- Pulse Radiolysis of Cycloserine in Aqueous Solutions. One-Electron Oxidation by OH Radicals
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The reaction of (R)-4-amino-3-isoxazolidinone (cycloserine) with OH radicals was studied in aqueous solutions by optical pulse radiolysis at pHs 6.5-12.It was concluded, from a comparison of the transient spectra with those obtained in a reaction with N3 radicals, that OH radicals attacked at the dissociated peptide group, -N-CO-, and an oxidized radical, -N.CO-, was produced through one-electron oxidation.From a kinetic analysis, the reaction was considered to have proceeded by two steps: The first step was the formation of OH adducts, where the rate constant, k(OH+cycloserine), was 8X109 mol-1dm3s-1 for the zwitterion form of cycloserine at pH 6.5 and 1.2X1010mol-1dm3s-1 for anion form at pHs 8-10.The second step was the formation of oxidized radicals at a rate of 3-4X106s-1.These radicals decayed with a second-order rate, suggesting a radical-radical recombination.D-Serine was detected as the major product.
- Tanaka, Masako,Sakuma, Hiroshi,Kohanawa, Osamu,Fukaya, Seijun,Katayama, Meiseki
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- Novel practical synthesis of d-cycloserine
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The synthesis of d-cycloserine has been successfully accomplished from the readily available d-serine through three simple and efficient routes. In each synthetic strategy, cyclization reactions are involved as the key step, and one-pot processes are employed. The simple treatment and mild reaction conditions are attractive features in this methodology.
- Kim, Hee-Kwon,Park, Kyoung-Joo Jenny
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- Simple and efficient synthetic routes to d-cycloserine
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d-Cycloserine has been successfully synthesized in good yields through three new synthetic routes from a readily available d-serine. In each synthesis, cyclization served as the key step, and two of the routes employed one-pot operations for the preparation of the target product. These methods featured the use of mild reaction conditions and simple treatments.
- Kim, Hee-Kwon,Park, Kyoung-Joo Jenny
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- The metabotropic glutamate receptor antagonist L-2-amino-3-phosphonopropionic acid inhibits phosphoserine phosphatase
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Phosphoserine phosphatase catalyzes the final step in the major pathway of L-serine biosynthesis in brain. Using D-phosphoserine as substrate, the metabotropic glutamate receptor antagonist L-2-amino-3-phosphonopropionic acid (L-AP3) inhibits phosphoserine phosphatase partially purified from rat brain with a K(i) of 151 μM. In contrast to AP3 enantioselectivity at metabotropic receptors, D-AP3 (K(i) 48 μM) is more potent as an inhibitor of phosphoserine phosphatase than L-AP3, whereas DL-AP3 has intermediate potency. D-, L-, and DL-AP3 are 6- to 8-fold more potent inhibitors using D-phosphoserine rather than L-phosphoserine as substrate, suggesting that AP3 may have selectivity for isoforms of phosphoserine phosphatase which preferentially cleave D-phosphoserine. D-AP3 decreases the apparent affinity of D- and L-phosphoserine with little or no change in maximal velocity indicating that it is a competitive inhibitor of the enzyme. Whereas L-AP3 has similar potency at metabotropic glutamate receptors and phosphoserine phosphatase, D-AP3 is selective for phosphoserine phosphatase and is the most potent and only known competitive inhibitor of this enzyme.
- Hawkinson, Jon E.,Acosta-Burruel, Manuel,Wood, Paul L.
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- D -Serine as a Key Building Block: Enzymatic Process Development and Smart Applications within the Cascade Enzymatic Concept
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An efficient enzymatic method catalyzed by an enzyme from the d-threonine aldolase (DTA) family was developed for d-serine production at industrial scale. This process was used for the synthesis of two valuable ketoses, l-erythrulose and d-fructose, within the cascade enzymatic concept involving two other enzymes. Indeed, d-serine was used as a substrate of d-amino acid oxidase (DAAO) for the in situ generation of the corresponding α-keto acid, hydroxypyruvic acid (HPA), a key donor substrate of transketolase (TK). This enzyme catalyzed the irreversible transfer of the ketol group from HPA to an aldehyde acceptor to form a (3S)-ketose by stereoselective carbon-carbon bond formation. The compatibility of all enzymes and substrates allowed a sequential three-step enzymatic process to be performed without purification of the intermediates. This strategy was validated with two TK aldehyde substrates to finally obtain the corresponding (3S)-ketoses with high control of the stereoselectivity and excellent aldehyde conversion rates.
- Auffray, Pascal,Charmantray, Franck,Collin, Jér?me,Hecquet, Laurence,L'Enfant, Mélanie,Martin, Juliette,Ocal, Nazim,Pollegioni, Loredano
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- The structure of mammalian serine racemase: Evidence for conformational changes upon inhibitor binding
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Serine racemase is responsible for the synthesis of D-serine, an endogenous co-agonist for N-methyl-D-aspartate receptor-type glutamate receptors (NMDARs). This pyridoxal 5′-phosphate-dependent enzyme is involved both in the reversible conversion of L- to D-serine and serine catabolism by α,β-elimination of water, thereby regulating D-serine levels. Because D-serine affects NMDAR signaling throughout the brain, serine racemase is a promising target for the treatment of disorders related to NMDAR dysfunction. To provide a molecular basis for rational drug design the x-ray crystal structures of human and rat serine racemase were determined at 1.5- and 2.1-A resolution, respectively, and in the presence and absence of the orthosteric inhibitor malonate. The structures revealed a fold typical of β-family pyridoxal 5′-phosphate enzymes, with both a large domain and a flexible small domain associated into a symmetric dimer, and indicated a ligand-induced rearrangement of the small domain that organizes the active site for specific turnover of the substrate.
- Smith, Myron A.,Mack, Volker,Ebneth, Andreas,Moraes, Isabel,Felicetti, Brunella,Wood, Michael,Schonfeld, Dorian,Mather, Owen,Cesura, Andrea,Barker, John
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- Structures and Biosynthetic Pathway of Coprisamides C and D, 2-Alkenylcinnamic Acid-Containing Peptides from the Gut Bacterium of the Carrion Beetle Silpha perforata
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Coprisamides C and D (1 and 2) were isolated from a gut bacterium, Micromonospora sp. UTJ3, of the carrion beetle Silpha perforata. Based on the combined analysis of UV, MS, and NMR spectral data, the planar structures of 1 and 2 were elucidated to be unreported derivatives of coprisamides A and B, cyclic depsipeptides bearing a 2-alkenylcinnamic acid unit and the unusual amino acids β-methylaspartic acid and 2,3-diaminopropanoic acid. The absolute configuration of 1 was determined using the advanced Marfey's method, phenylglycine methyl ester derivatization, and J-based configuration analysis. The biosynthetic gene clusters for the coprisamides were investigated based on genomic data from coprisamide-producing strains Micromonospora sp. UTJ3 and Streptomyces sp. SNU533. Coprisamide C (1) was active against the Mycobacterium tuberculosis mc26230 strain.
- Shin, Yern-Hyerk,Ban, Yeon Hee,Kim, Tae Ho,Bae, Eun Seo,Shin, Jongheon,Lee, Sang Kook,Jang, Jichan,Yoon, Yeo Joon,Oh, Dong-Chan
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- Targeted Isolation of Asperheptatides from a Coral-Derived Fungus Using LC-MS/MS-Based Molecular Networking and Antitubercular Activities of Modified Cinnamate Derivatives
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Under the guidance of MS/MS-based molecular networking, four new cycloheptapeptides, namely, asperheptatides A-D (1-4), were isolated together with three known analogues, asperversiamide A-C (5-7), from the coral-derived fungus Aspergillus versicolor. The planar structures of the two major compounds, asperheptatides A and B (1 and 2), were determined by comprehensive spectroscopic data analysis. The absolute configurations of the amino acid residues were determined by advanced Marfey's method. The two structurally related trace metabolites, asperheptatides C and D (3 and 4), were characterized by ESI-MS/MS fragmentation methods. A series of new derivatives (8-26) of asperversiamide A (5) were semisynthesized. The antitubercular activities of 1, 2, and 5-26 against Mycobacterium tuberculosis H37Ra were also evaluated. Compounds 9, 13, 23, and 24 showed moderate activities with MIC values of 12.5 μM, representing a potential new class of antitubercular agents.
- Chao, Rong,Hou, Xue-Mei,Xu, Wei-Feng,Hai, Yang,Wei, Mei-Yan,Wang, Chang-Yun,Gu, Yu-Cheng,Shao, Chang-Lun
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- Hydrogen Bond Assisted l to d Conversion of α-Amino Acids
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l to d conversion of unactivated α-amino acids was achieved by solubility-induced diastereomer transformation (SIDT). Ternary complexes of an α-amino acid with 3,5-dichlorosalicylaldehyde and a chiral guanidine (derived from corresponding chiral vicinal diamine) were obtained in good yield as diastereomerically pure imino acid salt complexes and were hydrolysed to obtain enantiopure α-amino acids. A combination of DFT computation, NMR spectroscopy, and crystal structure provide detailed insight into how two types of strong hydrogen bonds assist in rapid epimerization of the complexes that is essential for SIDT.
- Chin, Jik,Fu, Rui,Lough, Alan J.,So, Soon Mog
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supporting information
p. 4335 - 4339
(2020/02/11)
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- Pagoamide A, a Cyclic Depsipeptide Isolated from a Cultured Marine Chlorophyte, Derbesia sp., Using MS/MS-Based Molecular Networking
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A thiazole-containing cyclic depsipeptide with 11 amino acid residues, named pagoamide A (1), was isolated from laboratory cultures of a marine Chlorophyte, Derbesia sp. This green algal sample was collected from America Samoa, and pagoamide A was isolated using guidance by MS/MS-based molecular networking. Cultures were grown in a light- and temperature-controlled environment and harvested after several months of growth. The planar structure of pagoamide A (1) was characterized by detailed 1D and 2D NMR experiments along with MS and UV analysis. The absolute configurations of its amino acid residues were determined by advanced Marfey's analysis following chemical hydrolysis and hydrazinolysis reactions. Two of the residues in pagoamide A (1), phenylalanine and serine, each occurred twice in the molecule, once in the d- and once in the l-configuration. The biosynthetic origin of pagoamide A (1) was considered in light of other natural products investigations with coenocytic green algae.
- Cottrell, Garrison W.,Fang, Fang,Gerwick, Lena,Gerwick, William H.,Glukhov, Evgenia,Guan, Huashi,Kim, Hyunwoo,Leao, Tiago,Li, Yueying,Mao, Huanru Henry,Murray, Thomas F.,Pierce, Marsha L.,Yu, Hao-Bing,Zhang, Chen,Zhang, Yi
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supporting information
(2020/01/31)
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- Preparation and characterization of a new open-tubular capillary column for enantioseparation by capillary electrochromatography
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In order to use the enantioseparation capability of cationic cyclodextrin and to combine the advantages of capillary electrochromatography (CEC) with open-tubular (OT) column, in this study, a new OT-CEC, coated with cationic cyclodextrin (1-allylimidazolium-β-cyclodextrin [AI-β-CD]) as chiral stationary phase (CSP), was prepared and applied for enantioseparation. Synthesized AI-β-CD was characterized by infrared (IR) spectrometry and mass spectrometry (MS). The preparation conditions for the AI-β-CD-coated column were optimized with the orthogonal experiment design L9(34). The column prepared was characterized by scanning electron microscopy (SEM) and elemental analysis (EA). The results showed that the thickness of stationary phase in the inner surface of the AI-β-CD-coated columns was about 0.2 to 0.5?μm. The AI-β-CD content in stationary phase based on the EA was approximately 2.77?mmol·m?2. The AI-β-CD-coated columns could separate all 14 chiral compounds (histidine, lysine, arginine, glutamate, aspartic acid, cysteine, serine, valine, isoleucine, phenylalanine, salbutamol, atenolol, ibuprofen, and napropamide) successfully in the study and exhibit excellent reproducibility and stability. We propose that the column, coated with AI-β-CD, has a great potential for enantioseparation in OT-CEC.
- Li, Yingjie,Tang, Yimin,Qin, Shili,Li, Xue,Dai, Qiang,Gao, Lidi
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p. 283 - 292
(2019/02/05)
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- Dynamic Kinetic Resolution for Asymmetric Synthesis of L-Noncanonical Amino Acids from D-Ser Using Tryptophan Synthase and Alanine Racemase
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L-Ser is often used to synthesize some significant l-noncanonical α-amino acids(l-ncAAs), which are the prevalent intermediates and precursors for functional synthetic compounds. In this study, threonine aldolase from Escherichia coli k-12 MG1655 has been used to synthesize l-Ser. In contrast to the maximum catalytic capacity (20 g/L) for l-threonine aldolase(LTA), d-Ser was synthesized with high yield (240 g/L) from cheap Gly and paraformaldehyde using d-threonine aldolase (DTA) from Arthrobacter sp ATCC. In order to fully utilize d-Ser and expand the resource of l-Ser, a dynamic kinetic resolution system was constructed to convert d/dl-Ser to l-Ser through combining alanine racemase (Alr) from Bacillus subtilis with l-tryptophan synthase (TrpS) from Escherichia coli k-12 MG1655, and l-ncAAs including l-Trp and l-Cys derivatives were synthesized with excellent enantioselectivity and in high yields. The results indicated l-ncAAs could be efficiently synthesized from d-Ser using this original and green dynamic kinetic resolution system, and the reliable l-Ser resource has been established from simple and achiral substrates.
- Yu, Jinhai,Li, Jing,Gao, Xia,Zeng, Shuiyun,Zhang, Hongjuan,Liu, Junzhong,Jiao, Qingcai
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p. 6618 - 6625
(2019/11/03)
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- Complex-precipitation using functionalized chiral ionic liquids with L-proline anion and chromatographic analysis for enantioseparation of racemic amino acids
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As one kind of functionalized green medium, chiral ionic liquids (CILs) have been widely applied in fields of asymmetric catalysis, enantioseparation, and so on. In this study, four kinds of amino acid–based CILs were synthesized by using trimethylamine, N-methylpyrrolidine, N-methylimidazole, and tropine as cationic nucleus, respectively. Then their specific optical rotation and solubility in common solvents were determined for further resolution application. The effect of different cations in these CILs was explored on the separation of racemic phenylalanine in complex-precipitation way. Moreover, various factors were systematically investigated for their effects on resolution efficiency, including the type of additive copper salts, the molar ratio of Cu (II) to CIL, pH value, the amount of racemic phenylalanine, and temperature. Under the appropriate conditions, L-phenylalanine mainly existed in solid phase and could be separated from its enantiomers in liquid phase. Furthermore, the mechanism of resolution was studied by thermogravimetric analysis, infrared spectrum, and molecular simulation. The resolution system has characteristics of no organic solvent, fast separation speed, simple resolution process, and easy scale-up.
- Zang, Huimin,Yao, Shun,Luo, Yingjie,Tang, Dan,Song, Hang
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p. 1182 - 1194
(2018/09/12)
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- One-Pot Preparation of d-Amino Acids Through Biocatalytic Deracemization Using Alanine Dehydrogenase and Ω-Transaminase
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d-Amino acids are pharmaceutically important building blocks, leading to a great deal of research efforts to develop cost-effective synthetic methods. Preparation of d-amino acids by deracemization has been conceptually attractive owing to facile synthesis of racemic amino acids by Strecker synthesis. Here, we demonstrated biocatalytic deracemization of aliphatic amino acids into d-enantiomers by running cascade reactions; (1) stereoinversion of l-amino acid to a d-form by amino acid dehydrogenase and ω-transaminase and (2) regeneration of NAD+ by NADH oxidase. Under the cascade reaction conditions containing 100?mM isopropylamine and 1?mM NAD+, complete deracemization of 100?mM dl-alanine was achieved after 24?h with 95% reaction yield of d-alanine (> 99% eeD, 52% isolation yield). Graphical Abstract: [Figure not available: see fulltext.].
- Han, Sang-Woo,Shin, Jong-Shik
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p. 3678 - 3684
(2018/10/20)
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- Chromatographic Resolution of α-Amino Acids by (R)-(3,3'-Halogen Substituted-1,1'-binaphthyl)-20-crown-6 Stationary Phase in HPLC
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Three new chiral stationary phases (CSPs) for high-performance liquid chromatography were prepared from R-(3,3'-halogen substituted-1,1'-binaphthyl)-20-crown-6 (halogen = Cl, Br and I). The experimental results showed that R-(3,3'-dibromo-1,1'-binaphthyl)-20-crown-6 (CSP-1) possesses more prominent enantioselectivity than the two other halogen-substituted crown ether derivatives. All twenty-one α-amino acids have different degrees of separation on R-(3,3'-dibromo-1,1'-binaphthyl)-20-crown-6-based CSP-1 at room temperature. The enantioselectivity of CSP-1 is also better than those of some commercial R-(1,1'-binaphthyl)-20-crown-6 derivatives. Both the separation factors (α) and the resolution (Rs) are better than those of commercial crown ether-based CSPs [CROWNPAK CR(+) from Daicel] under the same conditions for asparagine, threonine, proline, arginine, serine, histidine and valine, which cannot be separated by commercial CR(+). This study proves the commercial usefulness of the R-(3,3'-dibromo-1,1'-binaphthyl)-20-crown-6 chiral stationary phase.
- Wu, Peng,Wu, Yuping,Zhang, Junhui,Lu, Zhenyu,Zhang, Mei,Chen, Xuexian,Yuan, Liming
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supporting information
p. 1037 - 1042
(2017/07/25)
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- Variochelins, Lipopeptide Siderophores from Variovorax boronicumulans Discovered by Genome Mining
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Photoreactive siderophores have a major impact on the growth of planktonic organisms. To date, these molecules have mainly been reported from marine bacteria, although evidence is now accumulating that some terrestrial bacteria also harbor the biosynthetic potential for their production. In this paper, we describe the genomics-driven discovery and characterization of variochelins, lipopeptide siderophores from the bacterium Variovorax boronicumulans, which thrives in soil and freshwater habitats. Variochelins are different from most other lipopeptide siderophores in that their biosynthesis involves a polyketide synthase. We demonstrate that the ferric iron complex of variochelin A possesses photoreactive properties and present the MS-derived structures of two degradation products that emerge upon light exposure.
- Kurth, Colette,Schieferdecker, Sebastian,Athanasopoulou, Kalliopi,Seccareccia, Ivana,Nett, Markus
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p. 865 - 872
(2016/05/24)
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- Fabrication of mesoporous carbon tube and foam: Application as supports in enantio-selective separation of optically pure amino acid from racemates
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The mesoporous monolithic carbon (MMC) foams and carbon tubes were newly fabricated in cmscale using the mixture of triblock copolymers and phenol/HCHO resin precursors. The regular mesoporosity were formed in the body of MMC foam and carbon fibers. In this work, the organic phases containing chiral ARCA adsorbent and a phase transfer catalyst were coated on the surfaces of mesoporous carbon support, and this ARCA/carbon mixture was adopted for the enantioselective separation of amino acid in the circulation system. (S)-ARCA coated MMC support showed high selcetivity up to 90% for the separation of D-type phenylalanine, serine and tryptophan from racemic mixtures.
- Jeon, Hoon-Gi,Lee, Ju-Hyun,Kim, Gye-Ryung,Park, Da-Min,Kim, Geon-Joong
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p. 334 - 338
(2015/03/18)
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- Efficient synthesis of chiral binaphthol aldehyde with phenyl ether linkage for enantioselective extraction of amino acids
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A binaphthol aldehyde with phenyl ether linkage, compound 2, has been synthesized starting from binaphthol-3-carboxylic acid. The axially chiral binaphthol ring was racemized during the synthesis due to high temperatures required in O-phenylation reaction. The enantiomerically pure form of 2 was obtained from the resolution of the diastereomeric imine of 2. Optically pure compound (S)-2 was applied to the enantioselective liquid-liquid extraction of amino acid between CH2Cl2 and aqueous layers.The stereoselectivities, that is, D/L ratio of the amino acid extracted, ranged from 3.57 to 11.1. One carbon was absent in compound (S)-2 compared to the compound (S)-1 with benzyl ether linkage, which differentiated the conformations of their imines formed with amino acids.
- Choi, Misun,Jun, Moo-Jin,Kim, Kwan Mook
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p. 1834 - 1837
(2015/07/15)
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- Anti-inflammatory activity of a new cyclic peptide, citrusin XI, isolated from the fruits of Citrus unshiu
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Ethnopharmacological relevance Citrus unshiu (Rutaceae) is an easy-peeling citrus fruit, which has been used as a traditional Korean medicine for improving skin elasticity, relieving fatigue and cough, and preventing bronchitis, flu, and various cancers. However, its active components associated with anti-inflammation and underlying mechanisms remain unknown. In this study, we investigated the active constituents from the fruits of Citrus unshiu and evaluated the anti-inflammatory activity in order to support the traditional usage of Citrus unshiu. Material and methods Repeated column chromatography, together with a semi-preparative HPLC purification was used to separate the bioactive constituent from the EtOAc soluble fraction of the EtOH extract of Citrus unshiu fruits. Anti-inflammatory effects of the isolated compounds on lipopolysaccharide (LPS)-induced production of pro-inflammatory mediators were examined using RAW264.7 macrophage cells. Results A new cyclic peptide, citrusin XI (1), was isolated and identified from the fruits of Citrus unshiu. The structure of compound 1 was elucidated by spectroscopic analysis, including 1D and 2D nuclear magnetic resonance (NMR) (1H, 13C, COSY, HMQC and HMBC experiments), and high resolution (HR)-mass spectrometry, and its absolute configurations were further confirmed by the Marfeys method. Compound 1 decreased NO production in LPS-stimulated RAW264.7 cells in a dose-dependent manner with an IC50 value of 70 μM. Compound 1 suppressed NO production by decreasing iNOS expression but COX-2 expression was slightly associated with the reduction by compound 1 in LPS-induced RAW264.7 cells. Furthermore, compound 1 inhibited NF-κB activation by blocking IκBα degradation and NF-κB phosphorylation in LPS-stimulated RAW264.7 cells. Conclusions These results indicate that a new cyclic peptide, citrusin XI, from Citrus unshiu fruits has anti-inflammatory properties that inhibit the release of pro-inflammatory mediators. Compound 1 decreases NO production by decreasing iNOS expression and NF-κB activation associated with IκBα degradation and NF-κB phosphorylation in LPS-induced RAW264.7 cells. This is the first study to clarify the underlying mechanism of the anti-inflammatory effect exerted by a pure isolated compound from Citrus unshiu in LPS-stimulated RAW264.7 macrophage cells. The phytochemical, citrusin XI of Citrus unshiu may serve as lead compound in the design of new agents for preventing and treating inflammatory diseases.
- Noh, Hyung Jun,Hwang, Dukhyun,Lee, Eun Suk,Hyun, Jae Wook,Yi, Pyoung Ho,Kim, Geum Soog,Lee, Seung Eun,Pang, Changhyun,Park, Yong Joo,Chung, Kyu Hyuck,Kim, Gun Do,Kim, Ki Hyun
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p. 106 - 112
(2015/03/05)
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- Fabrication of meso/macroporous carbon monolith and its application as a support for adsorptive separation of D-amino acid from racemates
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(S)-Alanine Racemase Chiral Analogue ((S)-ARCA) was used as an efficient adsorbent for the selective separation of D-amino acids (D-AAs), which are industrially important as chiral building blocks for the synthesis of pharmaceutical intermediates. The organic phase, containing (S)-ARCA adsorbent and phase transfer reagents, such as ionic liquid type molecules (Tetraphenylphosphonium chloride (TPPC), Octyltriphenylphosponium bromide (OTPPBr)), were coated on the surfaces of mesoporous carbon supports. For the immobilization of chiral adsorbents, meso/macroporous monolithic carbon (MMC), having bimodal pore structures with high surface areas and pore volumes, were fabricated. The separation of chiral AAs by adsorption onto the heterogeneous (S)-ARCA was performed using a continuous flow type packed bed reactor system. The effects of loading amount of ARCA on the support, the molar ratio of AA to ARCA, flow rates, and the type of phase transfer reagent (PTR) on the isolation yields and the optical purity of product D-AAs were investigated. D-AAs were selectively combined to (S)-ARCA through imine formation reaction in an aqueous basic solution of racemic D/L-AA. The (S)-ARCA coated MMC support showed a high selectivity, up to 95 ee%, for the separation of D-type phenylalanine, serine and tryptophan from racemic mixtures. The ionic liquids TPPC and OTPPBr exhibited superior properties to those of the ionic surfactant Cetyltrimethyl ammonium bromide (CTAB), as a PTR, showing constant optical purities of 95 ee%, with high isolation yields for five repeated reuses. The unique separation properties in this heterogeneous adsorption system should provide for an expansion of the applications of porous materials for commercial processes.
- Park, Da-Min,Jeon, Sang Kwon,Yang, Jin Yong,Choi, Sung Dae,Kim, Geon Joong
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p. 1720 - 1726
(2014/07/07)
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- Deracemization of amino acids by coupling transaminases of opposite stereoselectivity
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Biocatalytic deracemization of amino acids without relying on oxidase-based deamination of an unwanted enantiomer was demonstrated by coupling a-and w-transaminases displaying opposite stereoselectivity. This strategy employs isopropylamine and a keto acid as cosubstrates and is free of generation of hydrogen peroxide which is troublesome in the conventional oxidase-based methods.
- Park, Eul-Soo,Shin, Jong-Shik
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p. 3505 - 3509
(2015/02/19)
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- Cyclic lipodepsipeptides verlamelin A and B, isolated from entomopathogenic fungus Lecanicillium sp.
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Verlamelin and its new derivative (verlamelin B) were isolated from fermentation broth of entomopathogenic fungus Lecanicillium sp. HF627. As the structural elucidation of verlamelin so far was only preliminary, we studied and determined the absolute structure of these two compounds to be cyclo(5S-hydroxytetradecanoic acid-D-alloThr/Ser-D-Ala-L-Pro-L-Gln-D-Tyr-L-Val). This is the first study that precisely analyzed the structure of verlamelin.
- Ishidoh, Kei-Ichi,Kinoshita, Hiroshi,Igarashi, Yasuhiro,Ihara, Fumio,Nihira, Takuya
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p. 459 - 463
(2014/07/08)
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- SEPARATING AGENT AND MANUFACTURING METHOD THEREOF
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An embodiment of the present invention is a separating agent wherein a group represented by a chemical formula of: or a group represented by a chemical formula of: is introduced on a surface thereof.
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Paragraph 0067; 0068; 0069; 0070; 0071; 0072; 0091; 0092
(2015/01/07)
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- ω-Transaminase-catalyzed asymmetric synthesis of unnatural amino acids using isopropylamine as an amino donor
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Isopropylamine is an ideal amino donor for reductive amination of carbonyl compounds by ω-transaminase (ω-TA) owing to its cheapness and high volatility of a ketone product. Here we developed asymmetric synthesis of unnatural amino acids via ω-TA-catalyzed amino group transfer between α-keto acids and isopropylamine.
- Park, Eul-Soo,Dong, Joo-Young,Shin, Jong-Shik
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p. 6929 - 6933
(2013/10/08)
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- Functional annotation and three-dimensional structure of an incorrectly annotated dihydroorotase from cog3964 in the amidohydrolase superfamily
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The substrate specificities of two incorrectly annotated enzymes belonging to cog3964 from the amidohydrolase superfamily were determined. This group of enzymes are currently misannotated as either dihydroorotases or adenine deaminases. Atu3266 from Agrobacterium tumefaciens C58 and Oant2987 from Ochrobactrum anthropi ATCC 49188 were found to catalyze the hydrolysis of acetyl-(R)-mandelate and similar esters with values of kcat/K m that exceed 105 M-1 s-1. These enzymes do not catalyze the deamination of adenine or the hydrolysis of dihydroorotate. Atu3266 was crystallized and the structure determined to a resolution of 2.62 ?. The protein folds as a distorted (β/α)8 barrel and binds two zincs in the active site. The substrate profile was determined via a combination of computational docking to the three-dimensional structure of Atu3266 and screening of a highly focused library of potential substrates. The initial weak hit was the hydrolysis of N-acetyl-d-serine (kcat/Km = 4 M-1 s -1). This was followed by the progressive identification of acetyl-(R)-glycerate (kcat/Km = 4 × 102 M-1 s-1), acetyl glycolate (kcat/Km = 1.3 × 104 M-1 s-1), and ultimately acetyl-(R)-mandelate (kcat/Km = 2.8 × 105 M-1 s-1).
- Ornelas, Argentina,Korczynska, Magdalena,Ragumani, Sugadev,Kumaran, Desigan,Narindoshvili, Tamari,Shoichet, Brian K.,Swaminathan, Subramanyam,Raushel, Frank M.
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p. 228 - 238
(2013/03/13)
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- Identification of four new agr quorum sensing-interfering cyclodepsipeptides from a marine Photobacterium
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During our search for new natural products from the marine environment, we discovered a wide range of cyclic peptides from a marine Photobacterium, closely related to P. halotolerans. The chemical fingerprint of the bacterium showed primarily non-ribosomal peptide synthetase (NRPS)-like compounds, including the known pyrrothine antibiotic holomycin and a wide range of peptides, from diketopiperazines to cyclodepsipeptides of 500-900 Da. Purification of components from the pellet fraction led to the isolation and structure elucidation of four new cyclodepsipeptides, ngercheumicin F, G, H, and I. The ngercheumicins interfered with expression of virulence genes known to be controlled by the agr quorum sensing system of Staphylococcus aureus, although to a lesser extent than the previously described solonamides from the same strain of Photobacterium.
- Kjaerulff, Louise,Nielsen, Anita,Mansson, Maria,Gram, Lone,Larsen, Thomas O.,Ingmer, Hanne,Gotfredsen, Charlotte H.
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p. 5051 - 5062
(2014/02/14)
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- SEPARATING AGENT FOR CHROMATOGRAPHY
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A separating agent for chromatography is provided that is useful for the separation of specific compounds, e.g., for the optical resolution of amino acids. This separating agent for chromatography provides a higher productivity and contains a crown ether-like cyclic structure and optically active binaphthyl. This separating agent for chromatography containing a crown ether-like cyclic structure and optically active binaphthyl is provided by introducing a substitution group for binding to carrier into a specific commercially available 1,1′-binaphthyl derivative that has substituents at the 2, 2′, 3, and 3′ positions, then introducing a crown ether-like cyclic structure, and subsequently chemically bonding the binaphthyl derivative to the carrier through the substitution group for binding to carrier.
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Paragraph 0074; 0075
(2013/08/15)
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- Simple conversion of fully protected amino acids to zwitterions
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An operationally simple and efficient method under mild acidic conditions was developed to convert fully protected amino acids to the corresponding zwitterions without either isoelectric precipitation or ion exchange chromatography.
- Hao, Junliang,Reinhard, Matt,Henry, Steven S.,Seest, Eric P.,Belvo, Matthew D.,Monn, James A.
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experimental part
p. 1433 - 1434
(2012/04/10)
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- METHOD FOR OBTAINING OPTICALLY PURE AMINO ACIDS
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This invention relates to a method for obtaining optically pure amino acids, including optical resolution and optical conversion. This method significantly shortens the time taken for optical transformation, and enables the repeated use of an organic solution containing a enantioselective receptor, to thereby obtain optically pure amino acids in a simple and remarkably efficient manner, and to enable the very economical mass production of optically pure amino acids.
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Page/Page column 7
(2012/02/01)
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- METHOD FOR OBTAINING OPTICALLY PURE AMINO ACIDS
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This invention relates to a method for obtaining optically pure amino acids, including optical resolution and optical conversion. This method significantly shortens the time taken for optical transformation, and enables the repeated use of an organic solution containing a enantioselective receptor, to thereby obtain optically pure amino acids in a simple and remarkably efficient manner, and to enable the very economical mass production of optically pure amino acids.
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Page/Page column 10-11
(2012/02/14)
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- Aminolytic reaction catalyzed by d-stereospecific amidohydrolases from Streptomyces spp
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From investigation of 2000 soil isolates, we identified two serine-type amidohydrolases that can hydrolyze d-aminoacyl derivatives from the culture supernatant of Streptomyces species 82F2 and 83D12. The enzymes, redesignated as 82F2-DAP and 83D12-DAP, were purified for homogeneity and characterized. Each enzyme had molecular mass of approximately 40 kDa, and each showed moderate stability with respect to temperature and pH. Among hydrolytic activities toward d-aminoacyl-pNAs, the enzymes showed strict specificity toward d-Phe-pNA, but showed broad specificity toward d-aminoacyl esters. The specific activity for d-Phe-pNA hydrolysis of 82F2-DAP was ten-fold higher than that of 83D12-DAP. As a second function, each enzyme showed peptide bond formation activity by its function of aminolysis reaction. Based on results of d-Phe-d-Phe synthesis under various conditions, we propose a reaction mechanism for d-Phe-d-Phe production. Furthermore, the enzymes exhibited peptide elongation activity, producing oligo homopeptide in a one-pot reaction. We cloned the genes encoding each enzyme, which revealed that the primary structure of each enzyme showed 30-60% identity with those of peptidases belonging to the clan SE, S12 peptidase family categorized as serine peptidase with d-stereospecificity.
- Arima, Jiro,Ito, Hitomi,Hatanaka, Tadashi,Mori, Nobuhiro
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experimental part
p. 1460 - 1469
(2012/01/12)
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- Enantioselective catabolism of racemic serine: Preparation of d-serine using whole cells of Fusobacterium nucleatum
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Incubation of racemic serine with the anaerobic bacterium Fusobacterium nucleatum yielded d-serine in high enantiomeric excess (>95%). Selective degradation of the l-amino acid was most efficient when F. nucleatum was resuspended in a buffer at high cell densities (ca. 50-100 g damp cells/L); a single incubation effectively removed almost all l-serine from racemic mixtures at initial concentrations up to 800 mM, the solubility limit. The product d-amino acid was separated from the metabolic end-products (acetate, butyrate and lactate) and buffer components by a single cation-exchange step. After recrystallization, 83% of the d-serine in the initial racemate was recovered with >99% ee (HPLC) and 98% purity (HPLC). This anaerobic microbial approach provides a viable complementary method for generating d-serine, a valuable chiral starting material for chemical synthesis.
- Ramezani, Mohammad,White, Robert L.
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experimental part
p. 1473 - 1478
(2011/11/12)
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- Cyclodepsipeptides, sesquiterpenoids, and other cytotoxic metabolites from the filamentous fungus Trichothecium sp. (MSX 51320)
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Two new cyclodepsipeptides (1 and 2), two new sesquiterpenoids (3 and 4), and the known compounds guangomide A (5), roseotoxin S, and three simple trichothecenes were isolated from the cytotoxic organic extract of a terrestrial filamentous fungus, Trichothecium sp. The structures were determined using NMR spectroscopy and mass spectrometry. Absolute configurations of the cyclodepsipeptides were established by employing chiral HPLC, while the relative configurations of 3 and 4 were determined via NOESY data. The isolation of guangomide A was of particular interest, since it was reported previously from a marine-derived fungus.
- Sy-Cordero, Arlene A.,Graf, Tyler N.,Adcock, Audrey F.,Kroll, David J.,Shen, Qi,Swanson, Steven M.,Wani, Mansukh C.,Pearce, Cedric J.,Oberlies, Nicholas H.
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experimental part
p. 2137 - 2142
(2011/12/14)
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- A highly sensitive enzymatic assay for D- and total serine detection using D-serine dehydratase from Saccharomyces cerevisiae
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D-serine acts as a co-agonist of the N-methyl-D-aspartate (NMDA) receptor, an excitatory glutamate receptor in the mammalian brain that is thought to be involved in higher brain functions such as memory and study. A relationship between the concentration of D-serine in cerebrospinal fluid and neurological disorders such as schizophrenia and amyotrophic lateral sclerosis has been hypothesized. A simple and accurate D-serine assay system would be useful in the study and diagnosis of these diseases. Previously, we developed an enzymatic assay of D-serine using D-serine dehydratase from Saccharomyces cerevisiae, lactate dehydrogenase and NADH. Although this method can detect 10 μM D-serine, a 10-fold increase in sensitivity is required for the assay to be useful for the study and diagnosis of neurological disorders. In this study, we increased the sensitivity of this assay to detect submicromolar concentrations of D-serine. In the new assay, D-serine dehydratase converts D-serine to pyruvate, which is in turn oxidized by pyruvate oxidase. Then, in the presence of horseradish peroxidase, hydrogen peroxide formed during the oxidation converts 10-acetyl-3,7-dihydroxy-phenoxazine (Amplex Red) to resorufin, which exhibits a strong fluorescence. We show that this improved assay can be used to determine the concentration of D-serine in calf serum.
- Naka, Tomoko,Ito, Tomokazu,Hemmi, Hisashi,Yoshimura, Tohru
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scheme or table
p. 150 - 154
(2011/02/16)
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- Rapid asymmetric synthesis of amino acids via NiII complexes based on new fluorine containing chiral auxiliaries
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New fluorine-containing chiral auxiliaries (S)-N-(2-benzoylphenyl)-1-(2- fluorobenzyl)-, (S)-N-(2-benzoylphenyl)-1-(3-fluorobenzyl)-, and (S)-N-(2-benzoylphenyl)-1-(4-fluorobenzyl)-pyrrolidine-2-carboxamide and their NiII complexes of Schiff bases with glycine and alanine have been synthesized. The greater efficiency of the complexes in terms of faster reaction rates and stereoselectivities in the asymmetric synthesis of (S)-α-amino acids has also been demonstrated.
- Saghyan, Ashot S.,Dadayan, Ani S.,Dadayan, Slavik A.,Mkrtchyan, Anna F.,Geolchanyan, Arpine V.,Manasyan, Luiza L.,Ajvazyan, Hrant R.,Khrustalev, Victor N.,Hambardzumyan, Hasmik H.,Maleev, Victor I.
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experimental part
p. 2956 - 2965
(2011/03/19)
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- Structure, mechanism, and substrate profile for Sco3058: The closest bacterial homologue to human renal dipeptidase
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Human renal dipeptidase, an enzyme associated with glutathione metabolism and the hydrolysis of β-lactams, is similar in sequence to a cluster of ~400 microbial proteins currently annotated as nonspecific dipeptidases within the amidohydrolase superfamily. The closest homologue to the human renal dipeptidase from a fully sequenced microbe is Sco3058 from Streptomyces coelicolor. Dipeptide substrates of Sco3058 were identified by screening a comprehensive series of L-Xaa-L-Xaa, L-Xaa-D-Xaa, and D-Xaa-L-Xaa dipeptide libraries. The substrate specificity profile shows that Sco3058 hydrolyzes a broad range of dipeptides with a marked preference for an L-amino acid at the N-terminus and a D-amino acid at the C-terminus. The best substrate identified was L-Arg-D-Asp (kcat/Km = 7.6 x 105 M -1 s-1). The three-dimensional structure of Sco3058 was determined in the absence and presence of the inhibitors citrate and a phosphinate mimic of L-Ala-D-Asp. The enzyme folds as a (β/α)8 barrel, and two zinc ions are bound in the active site. Site-directed mutagenesis was used to probe the importance of specific residues that have direct interactions with the substrate analogues in the active site (Asp-22, His-150, Arg-223, and Asp-320). The solvent viscosity and kinetic effects of D2O indicate that substrate binding is relatively sticky and that proton transfers do not occurr during the rate-limiting step. A bell-shaped pH-rate profile for kcat and kcat/Km indicated that one group needs to be deprotonated and a second group must be protonated for optimal turnover. Computational docking of high-energy intermediate forms of L/D-Ala-L/D-Ala to the three-dimensional structure of Sco3058 identified the structural determinants for the stereochemical preferences for substrate binding and turnover.
- Cummings, Jennifer A.,Nguyen, Tinh T.,Fedorov, Alexander A.,Kolb, Peter,Xu, Chengfu,Fedorov, Elena V.,Shoichet, Brian K.,Barondeau, David P.,Almo, Steven C.,Raushel, Frank M.
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experimental part
p. 611 - 622
(2011/01/04)
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- Erythrochelin-a hydroxamate-type siderophore predicted from the genome of Saccharopolyspora erythraea
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The class of nonribosomally assembled siderophores encompasses a multitude of structurally diverse natural products. The genome of the erythromycin- producing strain Saccharopolyspora erythraea contains 25 secondary metabolite gene clusters that are mostly considered to be orphan, including two that are responsible for siderophore assembly. In the present study, we report the isolation and structural elucidation of the hydroxamate-type tetrapeptide siderophore erythrochelin, the first nonribosomal peptide synthetase-derived natural product of S. erythraea. In an attempt to substitute the traditional activity assay-guided isolation of novel secondary metabolites, we have employed a dedicated radio-LC-MS methodology to identify nonribosomal peptides of cryptic gene clusters in the industrially relevant strain. This methodology was based on transcriptome data and adenylation domain specificity prediction and resulted in the detection of a radiolabeled ornithine-inheriting hydroxamate-type siderophore. The improvement of siderophore production enabled the elucidation of the overall structure via NMR and MSn analysis and hydrolysate-derivatization for the determination of the amino acid configuration. The sequence of the tetrapeptide siderophore erythrochelin was determined to be d-α-N-acetyl-δ-N-acetyl-δ-N-hydroxyornithine- d-serine-cyclo(l-δ-N-hydroxyornithine-l-δ-N-acetyl-δ-N- hydroxyornithine). The results derived from the structural and functional characterization of erythrochelin enabled the proposal of a biosynthetic pathway. In this model, the tetrapeptide is assembled by the nonribosomal peptide synthetase EtcD, involving unusual initiation-and cyclorelease- mechanisms.
- Robbel, Lars,Knappe, Thomas A.,Linne, Uwe,Xie, Xiulan,Marahiel, Mohamed A.
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experimental part
p. 663 - 676
(2010/12/19)
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- Homophymines B-E and A1-E1, a family of bioactive cyclodepsipeptides from the sponge Homophymia sp.
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Nine new cyclodepsipeptides, homophymines B-E (2-5) and A1-E1 (1a-5a), were isolated from the polar extracts of the sponge Homophymia sp. The new structures, featuring new polyketide-derived end groups, were determined by interpretation of NMR and MS data
- Zampella, Angela,Sepe, Valentina,Bellotta, Filomena,Luciano, Paolo,D'Auria, Maria Valeria,Cresteil, Thierry,Debitus, Cecile,Petek, Sylvain,Poupat, Christiane,Ahond, Alain
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experimental part
p. 4037 - 4044
(2009/12/06)
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- Novel cyclic hexapeptides from marine-derived fungus, aspergillus sclerotiorum PT06-1
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Two novel cyclic hexapeptides containing both anthranilic acid and dehydroamino acid units, sclerotides A (1) and B (2), were isolated from the marine-derived halotolerant Aspergillus sclerotiorum PT06-1 in a nutrient-limited hypersaline medium. Both 1 an
- Zheng, Jinkai,Zhu, Huajie,Hong, Kui,Wang, Yi,Liu, Peipei,Wang, Xin,Peng, Xiaoping,Zhu, Weiming
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supporting information; experimental part
p. 5262 - 5265
(2010/03/24)
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- Occurrence of D-serine in rice and characterization of rice serine racemase
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Germinated, unpolished rice was found to contain a substantial amount of D-serine, with the ratio of the D-enantiomer to the L-enantiomer being higher for serine than for other amino acids. The relative amount of D-serine (D/(D + L)%) reached approximately 10% six days after germination. A putative serine racemase gene (serr, clone No. 001-110-B03) was found in chromosome 4 of the genomic DNA of Oryza sativa L. ssp. Japonica cv. Nipponbare. This was expressed as serr in Escherichia coli and its gene product (SerR) was purified to apparent homogeneity. SerR is a homodimer with a subunit molecular mass of 34.5 kDa, and is highly specific for serine. In addition to a serine racemase reaction, SerR catalyzes D- and L-serine dehydratase reactions, for which the specific activities were determined to be 2.73 and 1.42 nkatal/mg, respectively. The optimum temperature and pH were respectively determined for the racemase reaction (35 °C and pH 9.0) and for the dehydratase reaction (35 °C and pH 9.5). SerR was inhibited by PLP-enzyme inhibitors. ATP decreased the serine racemase activity of SerR but increased the serine dehydratase activity. Kinetic analysis showed that Mg2+ increases the catalytic efficiency of the serine racemase activity of SerR and decreases that of the serine dehydratase activity. Fluorescence-quenching analysis of the tryptophan residues in SerR indicated that the structure of SerR is distorted by the addition of Mg2+, and this structural change probably regulates the two enzymatic activities.
- Gogami, Yoshitaka,Ito, Katsuyoshi,Kamitani, Yuji,Matsushima, Yuki,Oikawa, Tadao
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experimental part
p. 380 - 387
(2009/08/07)
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- Optimization of the kinetic resolution of the DL-phospho-monoesters of threonine and serine by random mutagenesis of the acid phosphatase from Salmonella enterica
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Acid phosphatases are enzymes with a broad substrate specificity showing hydrolytic activity towards several different organic phosphate monoesters, such as nucleotides and sugar phosphates. The acid phosphatase from Salmonella enterica ser. typhimurium LT2 (PhoN-Se) is able to hydrolyze O-phospho-DL-threonine to yield L-threonine with a very high enantioselectivity (E > 200). When O-phospho-DL-serine was hydrolyzed by PhoN-Se, D-serine was formed, however, the ee values rapidly dropped to 50 %. Random mutagenesis by error-prone PCR was performed on the phosphatase in order to increase its enantioselectivity in the formation of D-serine. Two variants with increased selectivity from a library of 9600 mutants have been found, N151D and V78L showing E values of 18.1 and 4.1, respectively, compared to 3.4 for the wild-type (WT) enzyme.
- Van Herk, Teunie,Hartog, Aloysius F.,Ruijssenaars, Harald J.,Kerkman, Richard,Schoemaker, Hans E.,Wever, Ron
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p. 1349 - 1352
(2008/09/16)
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- Relative and absolute configuration of antitumor agent SW-163D
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Our interest on engineering non-ribosomal synthetase responsible for SW-163 biosynthesis prompted us to determine the relative and absolute configuration of antitumor cyclic depsipeptide SW-163s. We first isolated and identified SW-163 homologs D, F and G as known compounds UK-63598, UK-65662 and UK-63052, respectively. Both enantiomers of the unusual constitutive amino acid, N-methylnorcoromic acid, were synthesized in chiral forms starting from (R)- and (S)-1,2-propanediol. The hydrolyzate of SW-163D, a major constituent of this family, was converted with Marfey's reagent, 1-fluoro-2,4-dinitrophenyl-5-L- alanine-amide (L-FDAA), and the resulting mixture of amino acid derivatives was subjected to an LC/MS analysis. Compared with authentic samples, the analytical data unambiguously show that SW-163D consisted of L-Ala, D-Ser and (1S, 2S)-N-methylnorcoronamic acid. The remaining stereochemistry of the N-methylcysteine moieties was determined from NOE data.
- Nakaya, Mino,Oguri, Hiroki,Takahashi, Kosaku,Fukushi, Eri,Watanabe, Kenji,Oikawa, Hideaki
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p. 2969 - 2976
(2008/03/14)
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- Serine racemases from barley, Hordeum vulgare L., and other plant species represent a distinct eukaryotic group: Gene cloning and recombinant protein characterization
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Several d-amino acids have been identified in plants. However, the biosynthetic pathway to them is unclear. In this study, we cloned and sequenced a cDNA encoding a serine racemase from barley which contained an open reading frame encoding 337 amino acid residues. The deduced amino acid sequence showed significant identity to plant and mammalian serine racemases and contained conserved pyridoxal 5-phosphate (PLP)-binding lysine and PLP-interacting amino acid residues. The purified gene product catalyzed not only racemization of serine but also dehydration of serine to pyruvate. The enzyme requires PLP and divalent cations such as Ca2+, Mg2+, or Mn2+, but not ATP, whereas mammalian serine racemase activity is increased by ATP. In addition to the results regarding the effect of ATP on enzyme activity and the phylogenetic analysis of eukaryotic serine racemases, the antiserum against Arabidopsis serine racemase did not form a precipitate with barley and rice serine racemases. This suggests that plant serine racemases represent a distinct group in the eukaryotic serine racemase family and can be clustered into monocot and dicot types.
- Fujitani, Yoshiyuki,Horiuchi, Terumi,Ito, Kazutoshi,Sugimoto, Manabu
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p. 1530 - 1536
(2008/03/17)
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- Molecular and biochemical characterization of a serine racemase from Arabidopsis thaliana
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A cDNA encoding a homolog of mammalian serine racemase, a unique enzyme in eukaryotes, was isolated from Arabidopsis thaliana and expressed in Escherichia coli cells. The gene product, of which the amino acid residues for binding pyridoxal 5′-phosphate (PLP) are conserved in this as well as mammalian serine racemases, catalyzes not only serine racemization but also dehydration of serine to pyruvate. The enzyme is a homodimer and requires PLP and divalent cations, Ca2+, Mg2+, Mn2+, Fe2+, or Ni2+, at alkaline pH for both activities. The racemization process is highly specific toward l-serine, whereas l-alanine, l-arginine, and l-glutamine were poor substrates. The Vmax/Km values for racemase activity of l- and d-serine are 2.0 and 1.4 nmol/mg/min/mM, respectively, and those values for l- and d-serine on dehydratase activity are 13 and 5.3 nmol/mg/min/mM, i.e. consistent with the theory of racemization reaction and the specificity of dehydration toward l-serine. Hybridization analysis showed that the serine racemase gene was expressed in various organs of A. thaliana.
- Fujitani, Yoshiyuki,Nakajima, Nobuyoshi,Ishihara, Koji,Oikawa, Tadao,Ito, Kazutoshi,Sugimoto, Manabu
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p. 668 - 674
(2008/02/11)
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- Preparation of D-amino acids by enzymatic kinetic resolution using a mutant of penicillin-G acylase from E. coli
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We have demonstrated for the first time that d-glutamine (d-Gln) and d-glutamic acid (d-Glu) can be efficiently obtained in high ee (97% and 90%, respectively) by enzymatic kinetic resolution of d,l-Gln and d,l-Glu. This was achieved by enantioselective conversion of the l-enantiomers to their N-phenylacetyl derivatives in aqueous solution, using a mutant of penicillin-G acylase (PGA) from E. coli and phenylacetic acid methylester as the acyl donor. Kinetic modeling studies suggest that the high ee values obtained are both due to a strong enantiopreference for the l-amino acid in the deacylation step of the covalent enzyme intermediate, as well as to completeness of conversion that is transiently obtained as a result of the distinct preference of the mutant PGA for phenylacetic acid methylester over the N-phenylacetyl-l-amino acid product. For the other amino acids tested (Asn, Asp, and Ser), the highest ee values that were obtained for the remaining d-enantiomer are moderate (50-80%) because of lower enantioselectivity in the enzyme deacylation step and due to less complete conversion of the l-amino acid caused by competition for the active site between the acyl donor and the N-phenylacetyl-l-amino acid that is produced. The results demonstrate that the mutated PGA has great potential for the production of optically active D-amino acids by kinetic resolution.
- Carboni, Chiara,Kierkels, Hans G. T.,Gardossi, Lucia,Tamiola, Kamil,Janssen, Dick B.,Quaedflieg, Peter J. L. M.
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p. 245 - 251
(2007/10/03)
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- Convenient method for the kinetic resolution of β-aminoalcohols
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A variety of easily removable protecting groups were tested in the kinetic resolution of N-protected β-aminoalcohols using chiral catalysts derived from N-4′-pyridinyl-α-methyl proline. The trifluoroacetyl group was the most promising protecting group as it gave the highest selectivities with all alcohols tested and can easily be removed without loss of enantiomeric excess. This strategy constitutes a convenient method for the kinetic resolution of β-aminoalcohols.
- Pelotier, Béatrice,Priem, Ghislaine,Macdonald, Simon J.F.,Anson, Mike S.,Upton, Richard J.,Campbell, Ian B.
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p. 9005 - 9007
(2007/10/03)
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- Enantioselective synthesis of both enantiomers of 2-amino-2-(2-furyl)ethan-1-ol as a flexible building block for the preparation of serine and azasugars
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The selective conversion of 1-(2-furyl)-2-hydroxyethan-1-one and ethyl 2-(2-furyl)-2-oxo acetate into (E)- and (Z)-oximes and oxime ethers followed by oxazaborolidine-catalyzed enantioselective reduction using different amino alcohols furnished both enantiomers of the important chiral building block 2-amino-2-(2-furyl)ethan-1-ol with an ee of up to 96%.
- Demir, Ayhan S.,Sesenoglu, Oezge,Aksoy-Cam, Hilal,Kaya, Handan,Aydogan, Kenan
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p. 1335 - 1340
(2007/10/03)
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- The origin of chemical and configurational stability of chiral nonracemic tert-butyl aziridinecarboxylate anions
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The origin of good chemical and configurational stability of aziridine ester anions derived from (R)-(-)-phenylglycinol has been investigated. Kinetic acidity seems to play an important role in the deprotonation step and chemical stability of the anionic species. Spectroscopic investigations showed that the good overall retention of configuration was governed by the directing effect of the nitrogen atom, which acts as a stereogenic centre in the alkylation step of the enolate intermediate.
- Alezra, Valerie,Bonin, Martine,Micouin, Laurent,Policar, Clotilde,Husson, Henri-Philippe
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p. 2589 - 2594
(2007/10/03)
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- Compounds for and methods of inhibiting matrix metalloproteinases
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The present invention relates to compounds of Formula I that inhibit matrix metalloproteinases and to a method of inhibiting matrix metalloproteinases using the compounds More particularly, the present invention relates to a method of treating diseases in which matrix metalloproteinases are involved such as multiple sclerosis, atherosclerotic plaque rupture, restenosis, aortic aneurysm, heart failure, periodontal disease, corneal ulceration, burns, decubital ulcers, chronic ulcers or wounds, cancer metastasis, tumor angiogenesis, osteoporosis, rheumatoid or osteoarthritis, renal disease, left ventricular dilatation, or other autoimmune or inflammatory diseases dependent upon tissue invasion by leukocytes.
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- Enantioselective synthesis of α-amino acids and monosubstituted 1,2- diamines by conjugate addition of 4-phenyl-2-oxazolidinone to nitroalkenes
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The addition of the potassium salt of (R)- or (S)-4-phenyl-2- oxazolidinone to monosubstituted nitroalkenes proceeded with very good diastereoselectivity. Several of the addition products were converted into α-amino acids and monosubstituted 1,2-diamines of high enantiomeric purity.
- Lucet, Denis,Sabelle, Stephane,Kostelitz, Olivier,Le Gall, Thierry,Mioskowski, Charles
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p. 2583 - 2591
(2007/10/03)
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- Reversal of Regioselection in the Sharpless Asymmetric Aminohydroxylation of Aryl Ester Substrates
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(Matrix Presented) The asymmetric synthesis of β-hydroxy-α-amino acids is reported which relies on the use of α,β-unsaturated aryl ester substrates and the dihydroquinyl alkaloid ligand system (DHQ)2-AQN to control the regio- and enantioselectivity of the asymmetric aminohydroxylation (AA) process. α,β-Unsaturated ester substrates of type 1 have a significant effect on the substrate - ligand recognition event which results in a reversal of regioselectivity in the AA reaction.
- Morgan, Adam J.,Masse, Craig E.,Panek, James S.
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p. 1949 - 1952
(2008/02/11)
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