechanisms regulate outgrowth in zebrafish fins.

  Authors: M Kathryn Iovine

  Nature chemical biology. 3(10):613-8.

  Regulation of size is one of the fundamental problems in biology. One general strategy has been to identify molecules required for cell growth and cell proliferation within an organ. This has beenRegulation of size is one of the fundamental problems in biology. One general strategy has been to identify molecules required for cell growth and cell proliferation within an organ. This has been particularly revealing, identifying cell-autonomous pathways involved in cell growth, survival and proliferation. In order to identify pathways regulating overall limb growth and morphology, experiments have evaluated gene expression, transplanted and removed tissues, and knocked out genes. This work has provided a vast amount of information identifying molecular mechanisms regulating limb axis formation, outgrowth, and pattern formation. Using the zebrafish fin, genetic, cellular and molecular strategies have also been employed to follow both normal patterns of fin growth and growth in fin mutants. This review will focus on cellular and molecular regulation of the outgrowth and patterning of the zebrafish caudal fin during regeneration, and will emphasize similarities to other systems. Future perspectives describe opportunities using the zebrafish fin to reveal mechanisms underlying the regulation of final size.

• Mammalian circadian signaling networks and therapeutic targets.

  Authors: Andrew C Liu, Warren G Lewis, Steve A Kay

  Nature chemical biology. 3(10):630-9.

  Virtually all cells in the body have an intracellular clockwork based on a negative feedback mechanism. The circadian timekeeping system in mammals is a hierarchical multi-oscillator network, withVirtually all cells in the body have an intracellular clockwork based on a negative feedback mechanism. The circadian timekeeping system in mammals is a hierarchical multi-oscillator network, with the suprachiasmatic nuclei (SCN) acting as the central pacemaker. The SCN synchronizes to daily light-dark cycles and coordinates rhythmic physiology and behavior. Synchronization in the SCN and at the organismal level is a key feature of the circadian clock system. In particular, intercellular coupling in the SCN synchronizes neuron oscillators and confers robustness against perturbations. Recent advances in our knowledge of and ability to manipulate circadian rhythms make available cell-based clock models, which lack strong coupling and are ideal for target discovery and chemical biology.

• Noninvasive optical imaging of cysteine protease activity using fluorescently quenched activity-based probes.

  Authors: Galia Blum, Georges von Degenfeld, Milton J Merchant, Helen M Blau, Matthew Bogyo

  Nature chemical biology. 3(10):668-77.

  We have generated a series of quenched near-infrared fluorescent activity-based probes (qNIRF-ABPs) that covalently target the papain-family cysteine proteases shown previously to be important inWe have generated a series of quenched near-infrared fluorescent activity-based probes (qNIRF-ABPs) that covalently target the papain-family cysteine proteases shown previously to be important in multiple stages of tumorigenesis. These 'smart' probes emit a fluorescent signal only after covalently modifying a specific protease target. After intravenous injection of NIRF-ABPs into mice bearing grafted tumors, noninvasive, whole-body imaging allowed direct monitoring of cathepsin activity. Importantly, the permanent nature of the probes also allowed secondary, ex vivo biochemical profiling to identify specific proteases and to correlate their activity with whole-body images. Finally, we demonstrate that these probes can be used to monitor small-molecule inhibition of protease targets both biochemically and by direct imaging methods. Thus, NIRF-ABPs are (i) potentially valuable new imaging agents for disease diagnosis and (ii) powerful tools for preclinical and clinical testing of small-molecule therapeutic agents in vivo.

• A new family of ATP-dependent oligomerization-macrocyclization biocatalysts.

  Authors: Nadia Kadi, Daniel Oves-Costales, Francisco Barona-Gomez, Gregory L Challis

  Nature chemical biology. 3(10):652-6.

  Oligomerization and macrocyclization reactions are key steps in the biosynthesis of many bioactive natural products. Important macrocycles include the antibiotic daptomycin (1; ref. 1), theOligomerization and macrocyclization reactions are key steps in the biosynthesis of many bioactive natural products. Important macrocycles include the antibiotic daptomycin (1; ref. 1), the immunosuppressant FK-506 (2; ref. 2), the anthelmintic avermectin B1a (3; ref. 3) and the insecticide spinosyn A (4; ref. 4); important oligomeric macrocycles include the siderophores enterobactin (5; ref. 5) and desferrioxamine E (6; ref. 6). Biosynthetic oligomerization and macrocyclization reactions typically involve covalently tethered intermediates and are catalyzed by thioesterase domains of polyketide synthase and nonribosomal peptide synthetase multienzymes. Here we report that the purified recombinant desferrioxamine siderophore synthetase DesD from Streptomyces coelicolor M145 catalyzes ATP-dependent trimerization-macrocyclization of a chemically synthesized 10-aminocarboxylic acid substrate via noncovalently bound intermediates. DesD is dissimilar to other known synthetase families but is similar to other enzymes known or proposed to be required for the biosynthesis of omega-aminocarboxylic acid-derived cyclodimeric siderophores. This suggests that DesD is the first biochemically characterized member of a new family of oligomerizing and macrocyclizing synthetases.

• Structural and mechanistic basis of penicillin-binding protein inhibition by lactivicins.

  Authors: Pauline Macheboeuf, Delphine S Fischer, Tom Brown, Astrid Zervosen, André Luxen, Bernard Joris, Andréa Dessen, Christopher J Schofield

  Nature chemical biology. 3(9):565-9.

  Beta-lactam antibiotics, including penicillins and cephalosporins, inhibit penicillin-binding proteins (PBPs), which are essential for bacterial cell wall biogenesis. Pathogenic bacteria have evolvedBeta-lactam antibiotics, including penicillins and cephalosporins, inhibit penicillin-binding proteins (PBPs), which are essential for bacterial cell wall biogenesis. Pathogenic bacteria have evolved efficient antibiotic resistance mechanisms that, in Gram-positive bacteria, include mutations to PBPs that enable them to avoid beta-lactam inhibition. Lactivicin (LTV; 1) contains separate cycloserine and gamma-lactone rings and is the only known natural PBP inhibitor that does not contain a beta-lactam. Here we show that LTV and a more potent analog, phenoxyacetyl-LTV (PLTV; 2), are active against clinically isolated, penicillin-resistant Streptococcus pneumoniae strains. Crystallographic analyses of S. pneumoniae PBP1b reveal that LTV and PLTV inhibition involves opening of both monocyclic cycloserine and gamma-lactone rings. In PBP1b complexes, the ring-derived atoms from LTV and PLTV show a notable structural convergence with those derived from a complexed cephalosporin (cefotaxime; 3). The structures imply that derivatives of LTV will be useful in the search for new antibiotics with activity against beta-lactam-resistant bacteria.

• Enzymatic total synthesis of enterocin polyketides.

  Authors: Qian Cheng, Longkuan Xiang, Miho Izumikawa, Dario Meluzzi, Bradley S Moore

  Nature chemical biology. 3(9):557-8.

  Polyketides are clinically important natural products that often require elaborate organic syntheses owing to their complex chemical structures. Here we report the multienzyme total synthesis of thePolyketides are clinically important natural products that often require elaborate organic syntheses owing to their complex chemical structures. Here we report the multienzyme total synthesis of the Streptomyces maritimus enterocin and wailupemycin bacteriostatic agents in a single reaction vessel from simple benzoate and malonate substrates. To our knowledge, our results represent the first in vitro assembly of a complete type II polyketide synthase enzymatic pathway to natural products.

• Small molecules not direct activators of caspases.

  Authors: Jean-Bernard Denault, Marcin Drag, Guy S Salvesen, Juliano Alves, Analeah B Heidt, Quinn Deveraux, Jennifer L Harris

  Nature chemical biology. 3(9):519; author reply 520.

• Berkeley center for synthetic biology.

  Authors: Mirella Bucci

  Nature chemical biology. 3(9):527.

• Targeting the spliceosome.

  Authors: Brian Rymond

  Nature chemical biology. 3(9):533-5.

• Cleaving C-Hg bonds: two thiolates are better than one.

  Authors: Susan M Miller

  Nature chemical biology. 3(9):537-8.

• Combating bacteria and drug resistance by inhibiting mechanisms of persistence and adaptation.

  Authors: Peter A Smith, Floyd E Romesberg

  Nature chemical biology. 3(9):549-56.

  Antibiotics have revolutionized the treatment of infectious disease but have also rapidly selected for the emergence of resistant pathogens. Traditional methods of antibiotic discovery have failed toAntibiotics have revolutionized the treatment of infectious disease but have also rapidly selected for the emergence of resistant pathogens. Traditional methods of antibiotic discovery have failed to keep pace with the evolution of this resistance, which suggests that new strategies to combat bacterial infections may be required. An improved understanding of bacterial stress responses and evolution suggests that in some circumstances, the ability of bacteria to survive antibiotic therapy either by transiently tolerating antibiotics or by evolving resistance requires specific biochemical processes that may themselves be subject to intervention. Inhibiting these processes may prolong the efficacy of current antibiotics and provide an alternative to escalating the current arms race between antibiotics and bacterial resistance. Though these approaches are not clinically validated and will certainly face their own set of challenges, their potential to protect our ever-shrinking arsenal of antibiotics merits their investigation. This Review summarizes the early efforts toward this goal.

• Splicing factor SF3b as a target of the antitumor natural product pladienolide.

  Authors: Yoshihiko Kotake, Koji Sagane, Takashi Owa, Yuko Mimori-Kiyosue, Hajime Shimizu, Mai Uesugi, Yasushi Ishihama, Masao Iwata, Yoshiharu Mizui

  Nature chemical biology. 3(9):570-5.

  Pladienolide is a naturally occurring antitumor macrolide that was discovered by using a cell-based reporter gene expression assay controlled by the human vascular endothelial growth factor promoter.Pladienolide is a naturally occurring antitumor macrolide that was discovered by using a cell-based reporter gene expression assay controlled by the human vascular endothelial growth factor promoter. Despite the unique mechanisms of action and prominent antitumor activities of pladienolides B and D in diverse in vitro and in vivo systems, their target protein has remained unclear. We used 3H-labeled, fluorescence-tagged and photoaffinity/biotin (PB)-tagged 'chemical probes' to identify a 140-kDa protein in splicing factor SF3b as the binding target of pladienolide. Immunoblotting of an enhanced green fluorescent protein fusion protein of SF3b subunit 3 (SAP130) revealed direct interaction between the PB probe and SAP130. The binding affinities of pladienolide derivatives to the SF3b complex were highly correlated with their inhibitory activities against reporter gene expression and cell proliferation. Furthermore, pladienolide B impaired in vivo splicing in a dose-dependent manner. Our results demonstrate that the SF3b complex is a pharmacologically relevant protein target of pladienolide and suggest that this splicing factor is a potential antitumor drug target.

• Synthesis and evaluation of stimulatory properties of Sphingomonadaceae glycolipids.

  Authors: Xiangtian Long, Shenglou Deng, Jochen Mattner, Zhuo Zang, Dapeng Zhou, Nathan McNary, Randal D Goff, Luc Teyton, Albert Bendelac, Paul B Savage

  Nature chemical biology. 3(9):559-64.

  Glycosphingolipids (GSLs) from the Sphingomonadaceae family of bacteria have been reported to be potent stimulators of natural killer T cells. These glycolipids include mono-, tri- andGlycosphingolipids (GSLs) from the Sphingomonadaceae family of bacteria have been reported to be potent stimulators of natural killer T cells. These glycolipids include mono-, tri- and tetraglycosylceramides. Here we have prepared the GSL-1 to GSL-4 series of glycolipids and tested their abilities to stimulate natural killer T cells. Among these glycolipids, only GSL-1 (1) is a potent stimulator. Using a series of synthetic diglycosylceramides, we show that oligoglycosylceramides from Sphingomonadaceae are not effectively truncated to GSL-1 in lysosomes in antigen-presenting cells, possibly because the higher-order GSLs are poor substrates for lysosomal acyltransfer enzymes.

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