当前位置： SCI文献检索 > ACS Chemical Biology期刊下所有文献 > De novo engineering of a human cystathionine-γ-lyase for systemic (L)-Methionine depletion cancer therapy.

De novo engineering of a human cystathionine-γ-lyase for systemic (L)-Methionine depletion cancer therapy.

Abstract：

:It has been known for nearly a half century that human tumors, including those derived from the nervous system such as glioblastomas, medulloblastoma, and neuroblastomas are much more sensitive than normal tissues to l-methionine (l-Met) starvation. More recently, systemic l-Met depletion by administration of Pseudomonas putida methionine-γ-lyase (MGL) could effectively inhibit human tumors xenografted in mice. However, bacterial-derived MGLs are unstable in serum (t(1/2) = 1.9 ± 0.2 h) and highly immunogenic in primates. Since the human genome does not encode a human MGL enzyme, we created de novo a methionine degrading enzyme by reengineering the structurally homologous pyridoxal phosphate-dependent human enzyme cystathionine-γ-lyase (hCGL). hCGL degrades l-cystathionine but displays no promiscuous activity toward l-Met. Rational design and scanning saturation mutagenesis led to the generation of a variant containing three amino acid substitutions (hCGL-NLV) that degraded l-Met with a k(cat)/K(M) of 5.6 × 10(2) M(-1) s(-1) and displayed a serum deactivation t(1/2) = 78 ± 5 h (non-PEGylated). In vitro, the cytotoxicity of hCGL-NLV toward 14 neuroblastoma cell lines was essentially indistinguishable from that of the P. putida MGL. Intravenous administration of PEGylated hCGL-NLV in mice reduced serum l-Met from 123 μM to <5 μM for over 30 h. Importantly, treatment of neuroblastoma mouse xenografts with PEGylated hCGL-NLV resulted in near complete cessation of tumor growth. Since the mode of action of hCGL-NLV does not require breaching the blood-brain barrier, this enzyme may have potential application for sensitive tumors that arise from or metastasize to the central nervous system.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Stone E,Paley O,Hu J,Ekerdt B,Cheung NK,Georgiou G

doi

10.1021/cb300335j

subject

Has Abstract

pub_date

2012-11-16 00:00:00

pages

1822-9

issue

11

eissn

1554-8929

issn

1554-8937

journal_volume

7

pub_type

杂志文章

相关文献

ACS Chemical Biology文献大全
  • A derivatized scorpion toxin reveals the functional output of heteromeric KCNQ1-KCNE K+ channel complexes.

    abstract：:KCNE transmembrane peptides are a family of modulatory beta-subunits that assemble with voltage-gated K+ channels, producing the diversity of potassium currents needed for proper function in a variety of tissues. Although all five KCNE transcripts have been found in cardiac and other tissues, it is unclear whether two...

    journal_title：ACS chemical biology

    pub_type： 信件

    doi：10.1021/cb700089s

    authors： Morin TJ,Kobertz WR

    更新日期：2007-07-20 00:00:00

  • Competitive binding of a benzimidazole to the histone-binding pocket of the Pygo PHD finger.

    abstract：:The Pygo-BCL9 complex is a chromatin reader, facilitating β-catenin-mediated oncogenesis, and is thus emerging as a potential therapeutic target for cancer. Its function relies on two ligand-binding surfaces of Pygo's PHD finger that anchor the histone H3 tail methylated at lysine 4 (H3K4me) with assistance from the B...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb500585s

    authors： Miller TC,Rutherford TJ,Birchall K,Chugh J,Fiedler M,Bienz M

    更新日期：2014-12-19 00:00:00

  • Conformational dynamics of a regulator of G-protein signaling protein reveals a mechanism of allosteric inhibition by a small molecule.

    abstract：:Regulators of G protein signaling (RGS) proteins are key players in regulating signaling via G protein-coupled receptors. RGS proteins directly bind to the Gα-subunits of activated heterotrimeric G-proteins, and accelerate the rate of GTP hydrolysis, thereby rapidly deactivating G-proteins. Using atomistic simulations...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb400568g

    authors： Vashisth H,Storaska AJ,Neubig RR,Brooks CL 3rd

    更新日期：2013-12-20 00:00:00

  • Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs.

    abstract：:Designed second mitochondrial activator of caspases (Smac) mimetics based on an accessible [7,5]-bicyclic scaffold bind to and antagonize protein interactions involving the inhibitor of apoptosis (IAP) proteins, X-chromosome-linked IAP (XIAP), melanoma IAP (ML-IAP), and c-IAPs 1 and 2 (cIAP1 and cIAP2). The design rat...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb600276q

    authors： Zobel K,Wang L,Varfolomeev E,Franklin MC,Elliott LO,Wallweber HJ,Okawa DC,Flygare JA,Vucic D,Fairbrother WJ,Deshayes K

    更新日期：2006-09-19 00:00:00

  • Use of calculated cation-pi binding energies to predict relative strengths of nicotinic acetylcholine receptor agonists.

    abstract：:Agonists and antagonists of the nicotinic acetylcholine receptor (nAChR) are used to treat nicotine addiction, neuromuscular disorders, and neurological diseases. In designing small molecule therapeutics with the nAChR as a target, it is useful to identify chemical parameters that correlate with ability to activate th...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb800189y

    authors： Tantama M,Licht S

    更新日期：2008-11-21 00:00:00

  • Progressive Stereo Locking (PSL): A Residual Dipolar Coupling Based Force Field Method for Determining the Relative Configuration of Natural Products and Other Small Molecules.

    abstract：:Establishing the relative configuration of a bioactive natural product represents the most challenging part in determining its structure. Residual dipolar couplings (RDCs) are sensitive probes of the relative spatial orientation of internuclear vectors. We adapted a force field structure calculation methodology to all...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.7b00281

    authors： Cornilescu G,Ramos Alvarenga RF,Wyche TP,Bugni TS,Gil RR,Cornilescu CC,Westler WM,Markley JL,Schwieters CD

    更新日期：2017-08-18 00:00:00

  • Turn-on Fluorene Push-Pull Probes with High Brightness and Photostability for Visualizing Lipid Order in Biomembranes.

    abstract：:The rational design of environmentally sensitive dyes with superior properties is critical for elucidating the fundamental biological processes and understanding the biophysical behavior of cell membranes. In this study, a novel group of fluorene-based push-pull probes was developed for imaging membrane lipids. The de...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.7b00658

    authors： Shaya J,Collot M,Bénailly F,Mahmoud N,Mély Y,Michel BY,Klymchenko AS,Burger A

    更新日期：2017-12-15 00:00:00

  • Mad2 Inhibitor-1 (M2I-1): A Small Molecule Protein-Protein Interaction Inhibitor Targeting the Mitotic Spindle Assembly Checkpoint.

    abstract：:The genetic integrity of each organism depends on the faithful segregation of its genome during mitosis. To meet this challenge, a cellular surveillance mechanism, termed the spindle assembly checkpoint (SAC), evolved that monitors the correct attachment of chromosomes and blocks progression through mitosis if correct...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.5b00121

    authors： Kastl J,Braun J,Prestel A,Möller HM,Huhn T,Mayer TU

    更新日期：2015-07-17 00:00:00

  • Parsimonious discovery of synergistic drug combinations.

    abstract：:Combination therapies that enhance efficacy or permit reduced dosages to be administered have seen great success in a variety of therapeutic applications. More fundamentally, the discovery of epistatic pathway interactions not only informs pharmacologic intervention but can be used to better understand the underlying ...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb2003225

    authors： Severyn B,Liehr RA,Wolicki A,Nguyen KH,Hudak EM,Ferrer M,Caldwell JS,Hermes JD,Li J,Tudor M

    更新日期：2011-12-16 00:00:00

  • Structural analysis of the contacts anchoring moenomycin to peptidoglycan glycosyltransferases and implications for antibiotic design.

    abstract：:Peptidoglycan glycosyltransferases (PGTs), enzymes that catalyze the formation of the glycan chains of the bacterial cell wall, have tremendous potential as antibiotic targets. The moenomycins, a potent family of natural product antibiotics, are the only known active site inhibitors of the PGTs and serve as blueprints...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb800078a

    authors： Yuan Y,Fuse S,Ostash B,Sliz P,Kahne D,Walker S

    更新日期：2008-07-18 00:00:00

  • CB-6644 Is a Selective Inhibitor of the RUVBL1/2 Complex with Anticancer Activity.

    abstract：:RUVBL1 and RUVBL2 are ATPases associated with diverse cellular activities (AAAs) that form a complex involved in a variety of cellular processes, including chromatin remodeling and regulation of gene expression. RUVBLs have a strong link to oncogenesis, where overexpression is correlated with tumor growth and poor pro...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.8b00904

    authors： Assimon VA,Tang Y,Vargas JD,Lee GJ,Wu ZY,Lou K,Yao B,Menon MK,Pios A,Perez KC,Madriaga A,Buchowiecki PK,Rolfe M,Shawver L,Jiao X,Le Moigne R,Zhou HJ,Anderson DJ

    更新日期：2019-02-15 00:00:00

  • Role of stoichiometry in the dimer-stabilizing effect of AMPA receptor allosteric modulators.

    abstract：:Protein dimerization provides a mechanism for the modulation of cellular signaling events. In α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors, the rapidly desensitizing, activated state has been correlated with a weakly dimeric, glutamate-binding domain conformation. Allosteric modulators can fo...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb4007166

    authors： Ptak CP,Hsieh CL,Weiland GA,Oswald RE

    更新日期：2014-01-17 00:00:00

  • Analysis of amyloid nanostructures using photo-cross-linking: in situ comparison of three widely used photo-cross-linkers.

    abstract：:Photoinduced cross-linking (PIC) has become a powerful tool in chemical biology for the identification and mapping of stable or transient interactions between biomacromolecules and their (unknown) ligands. However, the value of PIC for in vitro and in vivo structural proteomics can be realized only if cross-linking re...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb400731s

    authors： Preston GW,Radford SE,Ashcroft AE,Wilson AJ

    更新日期：2014-03-21 00:00:00

  • Repair of Alkylation Damage in Eukaryotic Chromatin Depends on Searching Ability of Alkyladenine DNA Glycosylase.

    abstract：:Human alkyladenine DNA glycosylase (AAG) initiates the base excision repair pathway by excising alkylated and deaminated purine lesions. In vitro biochemical experiments demonstrate that AAG uses facilitated diffusion to efficiently search DNA to find rare sites of damage and suggest that electrostatic interactions ar...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.5b00409

    authors： Zhang Y,O'Brien PJ

    更新日期：2015-11-20 00:00:00

  • Expanding the genetic code of Caenorhabditis elegans using bacterial aminoacyl-tRNA synthetase/tRNA pairs.

    abstract：:The genetic code specifies 20 common amino acids and is largely preserved in both single and multicellular organisms. Unnatural amino acids (Uaas) have been genetically incorporated into proteins by using engineered orthogonal tRNA/aminoacyl-tRNA synthetase (RS) pairs, enabling new research capabilities and precision ...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb200542j

    authors： Parrish AR,She X,Xiang Z,Coin I,Shen Z,Briggs SP,Dillin A,Wang L

    更新日期：2012-07-20 00:00:00

  • ANS binding reveals common features of cytotoxic amyloid species.

    abstract：:Oligomeric assemblies formed from a variety of disease-associated peptides and proteins have been strongly associated with toxicity in many neurodegenerative conditions, such as Alzheimer's disease. The precise nature of the toxic agents, however, remains still to be established. We show that prefibrillar aggregates o...

    journal_title：ACS chemical biology

    pub_type： 信件

    doi：10.1021/cb1001203

    authors： Bolognesi B,Kumita JR,Barros TP,Esbjorner EK,Luheshi LM,Crowther DC,Wilson MR,Dobson CM,Favrin G,Yerbury JJ

    更新日期：2010-08-20 00:00:00

  • An antibody CDR3-erythropoietin fusion protein.

    abstract：:X-ray crystallographic analysis of a bovine antibody (BLV1H12) revealed a unique scaffold in its ultralong heavy chain complementarity determining region 3 (CDR3H) that folds into a solvent exposed, antiparallel β-stranded "stalk" fused with a disulfide cross-linked "knob" domain. This unusual variable region motif pr...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb4004749

    authors： Zhang Y,Wang D,Welzel G,Wang Y,Schultz PG,Wang F

    更新日期：2013-10-18 00:00:00

  • Modular strategy for the semisynthesis of a K+ channel: investigating interactions of the pore helix.

    abstract：:Chemical synthesis is a powerful method for precise modification of the structural and electronic properties of proteins. The difficulties in the synthesis and purification of peptides containing transmembrane segments have presented obstacles to the chemical synthesis of integral membrane proteins. Here, we present a...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb900210r

    authors： Komarov AG,Linn KM,Devereaux JJ,Valiyaveetil FI

    更新日期：2009-12-18 00:00:00

  • Targeting conformational plasticity of protein kinases.

    abstract：:The quest for ever more selective kinase inhibitors as potential future drugs has yielded a large repertoire of chemical probes that are selective for specific kinase conformations. These probes have been useful tools to obtain structural snapshots of kinase conformational plasticity. Similarly, kinetic and thermodyna...

    journal_title：ACS chemical biology

    pub_type： 杂志文章,评审

    doi：10.1021/cb500870a

    authors： Tong M,Seeliger MA

    更新日期：2015-01-16 00:00:00

  • Esterase-Triggered Self-Immolative Thiocarbamates Provide Insights into COS Cytotoxicity.

    abstract：:Hydrogen sulfide (H2S) is an important gasotransmitter and biomolecule, and many synthetic small-molecule H2S donors have been developed for H2S-related research. One important class of triggerable H2S donors is self-immolative thiocarbamates, which function by releasing carbonyl sulfide (COS), which is rapidly conver...

    journal_title：ACS chemical biology

    pub_type： 信件

    doi：10.1021/acschembio.8b00981

    authors： Levinn CM,Steiger AK,Pluth MD

    更新日期：2019-02-15 00:00:00

  • Diverse functional roles of reactive cysteines.

    abstract：:Cysteine residues on proteins play key roles in catalysis and regulation. These functional cysteines serve as active sites for nucleophilic and redox catalysis, sites of allosteric regulation, and metal-binding ligands on proteins from diverse classes including proteases, kinases, metabolic enzymes, and transcription ...

    journal_title：ACS chemical biology

    pub_type： 杂志文章,评审

    doi：10.1021/cb3005269

    authors： Pace NJ,Weerapana E

    更新日期：2013-02-15 00:00:00

  • Imaging the lipidome: omega-alkynyl fatty acids for detection and cellular visualization of lipid-modified proteins.

    abstract：:Fatty acylation or lipid modification of proteins controls their cellular activation and diverse roles in physiology. It mediates protein-protein and protein-membrane interactions and plays an important role in regulating cellular signaling pathways. Currently, there is need for visualizing lipid modifications of prot...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb900085z

    authors： Hannoush RN,Arenas-Ramirez N

    更新日期：2009-07-17 00:00:00

  • Rational Design of Hybrid Natural Products by Utilizing the Promiscuity of an Amide Synthetase.

    abstract：:WS9326A and annimycin are produced by Streptomyces asterosporus DSM 41452. WS9326A is a nonribosomal peptide synthetase-(NRPS-) derived depsipeptide containing a cinnamoyl moiety, while annimycin is a linear polyketide bearing a 2-amino-3-hydroxycyclopent-2-enone (C5N) group. Both gene clusters have been sequenced and...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.9b00351

    authors： Zhu J,Zhang S,Zechel DL,Paululat T,Bechthold A

    更新日期：2019-08-16 00:00:00

  • NMR structure of the S-linked glycopeptide sublancin 168.

    abstract：:Sublancin 168 is a member of a small group of glycosylated antimicrobial peptides known as glycocins. The solution structure of sublancin 168, a 37-amino-acid peptide produced by Bacillus subtilis 168, has been solved by nuclear magnetic resonance (NMR) spectroscopy. Sublancin comprises two α-helices and a well-define...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb4008106

    authors： Garcia De Gonzalo CV,Zhu L,Oman TJ,van der Donk WA

    更新日期：2014-03-21 00:00:00

  • Small-molecule screening: advances in microarraying and cell-imaging technologies.

    abstract：:Cell-permeable small molecules can be used to modulate protein function selectively, rapidly, reversibly, and conditionally with temporal and quantitative control in biological systems. The identification of these chemical probes can require the screening of large numbers of small molecules. With the advent of new tec...

    journal_title：ACS chemical biology

    pub_type： 杂志文章,评审

    doi：10.1021/cb600321j

    authors： Nicholson RL,Welch M,Ladlow M,Spring DR

    更新日期：2007-01-23 00:00:00

  • Antagonists for Constitutively Active Mutant Estrogen Receptors: Insights into the Roles of Antiestrogen-Core and Side-Chain.

    abstract：:A major risk for patients having estrogen receptor α (ERα)-positive breast cancer is the recurrence of drug-resistant metastases after initial successful treatment with endocrine therapies. Recent studies have implicated a number of activating mutations in the ligand-binding domain of ERα that stabilize the agonist co...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.8b00877

    authors： Sharma A,Toy W,Guillen VS,Sharma N,Min J,Carlson KE,Mayne CG,Lin S,Sabio M,Greene G,Katzenellenbogen BS,Chandarlapaty S,Katzenellenbogen JA

    更新日期：2018-12-21 00:00:00

  • Lysine-specific histone demethylase 1 inhibitors control breast cancer proliferation in ERα-dependent and -independent manners.

    abstract：:Lysine specific demethylase 1 (LSD1, also known as KDM1) is a histone modifying enzyme that regulates the expression of many genes important in cancer progression and proliferation. It is present in various transcriptional complexes including those containing the estrogen receptor (ER). Indeed, inhibition of LSD1 acti...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb300108c

    authors： Pollock JA,Larrea MD,Jasper JS,McDonnell DP,McCafferty DG

    更新日期：2012-07-20 00:00:00

  • Effect of sequence and structural properties on 14-helical beta-peptide activity against Candida albicans planktonic cells and biofilms.

    abstract：:Beta-peptides (beta-amino acid oligomers) that mimic the amphiphilic, helical, and cationic properties of natural antimicrobial peptides have previously been shown to display antifungal activity against planktonic Candida albicans cells. Beta-peptides offer several advantages over conventional peptides composed of alp...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb900093r

    authors： Karlsson AJ,Pomerantz WC,Neilsen KJ,Gellman SH,Palecek SP

    更新日期：2009-07-17 00:00:00

  • Engineered Reader Proteins for Enhanced Detection of Methylated Lysine on Histones.

    abstract：:Histone post-translational modifications (PTMs) are crucial for many cellular processes including mitosis, transcription, and DNA repair. The cellular readout of histone PTMs is dependent on both the chemical modification and histone site, and the array of histone PTMs on chromatin is dynamic throughout the eukaryotic...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.9b00651

    authors： Albanese KI,Krone MW,Petell CJ,Parker MM,Strahl BD,Brustad EM,Waters ML

    更新日期：2020-01-17 00:00:00

  • The Importance of Charge in Perturbing the Aromatic Glue Stabilizing the Protein-Protein Interface of Homodimeric tRNA-Guanine Transglycosylase.

    abstract：:Bacterial tRNA-guanine transglycosylase (Tgt) is involved in the biosynthesis of the modified tRNA nucleoside queuosine present in the anticodon wobble position of tRNAs specific for aspartate, asparagine, histidine, and tyrosine. Inactivation of the tgt gene leads to decreased pathogenicity of Shigella bacteria. Ther...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.0c00700

    authors： Nguyen A,Nguyen D,Phong Nguyen TX,Sebastiani M,Dörr S,Hernandez-Alba O,Debaene F,Cianférani S,Heine A,Klebe G,Reuter K

    更新日期：2020-11-20 00:00:00