3,620 results match your criteria ACS Chemical Biology [Journal]


Biosynthesis of cittilins, unusual ribosomally synthesized and post-translationally modified peptides from .

ACS Chem Biol 2020 Jul 8. Epub 2020 Jul 8.

Cittilins are secondary metabolites from myxobacteria comprised of three L-tyrosines and one L-isoleucine forming a bicyclic tetrapeptide scaffold with biaryl and aryl-oxygen-aryl ether bonds. Here we reveal that cittilins belong to the ribosomally synthesized and post-translationally modified peptide (RiPP) family of natural products, for which only the crocagins have been reported from myxobacteria. A 27 amino acid precursor peptide harbors a C-terminal four amino acid core peptide, which is enzymatically modified and finally exported to yield cittilins. Read More

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http://dx.doi.org/10.1021/acschembio.0c00430DOI Listing

Inhibition and Crystal Structure of the Human DHTKD1-Thiamin Diphosphate Complex.

ACS Chem Biol 2020 Jul 7. Epub 2020 Jul 7.

DHTKD1 is the E1 component of the 2-oxoadipate dehydrogenase complex, an enzyme involved in the catabolism of (hydroxy-)lysine and tryptophan. Mutations in have been associated with 2-aminoadipic and 2-oxoadipic aciduria, Charcot-Marie-Tooth disease type 2Q and eosinophilic esophagitis, but the pathophysiology of these clinically distinct disorders remains elusive. Here we report the identification of adipoylphosphonic acid and tenatoprazole as DHTKD1 inhibitors using targeted and high throughput screening, respectively. Read More

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http://dx.doi.org/10.1021/acschembio.0c00114DOI Listing

The Role of Electrostatics in the Mechanism of Cardiac Thin Filament Based Sensitizers.

ACS Chem Biol 2020 Jul 7. Epub 2020 Jul 7.

Heart muscle contraction is regulated by Ca2+ binding to cardiac troponin C. This induces troponin I (cTnI) switch region binding to the regulatory domain of troponin C (cNTnC), pulling the cTnI inhibitory region off actin, and triggering muscle contraction. Small molecules targeting this cNTnC-cTnI interface have potential in the treatment of heart disease. Read More

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http://dx.doi.org/10.1021/acschembio.0c00519DOI Listing

Epitranscriptomic N6-methyladenosine modification is required for direct lineage reprogramming into neurons.

ACS Chem Biol 2020 Jul 7. Epub 2020 Jul 7.

N6-methyladenosine (m6A), a conserved epitranscriptomic modification of eukaryotic messenger RNA (mRNA), plays a critical role in a variety of biological processes. Here, we report that m6A modification plays a key role for governing direct lineage reprogramming into induced neuronal cells (iNs). We found that m6A modification is required for the remodeling of specific mRNAs required for the neuronal direct conversion. Read More

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http://dx.doi.org/10.1021/acschembio.0c00265DOI Listing

Improving membrane permeation in the beyond rule-of-five space by using prodrugs to mask hydrogen bond donors.

ACS Chem Biol 2020 Jul 6. Epub 2020 Jul 6.

A wide range of drug targets can be effectively modulated by peptides and macrocycles. Unfortunately, the size and polarity of these compounds prevents them from crossing the cell membrane to reach target sites in the cell cytosol. As such, these compounds do not conform to standard measures of drug-likeness and exist in beyond the rule-of-5 space. Read More

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http://dx.doi.org/10.1021/acschembio.0c00218DOI Listing

Photo-SNAP-tag, a light-regulated chemical labeling system.

ACS Chem Biol 2020 Jul 5. Epub 2020 Jul 5.

Methods that allow labeling and tracking of proteins have been instrumental for understanding their function. Traditional methods for labeling proteins include fusion to fluorescent proteins or self-labeling chemical tagging systems such as SNAP-tag or Halo-tag. These latter approaches allow bright fluorophores or other chemical moieties to be attached to a protein of interest though a small fusion tag. Read More

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http://dx.doi.org/10.1021/acschembio.0c00412DOI Listing

Coibamide A targets Sec61 to prevent biogenesis of secretory and membrane proteins.

ACS Chem Biol 2020 Jul 1. Epub 2020 Jul 1.

Coibamide A (CbA) is a marine natural product with potent antiproliferative activity against human cancer cells and a unique selectivity profile. Despite promising antitumor activity, the mechanism of cytotoxicity and specific cellular target of CbA remain unknown. Here, we develop an optimized synthetic CbA photoaffinity probe (photo-CbA) and use it to demonstrate that CbA directly targets the Sec61α subunit of the Sec61 protein translocon. Read More

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http://dx.doi.org/10.1021/acschembio.0c00325DOI Listing

Structural Characterization of Complex of Adenylation Domain and Carrier Protein by Using Pantetheine Cross-Linking Probe.

ACS Chem Biol 2020 Jul 7. Epub 2020 Jul 7.

Department of Chemistry, Tokyo Institute of Technology, 2-12-1 Meguro-ku, O-okayama, Tokyo 152-8551, Japan.

Adenylation domains (A-domains) are responsible for selective incorporation of carboxylic acid substrates in the biosynthesis of various natural products. Each A-domain must recognize a cognate carrier protein (CP) for functional substrate transfer. The transient interactions between an A-domain and CP have been investigated by using acyl vinylsulfonamide adenosine inhibitors as probes to determine the structures of several A-domain-CP complexes. Read More

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http://dx.doi.org/10.1021/acschembio.0c00403DOI Listing

Release Factor Inhibiting Antimicrobial Peptides Improve Nonstandard Amino Acid Incorporation in Wild-type Bacterial Cells.

ACS Chem Biol 2020 Jun 30. Epub 2020 Jun 30.

Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, United States.

We report a tunable chemical genetics approach for enhancing genetic code expansion in different wild-type bacterial strains that employ apidaecin-like, antimicrobial peptides observed to temporarily sequester and thereby inhibit Release Factor 1 (RF1). In a concentration-dependent matter, these peptides granted a conditional lambda phage resistance to a recoded strain with nonessential RF1 activity and promoted multisite nonstandard amino acid (nsAA) incorporation at in-frame amber stop codons and . When exogenously added, the peptides stimulated specific nsAA incorporation in a variety of sensitive, wild-type (RF1+) strains, including , a species in which nsAA incorporation has not been previously reported. Read More

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http://dx.doi.org/10.1021/acschembio.0c00055DOI Listing

In Vitro Evolution Reveals a Single Mutation as Sole Source of Src-family Kinase C-helix-out Inhibitor Resistance.

ACS Chem Biol 2020 Jun 30. Epub 2020 Jun 30.

Understanding cancer cell drug resistance to protein-tyrosine kinase inhibitors, which often arises from acquired mutations in the target kinase, is central to the development of more durable therapies. Experimental systems that reveal potential paths to resistance for a given inhibitor and kinase target have an important role in preclinical development of kinase inhibitor drugs. Here we employed a codon mutagenesis strategy to define the mu-tational landscape of acquired resistance in HCK, a member of the SRC tyrosine kinase family and therapeutic target in acute myeloid leukemia (AML). Read More

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http://dx.doi.org/10.1021/acschembio.0c00373DOI Listing

Identifying the Target of an Antiparasitic Compound in Using Thermal Proteome Profiling.

ACS Chem Biol 2020 Jul 6. Epub 2020 Jul 6.

Department of Biology, Massachusetts Institute of Technology, 30 Ames St, Cambridge, Massachusetts 02142, United States.

Apicomplexan parasites include the causative agents of malaria and toxoplasmosis. Cell-based screens in previously identified a chemical modulator of calcium signaling (ENH1) that blocked parasite egress from host cells and exhibited potent antiparasitic activity. To identify the targets of ENH1, we adapted thermal proteome profiling to , which revealed calcium-dependent protein kinase 1 (CDPK1) as a target. Read More

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http://dx.doi.org/10.1021/acschembio.0c00369DOI Listing

Thiopeptides Induce Proteasome-Independent Activation of Cellular Mitophagy.

ACS Chem Biol 2020 Jun 26. Epub 2020 Jun 26.

Thiopeptide antibiotics are emerging clinical candidates that exhibit potent antibacterial activity against a variety of intracellular pathogens, including Mycobacterium tuberculosis (Mtb). Many thiopeptides directly inhibit bacterial growth by disrupting protein synthesis. However, recent work has shown that one thiopeptide, thiostrepton (TSR), can also induce autophagy in infected macrophages, which has the potential to be exploited for host-directed therapies against intracellular pathogens, such as Mtb. Read More

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http://dx.doi.org/10.1021/acschembio.0c00364DOI Listing

Rational Redesign of Monoamine Oxidase A into a Dehydrogenase to Probe ROS in Cardiac Aging.

ACS Chem Biol 2020 Jun 30. Epub 2020 Jun 30.

Department of Biology and Biotechnology, University of Pavia, Milan, Italy.

Cardiac senescence is a typical chronic frailty condition in the elderly population, and cellular aging is often associated with oxidative stress. The mitochondrial-membrane flavoenzyme monoamine oxidase A (MAO A) catalyzes the oxidative deamination of neurotransmitters, and its expression increases in aged hearts. We produced recombinant human MAO A variants at Lys305 that play a key role in O reactivity leading to HO production. Read More

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http://dx.doi.org/10.1021/acschembio.0c00366DOI Listing

Miclxin, a novel MIC60 inhibitor, induces apoptosis via mitochondrial stress in β-catenin mutant tumor cells.

ACS Chem Biol 2020 Jun 25. Epub 2020 Jun 25.

The Wnt signaling pathway regulates diverse cellular processes. β-catenin is one of the major components of this pathway, in which it plays a main role. Although it has been established that β-catenin is mutated in a wide variety of tumors, there are currently no effective therapeutic agents targeting β-catenin. Read More

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http://dx.doi.org/10.1021/acschembio.0c00381DOI Listing

Scientific Response to the Coronavirus Crisis in Spain: Collaboration and Multidisciplinarity.

ACS Chem Biol 2020 Jun 25. Epub 2020 Jun 25.

CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology Park, Building 800, 48160 Derio, Spain.

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http://dx.doi.org/10.1021/acschembio.0c00496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323048PMC

Biocatalytic and FMN Prenylation and (De)carboxylase Activation.

ACS Chem Biol 2020 Jul 7. Epub 2020 Jul 7.

Department of Chemical Engineering and Applied Sciences, University of Toronto, Toronto, Ontario M5S 3E5, Canada.

Reversible UbiD-like (de)carboxylases represent a large family of mostly uncharacterized enzymes, which require the recently discovered prenylated FMN (prFMN) cofactor for activity. Functional characterization of novel UbiDs is hampered by a lack of robust protocols for prFMN generation and UbiD activation. Here, we report two systems for and FMN prenylation and UbiD activation under aerobic conditions. Read More

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http://dx.doi.org/10.1021/acschembio.0c00136DOI Listing

Inhibiting Protein Prenylation with Benzoxaboroles to Target Fungal Plant Pathogens.

ACS Chem Biol 2020 Jun 23. Epub 2020 Jun 23.

Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1M1, Canada.

Fungal pathogens pose an increasing threat to global food security through devastating effects on staple crops and contamination of food supplies with carcinogenic toxins. Widespread deployment of agricultural fungicides has increased crop yields but is driving increasingly frequent resistance to available agents and creating environmental reservoirs of drug-resistant fungi that can also infect susceptible human populations. To uncover non-cross-resistant modes of antifungal action, we leveraged the unique chemical properties of boron chemistry to synthesize novel 6-thiocarbamate benzoxaboroles with broad spectrum activity against diverse fungal plant pathogens. Read More

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http://dx.doi.org/10.1021/acschembio.0c00290DOI Listing

A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL.

ACS Chem Biol 2020 Jun 25. Epub 2020 Jun 25.

Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States.

Targeted protein degradation (TPD) and proteolysis-targeting chimeras (PROTACs) have arisen as powerful therapeutic modalities for degrading specific proteins in a proteasome-dependent manner. However, a major limitation of TPD is the lack of E3 ligase recruiters. Recently, we discovered the natural product nimbolide as a covalent recruiter for the E3 ligase RNF114. Read More

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http://dx.doi.org/10.1021/acschembio.0c00348DOI Listing

Design, Synthesis, and Biophysical Evaluation of Mechanism-Based Probes for Condensation Domains of Nonribosomal Peptide Synthetases.

ACS Chem Biol 2020 Jun 25. Epub 2020 Jun 25.

Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, United States.

Nonribosomal peptide synthetases (NRPSs) are remarkable modular enzymes that synthesize peptide natural products. The condensation (C) domain catalyzes the key amide bond-forming reaction, but structural characterization with bound donor and acceptor substrates has proven elusive. We describe the chemoenzymatic synthesis of condensation domain probes and designed to cross-link the donor and acceptor substrates within the condensation domain active site. Read More

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http://dx.doi.org/10.1021/acschembio.0c00411DOI Listing

Structural Motifs for CTD Kinase Specificity on RNA Polymerase II during Eukaryotic Transcription.

ACS Chem Biol 2020 Jun 22. Epub 2020 Jun 22.

The phosphorylation states of RNA polymerase II coordinate the process of eukaryotic transcription by recruitment of transcription regulators. The individual residues of the repetitive heptad of the C-terminal domain of the biggest subunit of RNA polymerase II (CTD) are phosphorylated temporally at different stages of transcription. Intriguingly, despite similar flanking residues, phosphorylation of Ser2 and Ser5 in CTD heptads play dramatically different roles. Read More

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http://dx.doi.org/10.1021/acschembio.0c00474DOI Listing

Metalloid Reductase Activity Modified by a Fused Se Binding Peptide.

ACS Chem Biol 2020 Jul 6. Epub 2020 Jul 6.

Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States.

A selenium nanoparticle binding peptide was isolated from a phage display library and genetically fused to a metalloid reductase that reduces selenite (SeO) to a Se nanoparticle (SeNP) form. The fusion of the Se binding peptide to the metalloid reductase regulates the size of the resulting SeNP to ∼35 nm average diameter, where without the peptide, SeNPs grow to micron sized polydisperse precipitates. The SeNP product remains associated with the enzyme/peptide fusion. Read More

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http://dx.doi.org/10.1021/acschembio.0c00387DOI Listing

Discovery of Novel Antibiotics as Covalent Inhibitors of Fatty Acid Synthesis.

ACS Chem Biol 2020 Jul 6. Epub 2020 Jul 6.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

The steady increase in the prevalence of multidrug-resistant has made the search for novel antibiotics to combat this clinically important pathogen an urgent matter. In an effort to discover antibacterials with new chemical structures and mechanisms, we performed a growth inhibition screen of a synthetic library against and discovered a promising scaffold with a 1,3,5-oxadiazin-2-one core. These compounds are potent against both methicillin-sensitive and methicillin-resistant strains. Read More

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http://dx.doi.org/10.1021/acschembio.9b00982DOI Listing

Inhibition of NRAS Signaling in Melanoma Through Direct Depalmitoylation Using Amphiphilic Nucleophiles.

ACS Chem Biol 2020 Jun 22. Epub 2020 Jun 22.

Activating mutations in the small GTPase NRAS are responsible for driving tumor growth in several cancers. Unfortunately, the development of NRAS inhibitors has proven difficult due to the lack of hydrophobic binding pockets on the protein's surface. To overcome this limitation, we chose to target the posttranslational S-palmitoyl modification of NRAS, which is required for its signaling activity. Read More

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http://dx.doi.org/10.1021/acschembio.0c00222DOI Listing

Gini coefficients as a single value metric to define chemical probe selectivity.

ACS Chem Biol 2020 Jun 22. Epub 2020 Jun 22.

Selectivity is a key requirement of high-quality chemical probes and lead medicines, however methods to quantify and compare the selectivity of small molecules have not been standardized across the field. Herein, we discuss the origins and use of a comprehensive, single value term to quantify selectivity, the Gini coefficient. Case studies presented include compounds that target protein kinases, small molecules that bind RNA structures, and small molecule chimeras that bind to and degrade target RNA. Read More

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http://dx.doi.org/10.1021/acschembio.0c00486DOI Listing

A Toxic RNA Templates the Synthesis of Its Own Fluorogenic Inhibitor by Using a Bio-orthogonal Tetrazine Ligation in Cells and Tissues.

ACS Chem Biol 2020 Jun 17. Epub 2020 Jun 17.

Department of Chemistry, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States.

Expanded RNA repeats cause more than 30 incurable diseases. One approach to mitigate their toxicity is by using small molecules that assemble into potent, oligomeric species upon binding to the disease-causing RNA in cells. Herein, we show that the expanded repeat [r(CUG)] that causes myotonic dystrophy type 1 (DM1) catalyzes the synthesis of its own inhibitor using an RNA-templated tetrazine ligation in DM1 patient-derived cells. Read More

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http://dx.doi.org/10.1021/acschembio.0c00417DOI Listing

RNase I Modulates Motility, Metabolism, and Resistance.

ACS Chem Biol 2020 Jul 2. Epub 2020 Jul 2.

Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, United States.

Bacteria are constantly adapting to their environment by sensing extracellular factors that trigger production of intracellular signaling molecules, known as second messengers. Recently, 2',3'-cyclic nucleotide monophosphates (2',3'-cNMPs) were identified in and have emerged as possible novel signaling molecules. 2',3'-cNMPs are produced through endonucleolytic cleavage of short RNAs by the T2 endoribonuclease, RNase I; however, the physiological roles of RNase I remain unclear. Read More

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http://dx.doi.org/10.1021/acschembio.0c00390DOI Listing

Fluorescence Probes Exhibit Photoinduced Structural Planarization: Sensing and Microscopic Dynamics of Viscosity Free from Polarity Interference.

ACS Chem Biol 2020 Jun 30. Epub 2020 Jun 30.

Department of Chemistry, National Taiwan University, Taipei 10607, Taiwan.

We demonstrate the construction of wavelength λ-ratiometric images that allow visualizing the distribution of microscopic dynamics within living cells and tissues by using the newly developed principle of fluorescence response. The bent-to-planar motion in the excited state of incorporated fluorescence probes leads to elongation of the π-delocalization, resulting in microviscosity-dependent but polarity-insensitive interplay between well-separated blue and red bands in emission spectra. This allows constructing the exceptionally contrasted images of cellular dynamics. Read More

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http://dx.doi.org/10.1021/acschembio.0c00100DOI Listing

Physicochemical Tools for Visualizing and Quantifying Cell-Generated Forces.

ACS Chem Biol 2020 Jun 26. Epub 2020 Jun 26.

School of Chemistry, School of Materials Science and Engineering, Australian Centre for Nanomedicine, University of New South Wales, Sydney, New South Wales 2052, Australia.

To discern how mechanical forces coordinate biological outcomes, methods that map cell-generated forces in a spatiotemporal manner, and at cellular length scales, are critical. In their native environment, whether it be within compact multicellular three-dimensional structures or sparsely populated fibrillar networks of the extracellular matrix, cells are constantly exposed to a slew of physical forces acting on them from all directions. At the same time, cells exert highly localized forces of their own on their surroundings and on neighboring cells. Read More

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http://dx.doi.org/10.1021/acschembio.0c00304DOI Listing

Dinucleoside Polyphosphates as RNA Building Blocks with Pairing Ability in Transcription Initiation.

ACS Chem Biol 2020 Jun 18. Epub 2020 Jun 18.

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nam. 2, 16610 Prague 6, Czech Republic.

Dinucleoside polyphosphates (NpNs) were discovered 50 years ago in all cells. They are often called alarmones, even though the molecular target of the alarm has not yet been identified. Recently, we showed that they serve as noncanonical initiating nucleotides (NCINs) and fulfill the role of 5' RNA caps in . Read More

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http://dx.doi.org/10.1021/acschembio.0c00178DOI Listing

Photostable and Orthogonal Solvatochromic Fluorophores for Simultaneous Quantification of Multiple Cellular Signaling Molecules.

ACS Chem Biol 2020 Jun 25. Epub 2020 Jun 25.

Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, United States.

Ratiometric fluorescence sensors are powerful tools for direct quantification of diverse biological analytes. To overcome a shortage of solvatochromic fluorophores crucial for ratiometric imaging of biological targets, we prepared and characterized a small library of modular fluorophores with diverse spectral properties. Among them, WCB and WCR showed excellent spectral properties, including high photostability, brightness, and solvatochromism, and are ideally suited for dual ratiometric imaging due to their spectral orthogonality. Read More

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http://dx.doi.org/10.1021/acschembio.0c00241DOI Listing

Aromatic Cytokinin Arabinosides Promote PAMP-like Responses and Positively Regulate Leaf Longevity.

ACS Chem Biol 2020 Jun 29. Epub 2020 Jun 29.

Department of Chemical Biology and Genetics, Centre of the Region Haná for Biotechnological and Agricultural Research, Faculty of Science, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic.

Cytokinins are plant hormones with biological functions ranging from coordination of plant growth to the regulation of biotic and abiotic stress-related responses and senescence. The components of the plant immune system can learn from past elicitations by microbial pathogens and herbivores and adapt to new threats. It is known that plants can enter the primed state of enhanced defense induced by either natural or synthetic compounds. Read More

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http://dx.doi.org/10.1021/acschembio.0c00306DOI Listing

New Malonate-Derived Tetraglucoside Detergents for Membrane Protein Stability.

ACS Chem Biol 2020 Jun 5;15(6):1697-1707. Epub 2020 Jun 5.

Department of Bionanotechnology, Hanyang University, Ansan, 15588, Korea.

Membrane proteins are widely studied in detergent micelles, a membrane-mimetic system formed by amphiphilic compounds. However, classical detergents have serious limitations in their utility, particularly for unstable proteins such as eukaryotic membrane proteins and membrane protein complexes, and thus, there is an unmet need for novel amphiphiles with enhanced ability to stabilize membrane proteins. Here, we developed a new class of malonate-derived detergents with four glucosides, designated malonate-derived tetra-glucosides (MTGs), and compared these new detergents with previously reported octyl glucose neopentyl glycol (OGNG) and -dodecyl-β-d-maltoside (DDM). Read More

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http://dx.doi.org/10.1021/acschembio.0c00316DOI Listing
June 2020
5.331 Impact Factor

The Progesterone 5β-Reductase/Iridoid Synthase Family: A Catalytic Reservoir for Specialized Metabolism across Land Plants.

ACS Chem Biol 2020 Jun 11. Epub 2020 Jun 11.

Department of Natural Product Biosynthesis, Max Planck Institute for Chemical Ecology Hans-Knöll-Straße 8, 07745 Jena, Germany.

Iridoids are plant-derived terpenoids with a rich array of bioactivities. The key step in iridoid skeleton formation is the reduction of 8-oxogeranial by certain members of the progesterone 5β-reductase/iridoid synthase (PRISE) family of short-chain alcohol dehydrogenases. Other members of the PRISE family have previously been implicated in the biosynthesis of the triterpenoid class of cardenolides, which requires the reduction of progesterone. Read More

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http://dx.doi.org/10.1021/acschembio.0c00220DOI Listing

Substrate Plasticity of a Fungal Peptide α--Methyltransferase.

ACS Chem Biol 2020 Jun 19. Epub 2020 Jun 19.

Institute of Microbiology, Department of Biology, Eidgenössische Technische Hochschule (ETH) Zürich, Zürich, Switzerland.

The methylation of amide nitrogen atoms can improve the stability, oral availability, and cell permeability of peptide therapeutics. Chemical -methylation of peptides is challenging. Omphalotin A is a ribosomally synthesized, macrocylic dodecapeptide with nine backbone -methylations. Read More

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http://dx.doi.org/10.1021/acschembio.0c00237DOI Listing

Multiplexed Photoactivation of mRNA with Single-Cell Resolution.

ACS Chem Biol 2020 Jun 12. Epub 2020 Jun 12.

Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, United States.

We demonstrate sequential optical activation of two types of mRNAs in the same mammalian cell through the sequential photocleavage of small molecule caging groups ("photocages") tethered to the 5'-untranslated region (5'-UTR) of mRNAs. Synthetic photocages were conjugated onto target mRNA using RNA-TAG, an enzymatic site-specific RNA modification technique. Translation of mRNA was severely reduced upon conjugation of the photocages onto the 5'-UTR. Read More

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http://dx.doi.org/10.1021/acschembio.0c00205DOI Listing

The Stereocontrolled Biosynthesis of Mirror-Symmetric 2,4-Diaminobutyric Acid Homopolymers Is Critically Governed by Adenylation Activations.

ACS Chem Biol 2020 Jun 16. Epub 2020 Jun 16.

Department of Life Science and Biotechnology, Graduate School of Science and Engineering, Kansai University, 3-3-35 Yamate-Cho, Suita, Osaka 564-8680, Japan.

Among the four bioactive cationic homo-poly(amino acids) discovered in nature, two are mirror-image isomers of poly(2,4-diaminobutyric acid) (poly-Dab) whose biosynthesis has long been unexplained. Their structural analogy plausibly suggested that they could share a common biosynthetic pathway utilizing ε-poly(l-lysine) synthetase-like enzymology but with an unprecedented process for enantiomeric inversion of polymer building blocks. To investigate this possibility, we comparatively explored the biosynthesis of poly-l-Dab and its mirror-image isomer poly-d-Dab in USE31 and NBRC15115, respectively, through genome mining, genetic inactivation, and heterologous expression combined with biochemical assays. Read More

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http://dx.doi.org/10.1021/acschembio.0c00321DOI Listing

Genome Mining Reveals the Phosphonoalamide Natural Products and a New Route in Phosphonic Acid Biosynthesis.

ACS Chem Biol 2020 Jun 15. Epub 2020 Jun 15.

Department of Microbiology, The Ohio State University, Columbus, Ohio 43210, United States.

Phosphonic acid natural products have potent inhibitory activities that have led to their application as antibiotics. Recent studies uncovered large collections of gene clusters encoding for unknown phosphonic acids across microbial genomes. However, our limited understanding of their metabolism presents a significant challenge toward accurately informing the discovery of new bioactive compounds directly from sequence information alone. Read More

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http://dx.doi.org/10.1021/acschembio.0c00256DOI Listing

Small Molecule Intervention in a Protein Kinase C-Gli Transcription Factor Axis.

ACS Chem Biol 2020 Jun 8;15(6):1321-1327. Epub 2020 Jun 8.

Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 E California Blvd, Pasadena, California 91125, United States.

Aberrations in the Hedgehog (Hh) signaling pathway are responsible for a broad range of human cancers, yet only a subset rely on the activity of the clinical target, Smoothened (Smo). Emerging cases of cancers that are insensitive to Smo-targeting drugs demand new therapeutic targets and agents for inhibition. As such, we sought to pursue a recently discovered connection between the Hedgehog pathway transcription factors, the glioma-associated oncogene homologues (Glis), and protein kinase C (PKC) isozymes. Read More

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http://dx.doi.org/10.1021/acschembio.0c00355DOI Listing

How ATP-Competitive Inhibitors Allosterically Modulate Tyrosine Kinases That Contain a Src-like Regulatory Architecture.

ACS Chem Biol 2020 Jun 23. Epub 2020 Jun 23.

Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794-8651, United States.

Small molecule kinase inhibitors that stabilize distinct ATP binding site conformations can differentially modulate the global conformation of Src-family kinases (SFKs). However, it is unclear which specific ATP binding site contacts are responsible for modulating the global conformation of SFKs and whether these inhibitor-mediated allosteric effects generalize to other tyrosine kinases. Here, we describe the development of chemical probes that allow us to deconvolute which features in the ATP binding site are responsible for the allosteric modulation of the global conformation of Src. Read More

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http://dx.doi.org/10.1021/acschembio.0c00429DOI Listing

Quantifying Intramolecular Halogen Bonds in Nucleic Acids: A Combined Protein Data Bank and Theoretical Study.

ACS Chem Biol 2020 Jun 15. Epub 2020 Jun 15.

Department of Chemistry, Universitat de les Illes Balears, Crta. de Valldemossa km 7.5, Palma, Baleares 07122, Spain.

In this study, we report experimental (Protein Data Bank (PDB) search) and theoretical (RI-MP2/def2-TZVP level of theory) evidence of the nature, stability, and directionality properties of intramolecular halogen bonding interactions (HaBs) between 5-bromo/5-iodoracil bases and backbone phosphate groups in nucleic acids (NAs). A PDB survey revealed relevant examples where intramolecular HaBs are undertaken and serve as a structural source of stability in RNA and DNA molecules. In order to develop suitable energy predictors, we started this investigation by calculating the interaction energy values and both the potential () and kinetic () energy densities (using Bader's "atoms in molecules" theory) of several halogen bond complexes involving 5-bromo/5-iodoracil molecules and biologically relevant electron donors. Read More

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http://dx.doi.org/10.1021/acschembio.0c00292DOI Listing
June 2020
5.331 Impact Factor

High-Throughput Screening to Identify Inhibitors of the Type I Interferon-Major Histocompatibility Complex Class I Pathway in Skeletal Muscle.

ACS Chem Biol 2020 Jun 10. Epub 2020 Jun 10.

National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland 20852, United States.

Immunosuppressants used to treat autoimmunity are often not curative and have many side effects. Our purpose was to identify therapeutics for autoimmunity of the skeletal muscle termed idiopathic inflammatory myopathies (myositis). Recent evidence shows that the pro-inflammatory type I interferons (IFN) and a downstream product major histocompatibility complex (MHC) class I are pathogenic in myositis. Read More

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http://dx.doi.org/10.1021/acschembio.0c00343DOI Listing

The integrity of the intradimer interface of the Hepatitis B Virus capsid protein dimer regulates capsid self-assembly.

ACS Chem Biol 2020 May 27. Epub 2020 May 27.

During the hepatitis B virus lifecycle, 120 copies of homodimeric capsid protein assemble around a copy of reverse transcriptase and viral RNA and go on to produce an infectious virion. Assembly needs to be tightly regulated by protein conformational change to ensure symmetry, fidelity and reproducibility. Here we show that structures at the intradimer interface regulate conformational changes at the distal interdimer interface and so regulate assembly. Read More

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http://dx.doi.org/10.1021/acschembio.0c00277DOI Listing

Genetic and Biochemical Reconstitution of Bromoform Biosynthesis in Lends Insights into Seaweed Reactive Oxygen Species Enzymology.

ACS Chem Biol 2020 Jun 8;15(6):1662-1670. Epub 2020 Jun 8.

School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States.

Marine macroalgae, seaweeds, are exceptionally prolific producers of halogenated natural products. Biosynthesis of halogenated molecules in seaweeds is inextricably linked to reactive oxygen species (ROS) signaling as hydrogen peroxide serves as a substrate for haloperoxidase enzymes that participate in the construction these halogenated molecules. Here, using red macroalga , a prolific producer of the ozone depleting molecule bromoform, we provide the discovery and biochemical characterization of a ROS-producing NAD(P)H oxidase from seaweeds. Read More

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http://dx.doi.org/10.1021/acschembio.0c00299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306000PMC

N-Myristoyltransferase as a Glycine and Lysine Myristoyltransferase in Cancer, Immunity, and Infections.

ACS Chem Biol 2020 Jun 10. Epub 2020 Jun 10.

Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States.

Protein myristoylation, the addition of a 14-carbon saturated acyl group, is an abundant modification implicated in biological events as diverse as development, immunity, oncogenesis, and infections. N-Myristoyltransferase (NMT) is the enzyme that catalyzes this modification. Many elegant studies have established the rules guiding the catalysis including substrate amino acid sequence requirements with the indispensable N-terminal glycine, and a co-translational mode of action. Read More

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http://dx.doi.org/10.1021/acschembio.0c00314DOI Listing

Cooperativity Between Orthosteric Inhibitors and Allosteric Inhibitor 8-Anilino-1-Naphthalene Sulfonic Acid (ANS) in Cyclin-Dependent Kinase 2.

ACS Chem Biol 2020 May 20. Epub 2020 May 20.

Institute for Therapeutics Discovery and Development, Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55414, United States.

While kinases have been attractive targets to combat many diseases, including cancer, selective kinase inhibition has been challenging, because of the high degree of structural homology in the active site, where many kinase inhibitors bind. We have previously discovered that 8-anilino-1-naphthalene sulfonic acid (ANS) binds an allosteric pocket in cyclin-dependent kinase 2 (Cdk2). Here, we detail the positive cooperativity between ANS and orthosteric Cdk2 inhibitors dinaciclib and roscovitine, which increase the affinity of ANS toward Cdk2 5-fold to 10-fold, and the relatively noncooperative effects of ATP. Read More

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http://dx.doi.org/10.1021/acschembio.0c00169DOI Listing

Small Molecule Channels Harness Membrane Potential to Concentrate Potassium in trk1Δtrk2Δ Yeast.

ACS Chem Biol 2020 Jun 3;15(6):1575-1580. Epub 2020 Jun 3.

Department of Biochemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Ave., Urbana, Illinois 61801, United States.

Many protein ion channels harness membrane potential to move ions in opposition to their chemical gradient. Deficiencies of such proteins cause several human diseases, including cystic fibrosis, Bartter Syndrome, and proximal renal tubular acidosis. Using yeast as a eukaryotic model system, we asked whether, in the context of a protein ion channel deficiency , small molecule channels could similarly harness membrane potential to concentrate ions. Read More

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http://dx.doi.org/10.1021/acschembio.0c00180DOI Listing

Structure-Guided Optimization of Inhibitors of Acetyltransferase Eis from .

ACS Chem Biol 2020 Jun 18;15(6):1581-1594. Epub 2020 May 18.

Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536-0596, United States.

The enhanced intracellular survival (Eis) protein of () is a versatile acetyltransferase that multiacetylates aminoglycoside antibiotics abolishing their binding to the bacterial ribosome. When overexpressed as a result of promoter mutations, Eis causes drug resistance. In an attempt to overcome the Eis-mediated kanamycin resistance of , we designed and optimized structurally unique thieno[2,3-]pyrimidine Eis inhibitors toward effective kanamycin adjuvant combination therapy. Read More

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http://dx.doi.org/10.1021/acschembio.0c00184DOI Listing

Validating Signal Transducer and Activator of Transcription (STAT) Protein-Inhibitor Interactions Using Biochemical and Cellular Thermal Shift Assays.

ACS Chem Biol 2020 Jul 2. Epub 2020 Jul 2.

Department of Oncology and Pathology, Karolinska Institutet, 171 65, Karolinska vägen A2:07, Solna 171 64, Sweden.

Signal transducer and activator of transcription (STAT) proteins have important biological functions; however, deregulation of STAT signaling is a driving force behind the onset and progression of inflammatory diseases and cancer. While their biological roles suggest that STAT proteins would be valuable targets for developing therapeutic agents, STAT proteins are notoriously difficult to inhibit using small drug-like molecules, as they do not have a distinct inhibitor binding site. Despite this, a multitude of small-molecule STAT inhibitors have been proposed, primarily focusing on inhibiting STAT3 protein to generate novel cancer therapies. Read More

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http://dx.doi.org/10.1021/acschembio.0c00046DOI Listing

Advancing Chemical Microbiology.

ACS Chem Biol 2020 05;15(5):1115-1118

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http://dx.doi.org/10.1021/acschembio.0c00330DOI Listing