- Polyketides, diketopiperazines and an isochromanone from the marine-derived fungal strain Fusarium graminearum FM1010 from Hawaii
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The fungal strain Fusarium graminearum FM1010 was isolated from a shallow-water volcanic rock known as “live rock” at the Carl Smith Beach, Hilo, Hawaii. Eleven specialised metabolites, including two undescribed diketopiperazines, three undescribed polyketides, and one undescribed isochromanone, along with five known fusarielin derivatives were obtained from F. graminearum FM1010. The structures of the six undescribed compounds were elucidated by extensive analysis of NMR spectroscopy, HRESIMS, chemical reactions, and electronic circular dichroism (ECD) data. Kaneoheoic acids G-I showed mild inhibitory activity against S. aureus with the MIC values in the range of 20–40 μg/mL when assayed in combination with chloramphenicol (half of the MIC, 1 μg/mL), an FDA approved antibiotic. Kaneoheoic acid I exhibited both anti-proliferative activity against ovarian cancer cell line A2780 and TNF-α induced NF-κB inhibitory activity with the IC50 values of 18.52 and 15.86 μM, respectively.
- Cao, Shugeng,Sarotti, Ariel M.,Uz Zaman, KH Ahammad,Wu, Xiaohua
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- Single-Cell-Based Screening and Engineering of d -Amino Acid Amidohydrolases Using Artificial Amidophenol Substrates and Microbial Biosensors
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Enantiomerically pure d-amino acids are important intermediates as chiral building blocks for peptidomimetics and semisynthetic antibiotics. Here, a transcriptional factor-based screening strategy was used for the rapid screening of d-stereospecific amino acid amidase via an enzyme-specific amidophenol substrate. We used a d-threonine amidophenyl derivative to produce 2-aminophenol that serves as a putative enzyme indicator in the presence of d-threonine amidases. Comparative analyses of known bacterial species indicated that several Bacillus strains produce amidase and form putative indicators in culture media. The estimated amidase was cloned and subjected to rapid directed evolution through biosensor cells. Consequently, we characterized the F119A mutation that significantly improved the catalytic activity toward d-alanine, d-threonine, and d-glutamate. Its beneficial effects were confirmed by higher conversions and recurrent applications of the mutant enzyme, compared to the wild-type. This study showed that rapid directed evolution with biosensors coupled to designed substrates is useful to develop biocatalytic processes.
- An, Jung-Ung,Kim, Haseong,Kwon, Kil Koang,Lee, Dae-Hee,Lee, Hyewon,Lee, Jin-Young,Lee, Seung-Goo,Park, Sung Hyun,Rha, Eugene,Yeom, Soo-Jin
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p. 1203 - 1211
(2022/01/27)
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- Structures and antitumor activities of ten new and twenty known surfactins from the deep-sea bacterium Limimaricola sp. SCSIO 53532
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Surfactins are natural biosurfactants with myriad potential applications in the areas of healthcare and environment. However, surfactins were almost exclusively produced by the bacterium Bacillus species in previous reported literatures, together with difficulty in isolating pure monomer, which resulted in making extensive effort to remove duplication and little discovery of new surfactins in recent years. In the present study, the result of Molecular Networking indicated that Limimaricola sp. SCSIO 53532 might well be a potential resource for surfacin-like compounds based on OSMAC strategy. To search for new surfactins with significant biological activity, further study was undertaken on the strain. As a result, ten new surfactins (1–10), along with twenty known surfactins (11–30), were isolated from the ethyl acetate extract of SCSIO 53532. Their chemical structures were established by detailed 1D and 2D NMR spectroscopy, HRESIMS data, secondary ion mass spectrometry (MS/MS) analysis, and chemical degradation (Marfey's method) analysis. Cytotoxic activities of twenty-seven compounds against five human tumor cell lines were tested, and five compounds showed significant antitumor activities with IC50 values less than 10 μM. Furtherly, analysis of structure–activity relationships revealed that the branch of side chain, the esterification of Glu or Asp residue, and the amino acid residue of position 7 possessed a great influence on antitumor activity.
- Chen, Min,Chen, Rouwen,Ding, Wenping,Li, Yanqun,Tian, Xinpeng,Yin, Hao,Zhang, Si
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- Enhanced carboxypeptidase efficacies and differentiation of peptide epimers
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Carboxypeptidases enzymatically cleave the peptide bond of C-terminal amino acids. In humans, it is involved in enzymatic synthesis and maturation of proteins and peptides. Carboxypeptidases A and Y have difficulty hydrolyzing the peptide bond of dipeptides and some other amino acid sequences. Early investigations into different N-blocking groups concluded that larger moieties increased substrate susceptibility to peptide bond hydrolysis with carboxypeptidases. This study conclusively demonstrates that 6-aminoquinoline-N-hydroxysuccimidyl carbamate (AQC) as an N-blocking group greatly enhances substrate hydrolysis with carboxypeptidase. AQC addition to the N-terminus of amino acids and peptides also improves chromatographic peak shapes and sensitivities via mass spectrometry detection. These enzymes have been used for amino acid sequence determination prior to the advent of modern proteomics. However, most modern proteomic methods assume that all peptides are comprised of L-amino acids and therefore cannot distinguish L-from D-amino acids within the peptide sequence. The majority of existing methods that allow for chiral differentiation either require synthetic standards or incur racemization in the process. This study highlights the resistance of D-amino acids within peptides to enzymatic hydrolysis by Carboxypeptidase Y. This stereoselectivity may be advantageous when screening for low abundance peptide stereoisomers.
- Sung, Yu-Sheng,Putman, Joshua,Du, Siqi,Armstrong, Daniel W.
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- Cyclic Tetrapeptides with Synergistic Antifungal Activity from the Fungus Aspergillus westerdijkiae Using LC-MS/MS-Based Molecular Networking
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Fungal natural products play a prominent role in the development of pharmaceuticalagents. Two new cyclic tetrapeptides (CTPs), westertide A (1) and B (2), with eight known compounds (3-10) were isolated from the fungus Aspergillus westerdijkiae guided by
- Chen, Baosong,Dai, Huanqin,Han, Junjie,Li, Erwei,Liu, Hongwei,Lyu, Zhitang,Song, Fuhang,Sun, Jingzu,Wang, Hanying,Wang, Tao,Wang, Wenzhao,Zhang, Rui
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- Inherently chiral dialkyloxy-calix[4]arene acetic acids as enantiodiscriminating additives for high-performance liquid chromatography separation of d,l-amino acids
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Inherently chiral dialkyloxy-calix[4]arene acetic acids with asymmetric placement of substituents on the lower rim of the macrocycle were first studied as enantiodiscriminating additives to the mobile phase MeCN/H2O/HCOOH (75/25/0.02 by volume) in the high-performance liquid chromatography (HPLC) separation of d,l-alanine and d,l-valine on the achiral stationary phase ZORBAX Original CN. The dependence of enantio-binding properties on the position of alkyl groups is demonstrated. The highest resolution (1.65) and enantioselectivity (1.80) were obtained for the 1,2-dipropyloxy-calix[4]arene acetic acid.
- Kalchenko, Olga I.,Trybrat, Oleksandr O.,Yesypenko, Oleksandr A.,Dyakonenko, Viktoriya V.,Shishkina, Svitlana V.,Kalchenko, Vitali I.
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p. 722 - 730
(2021/08/26)
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- Direct monitoring of biocatalytic deacetylation of amino acid substrates by1H NMR reveals fine details of substrate specificity
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Amino acids are key synthetic building blocks that can be prepared in an enantiopure form by biocatalytic methods. We show that thel-selective ornithine deacetylase ArgE catalyses hydrolysis of a wide-range ofN-acyl-amino acid substrates. This activity was revealed by1H NMR spectroscopy that monitored the appearance of the well resolved signal of the acetate product. Furthermore, the assay was used to probe the subtle structural selectivity of the biocatalyst using a substrate that could adopt different rotameric conformations.
- De Cesare, Silvia,McKenna, Catherine A.,Mulholland, Nicholas,Murray, Lorna,Bella, Juraj,Campopiano, Dominic J.
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supporting information
p. 4904 - 4909
(2021/06/16)
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- Simultaneous Preparation of (S)-2-Aminobutane and d -Alanine or d -Homoalanine via Biocatalytic Transamination at High Substrate Concentration
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(S)-2-Aminobutane, d-alanine, and d-homoalanine are important intermediates for the production of various active pharmaceutical ingredients and food additives. The preparation of these small chiral amine or amino acids with high water solubility still demands searching for efficient methods. In this work, we identified an ω-transaminase (ω-TA) from Sinirhodobacter hungdaonensis (ShdTA) that catalyzed the kinetic resolution of racemic 2-aminobutane at a concentration of 800 mM using pyruvate as the amino acceptor, leading to the simultaneous isolation of enantiopure (S)-2-aminobutane and d-alanine in 46% and 90% yield, respectively. In addition, (S)-2-aminobutane (98% ee) and d-homoalanine (99% ee) were isolated in 45% and 93% yield, respectively, in the kinetic resolution of racemic 2-aminobutane at a concentration of 400 mM coupled with deamination of l-threonine by threonine deaminase. We thus developed a biocatalytic process for the practical synthesis of these valuable small chiral amine and d-amino acids.
- Li, Jianjiong,Wang, Yingang,Wu, Qiaqing,Yao, Peiyuan,Yu, Shanshan,Zhu, Dunming
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supporting information
(2022/03/01)
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- A new amide from the marine sponge Haliclona baeri
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A new amide, baeriamide (1), along with nine known diketopiperazines (2-10), was isolated from the marine sponge Haliclona baeri. Their structures were identified by the means of UV, IR, MS and NMR. The absolute configuration of 1 was established by Marfey’s method and comparing the specific optical rotation with the known compound HCO-Val-Gly methyl ester. Compound 1 was derived from dehydration of formylated L-valine with γ-amino-butanoic acid methyl ester. Compounds 2-10 were isolated from the genus of Haliclona for the first time. The absolute confirmation of 7 was confirmed first by the means of single-crystal X-ray diffraction. The cytotoxic, antibacterial, antiviral and antifouling activities of these compounds were also tested. However, none of them exhibited significant bioactivities.
- Cui, Le-Zhi,Lei, Yu,Liao, Xiao-Jian,Wang, Can-Bin,Xiao, Yan-Fang,Xu, Jia-Yi,Xu, Shi-Hai,Zhao, Bing-Xin
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supporting information
(2021/07/06)
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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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- Rational engineering ofAcinetobacter tandoiiglutamate dehydrogenase for asymmetric synthesis ofl-homoalanine through biocatalytic cascades
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l-Homoalanine, a useful building block for the synthesis of several chiral drugs, is generally synthesized through biocascades using natural amino acids as cheap starting reactants. However, the addition of expensive external cofactors and the low efficiency of leucine dehydrogenases towards the intermediate 2-ketobutyric acid are two major challenges in industrial applications. Herein, a dual cofactor-dependent glutamate dehydrogenase fromAcinetobacter tandoii(AtGluDH) was identified to help make full use of the intracellular pool of cofactors when using whole-cell catalysis. Through reconstruction of the hydrophobic network between the enzyme and the terminal methyl group of the substrate 2-ketobutyric acid, the strict substrate specificity ofAtGluDH towards α-ketoglutarate was successfully changed, and the activity obtained by the most effective mutant (K76L/T180C) was 17.2 times higher than that of the wild-type protein. A three-enzyme co-expression system was successfully constructed in order to help release the mass transfer restriction. Using 1 Ml-threonine, which is close to the solubility limit, we obtained a 99.9% yield ofl-homoalanine in only 3.5 h without adding external coenzymes to the cascade, giving 99.9% ee and a 29.2 g L?1h?1space-time yield. Additionally, the activities of the engineeredAtGluDH towards some other hydrophobic amino acids were also improved to 1.1-11.2 fold. Therefore, the engineering design of some dual cofactor-dependent GluDHs could not only eliminate the low catalytic activity of unnatural substrates but also enhance the cofactor utilization efficiency of these enzymes in industrial applications.
- Diao, Shiqing,Jiang, Shuiqin,Liu, Yan,Sun, Yangyang,Wang, Hualei,Wang, Liuzhu,Wei, Dongzhi
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p. 4208 - 4215
(2021/06/30)
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- Isolation, Structure Determination, and Total Synthesis of Hoshinoamide C, an Antiparasitic Lipopeptide from the Marine Cyanobacterium Caldora penicillata
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Hoshinoamide C (1), an antiparasitic lipopeptide, was isolated from the marine cyanobacterium Caldora penicillata. Its planar structure was elucidated by spectral analyses, mainly 2D NMR, and the absolute configurations of the α-amino acid moieties were determined by degradation reactions followed by chiral-phase HPLC analyses. To clarify the absolute configuration of an unusual amino acid moiety, we synthesized two possible diastereomers of hoshinoamide C and determined its absolute configuration based on a comparison of their spectroscopic data with those of the natural compound. Hoshinoamide C (1) did not exhibit any cytotoxicity against HeLa or HL60 cells at 10 μM, but inhibited the growth of the parasites responsible for malaria (IC50 0.96 μM) and African sleeping sickness (IC50 2.9 μM).
- Iwasaki, Arihiro,Ohtomo, Keisuke,Kurisawa, Naoaki,Shiota, Ikuma,Rahmawati, Yulia,Jeelani, Ghulam,Nozaki, Tomoyoshi,Suenaga, Kiyotake
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p. 126 - 135
(2021/01/13)
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- Leveraging Peptaibol Biosynthetic Promiscuity for Next-Generation Antiplasmodial Therapeutics
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Malaria remains a worldwide threat, afflicting over 200 million people each year. The emergence of drug resistance against existing therapeutics threatens to destabilize global efforts aimed at controlling Plasmodium spp. parasites, which is expected to leave vast portions of humanity unprotected against the disease. To address this need, systematic testing of a fungal natural product extract library assembled through the University of Oklahoma Citizen Science Soil Collection Program has generated an initial set of bioactive extracts that exhibit potent antiplasmodial activity (EC50 25 μM, selectivity index > 250). The unique chemodiversity afforded by these fungal isolates serves to unlock new opportunities for translating peptaibols into a bioactive scaffold worthy of further development.
- Lee, Jin Woo,Collins, Jennifer E.,Wendt, Karen L.,Chakrabarti, Debopam,Cichewicz, Robert H.
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supporting information
p. 503 - 517
(2021/03/01)
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- Genomics-driven discovery of a new cyclodepsipeptide from the guanophilic fungusAmphichorda guana
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Two potential non-ribosomal peptide synthetases (NRPSs) were identified in the genome of a guanophilic fungusAmphichorda guanaby bioinformatics analysis and gene knockout experiments. Liquid chromatography coupled with mass spectrometry (LC-MS) guided isolation led to the discovery of a new cyclodepsipeptide isaridin H (1) and seven known analogs, desmethylisaridin E (2), isaridin E (3), isariin A (4), iso-isariin B (5), iso-isariin D (6), isariin E (7), and nodupetide (8). The absolute configuration of isaridin H (1) was achieved by Marfey's method. Isaridin H (1) showed significant antifungal activity againstBotrytis cinereaandAlternaria solani.
- Liang, Min,Lyu, Hai-Ning,Ma, Zi-Ying,Li, Er-Wei,Cai, Lei,Yin, Wen-Bing
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p. 1960 - 1964
(2021/03/16)
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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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- Komesuamide and odopenicillatamide, two linear lipopeptides from the marine cyanobacterium Caldora penicillata
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The linear lipopeptides komesuamide (1) and odopenicillatamide (2) were isolated from Caldora penicillata a marine cyanobacterium collected in Okinawa. The structures of these compounds were established by spectroscopic analyses, and the absolute configurations were determined by HPLC analyses of the acid hydrolysates. Both compounds showed glucose uptake activity at 40 μM in cultured L6 myotubes.
- Ozaki, Kaori,Jinno, Atsuhide,Natsume, Noriyuki,Sumimoto, Shimpei,Iwasaki, Arihiro,Suenaga, Kiyotake,Teruya, Toshiaki
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- Structure revision of isocereulide A, an isoform of the food poisoning emetic Bacillus cereus toxin cereulide
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The emetic Bacillus cereus toxin cereulide presents an enormous safety hazard in the food industry, inducing emesis and nausea after the consumption of contaminated foods. Additional to cereulide itself, seven structurally related isoforms, namely the isocereulides A-G, have already been elucidated in their chemical structure and could further be identified in B. cereus contaminated food samples. The newly performed isolation of isocereulide A allowed, for the first time, 1D- and 2D-NMR spectroscopy of a biosynthetically produced isocereulide, revealing results that contradict previous assumptions of an L-O-Leu moiety within its chemical structure. By furthermore applying posthydrolytical dipeptide analysis, amino acid and α-hydroxy acid analysis by means of UPLC-ESITOF- MS, as well as MSn sequencing, the structure of previously reported isocereulide A could be corrected. Instead of the L-O-Leu as assumed to date, one L-O-Ile unit could be verified in the cyclic dodecadepsipeptide, revising the structure of isocereulide A to [(D-O-Leu-D-Ala-L-O-Val-L-Val)2(DO- Leu-D-Ala-L-O-Ile-L-Val)].
- Ehling-Schulz, Monika,Hofmann, Thomas F.,Kranzler, Markus,Stark, Timo D.,Walser, Veronika
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supporting information
(2021/05/31)
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- Motobamide, an Antitrypanosomal Cyclic Peptide from a Leptolyngbya sp. Marine Cyanobacterium
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Motobamide (1), a new cyclic peptide containing a C-prenylated cyclotryptophan residue, was isolated from a marine Leptolyngbya sp. cyanobacterium. Its planar structure was established by spectroscopic and MS/MS analyses. The absolute configuration was elucidated based on a combination of chemical degradations, chiral-phase HPLC analyses, spectroscopic analyses, and computational chemistry. Motobamide (1) moderately inhibited the growth of bloodstream forms of Trypanosoma brucei rhodesiense (IC50 2.3 μM). However, it exhibited a weaker cytotoxicity against normal human cells (IC50 55 μM).
- Iwasaki, Arihiro,Jeelani, Ghulam,Kurisawa, Naoaki,Matsubara, Teruhiko,Nozaki, Tomoyoshi,Sato, Toshinori,Suenaga, Kiyotake,Suzuki, Ryota,Takahashi, Hiroki
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p. 1649 - 1655
(2021/05/29)
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- Argicyclamides A-C Unveil Enzymatic Basis for Guanidine Bis-prenylation
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Guanidine prenylation is an outstanding modification in alkaloid and peptide biosynthesis, but its enzymatic basis has remained elusive. We report the isolation of argicyclamides, a new class of cyanobactins with unique mono- and bis-prenylations on guanidine moieties, from Microcystis aeruginosa NIES-88. The genetic basis of argicyclamide biosynthesis was established by the heterologous expression and in vitro characterization of biosynthetic enzymes including AgcF, a new guanidine prenyltransferase. This study provides important insight into the biosynthesis of prenylated guanidines and offers a new toolkit for peptide modification.
- Balloo, Nandani,Fujita, Kei,Matsuda, Kenichi,Okino, Tatsufumi,Phan, Chin-Soon,Wakimoto, Toshiyuki
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supporting information
p. 10083 - 10087
(2021/07/26)
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- Method for photolysis of amido bonds
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The invention discloses a method for photo-splitting amido bonds, wherein the method is mild in reaction condition and can realize splitting of amido bonds by using illumination. The method for photo-splitting the amido bonds comprises the following steps: reacting 2,4-dinitrofluorobenzene with an amino group of a substance which contains alpha amino acid at the tail end and is shown as a structural formula I to generate a compound 1 represented by a structural formula II; and under light irradiation, carrying out amido bond cleavage reaction on the compound 1, wherein R1 is a side chain group of alpha-amino acid, and R2 is aryl, aliphatic hydrocarbon, -CH(R)-COOH or polypeptide.
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Paragraph 0046; 0048-0049; 0102-0105
(2021/06/26)
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- Powerful Steroid-Based Chiral Selector for High-Throughput Enantiomeric Separation of α-Amino Acids Utilizing Ion Mobility-Mass Spectrometry
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Stereospecific recognition of amino acids (AAs) plays a crucial role in chiral biomarker-based diagnosis and prognosis. Separation of AA enantiomers is a long and tedious task due to the requirement of AA derivatization prior to the chromatographic or electrophoretic steps which are also time-consuming. Here, a mass-tagged chiral selector named [d0]/[d5]-estradiol-3-benzoate-17β-chloroformate ([d0]/[d5]-17β-EBC) with high reactivity and good enantiomeric resolution in regard to AAs was developed. After a quick and easy chemical derivatization step of AAs using 17β-EBC as the single chiral selector before ion mobility-mass spectrometry analysis, good enantiomer separation was achieved for 19 chiral proteinogenic AAs in a single analytical run (~2 s). A linear calibration curve of enantiomeric excess was also established using [d0]/[d5]-17β-EBC. It was demonstrated to be capable of determining enantiomeric ratios down to 0.5% in the nanomolar range. 17β-EBC was successfully applied to investigate the absolute configuration of AAs among peptide drugs and detect trace levels of-AAs in complex biological samples. These results indicated that [d0]/[d5]-17β-EBC may contribute to entail a valuable step forward in peptide drug quality control and discovering chiral disease biomarkers.
- Li, Yuling,Zhou, Bowen,Wang, Keke,Zhang, Jing,Sun, Wenjian,Zhang, Li,Guo, Yinlong
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p. 13589 - 13596
(2021/10/21)
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- Semi-rational hinge engineering: modulating the conformational transformation of glutamate dehydrogenase for enhanced reductive amination activity towards non-natural substrates
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The active site is the common hotspot for rational and semi-rational enzyme activity engineering. However, the active site represents only a small portion of the whole enzyme. Identifying more hotspots other than the active site for enzyme activity engineering should aid in the development of biocatalysts with better catalytic performance. Glutamate dehydrogenases (GluDHs) are promising and environmentally benign biocatalysts for the synthesis of valuable chirall-amino acids by asymmetric reductive amination of α-keto acids. GluDHs contain an inter-domain hinge structure that facilitates dynamic reorientations of the domains relative to each other. Such hinge-bending conformational motions of GluDHs play an important role in regulating the catalytic activity. Thus, the hinge region represents a potential hotspot for catalytic activity engineering for GluDHs. Herein, we report semi-rational activity engineering of GluDHs with the hinge region as the hotspot. Mutants exhibiting significantly improved catalytic activity toward several non-natural substrates were identified and the highest activity increase reached 104-fold. Molecular dynamics simulations revealed that enhanced catalytic activity may arise from improving the open/closed conformational transformation efficiency of the protein with hinge engineering. In the batch production of three valuablel-amino acids, the mutants exhibited significantly improved catalytic efficiency, highlighting their industrial potential. Moreover, the catalytic activity of several active site tailored GluDHs was also increased by hinge engineering, indicating that hinge and active site engineering are compatible. The results show that the hinge region is a promising hotspot for activity engineering of GluDHs and provides a potent alternative for developing high-performance biocatalysts toward chirall-amino acid production.
- Liu, Yayun,Meng, Lijun,Wu, Jianping,Yang, Lirong,Yin, Xinjian,Zhou, Haisheng
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p. 3376 - 3386
(2020/06/09)
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- Bioelectrocatalytic Conversion from N2 to Chiral Amino Acids in a H2/α-Keto Acid Enzymatic Fuel Cell
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Enzymatic electrosynthesis is a promising approach to produce useful chemicals with the requirement of external electrical energy input. Enzymatic fuel cells (EFCs) are devices to convert chemical energy to electrical energy via the oxidation of fuel at the anode and usually the reduction of oxygen or peroxide at the cathode. The integration of enzymatic electrosynthesis with EFC architectures can simultaneously result in self-powered enzymatic electrosynthesis with more valuable usage of electrons to produce high-value-added chemicals. In this study, a H2/α-keto acid EFC was developed for the conversion from chemically inert nitrogen gas to chiral amino acids, powered by H2 oxidation. A highly efficient cathodic reaction cascade was first designed and constructed. Powered by an applied voltage, the cathode supplied enough reducing equivalents to support the NH3 production and NADH recycling catalyzed by nitrogenase and diaphorase. The produced NH3 and NADH were reacted in situ with leucine dehydrogenase (LeuDH) to generate l-norleucine with 2-ketohexanoic acid as the NH3 acceptor. A 92% NH3 conversion ratio and 87.1% Faradaic efficiency were achieved. On this basis, a H2-powered fuel cell with hyper-thermostable hydrogenase (SHI) as the anodic catalyst was combined with the cathodic reaction cascade to form the H2/α-keto acid EFC. After 10 h of reaction, the concentration of l-norleucine achieved 0.36 mM with >99% enantiomeric excess and 82% Faradaic efficiency. From the broad substrate scope and the high enzymatic enantioselectivity of LeuDH, the H2/α-keto acid EFC is an energy-efficient alternative to electrochemically produce chiral amino acids for biotechnology applications.
- Cai, Rong,Chen, Hsiaonung,Chen, Hui,Dong, Fangyuan,Minteer, Shelley D.,Prater, Matthew B.
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supporting information
p. 4028 - 4036
(2020/03/11)
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- Krisynomycins, Imipenem Potentiators against Methicillin-Resistant Staphylococcus aureus, Produced by Streptomyces canus
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A reinvestigation of the acetone extract of the strain CA-091830 of Streptomyces canus, producer of the imipenem potentiator krisynomycin, resulted in the isolation of two additional analogues, krisynomycins B (1) and C (2), with different chlorination patterns. Genome sequencing of the strain followed by detailed bioinformatics analysis led to the identification of the corresponding biosynthetic gene cluster (BGC) of this cyclic nonribosomal peptide family. The planar structure of the new molecules was determined using HRMS, ESI-qTOF-MS/MS, and 1D and 2D NMR data. Their absolute configuration was proposed using a combination of Marfey's and bioinformatic BGC analyses. The krisynomycins displayed weak to negligible antibiotic activity against methicillin-resistant Staphylococcus aureus (MRSA), which was significantly enhanced when tested in combination with sublethal concentrations of imipenem. The halogenation pattern plays a key role in the antimicrobial activity and imipenem-potentiating effects of the compounds, with molecules having a higher number of chlorine atoms potentiating the effect of imipenem at lower doses.
- De La Cruz, Mercedes,Genilloud, Olga,González, Ignacio,Martín, Jesús,Oves-Costales, Daniel,Pérez-Bonilla, Mercedes,Reyes, Fernando,Vicente, Francisca
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p. 2597 - 2606
(2020/10/12)
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- Homogeneous palladium-catalyzed enantioselective hydrogenation of 5-methylenhydantoin for the synthesis of L-Valine
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In this article, we present the development of a synthetic methodology based on homogeneous catalysis for the preparation of enantioenriched L-Valine aminoacid. The enantioselective hydrogenation of 5-methylenhydantoin has been developed through broad screenings of chiral ligands, metal precursors and reaction conditions including scale-up experiments and recyclability studies. A palladium catalyzed asymmetric hydrogenation of 5-methylenhydantoin afforded the corresponding hydrogenated product in a 70% enantiomeric excess using a substrate/catalyst ratio of 500/1. A partial racemization was observed upon hydrolysis and recovery of L-Valine.
- Agbossou-Niedercorn, Francine,Bellière-Baca, Virginie,Hayouni, Safa,Michon, Christophe,Morvan, Didier
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supporting information
(2020/10/18)
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- Exploration of Transaminase Diversity for the Oxidative Conversion of Natural Amino Acids into 2-Ketoacids and High-Value Chemicals
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The use of 2-ketoacids is very common in feeds, food additives, and pharmaceuticals, and 2-ketoacids are valuable precursors for a plethora of chemically diverse compounds. Biocatalytic synthesis of 2-ketoacids starting from l-amino acids would be highly desirable because the substrates are readily available from biomass feedstock. Here, we report bioinformatic exploration of a series of aminotransferases (ATs) to achieve the desired conversion. Thermodynamic control was achieved by coupling an l-glutamate oxidation reaction in the cascade for the recycling of the amine acceptor. These enzymes were able to convert a majority of proteinogenic amino acids into the corresponding 2-ketoacids with high conversion (up to 99percent) and atom-efficiency. Furthermore, this enzyme cascade was extendable, and one-pot two-step processes were established for the synthesis of d-amino acids and N-methylated amino acids, achieving great overall conversion (up to 99percent) and high ee values (>99percent). These developed enzymatic methodologies offer convenient routes for utilizing amino acids as synthetic reagents.
- Chen, Yanchun,Cui, Xuexian,Cui, Yinglu,Li, Chuijian,Li, Ruifeng,Li, Tao,Sun, Jinyuan,Wu, Bian,Zhu, Tong
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p. 7950 - 7957
(2020/08/21)
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- Highly Efficient Synthesis of Amino Acids by Amination of Bio-Derived Hydroxy Acids with Ammonia over Ru Supported on N-Doped Carbon Nanotubes
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The amino acids have extensive applications, and their productions from biomass-derived feedstocks are very attractive. In this work, the synthesis of amino acids by amination of bio-derived hydroxy acids with ammonia over different metallic nano-catalysts supported on various supports is studied. It is found that Ru nano-catalysts on the nitrogen-doped carbon nanotubes (Ru/N?CNTs) have an outstanding performance for the reaction. Different hydroxy acids can be catalytically converted into the corresponding amino acids with yields up to 70.0 % under mild conditions, which is higher than those reported. The reasons for the high efficiency of the catalyst are investigated, and the reaction pathway is proposed on the basis of control experiments.
- Xie, Zhenbing,Chen, Bingfeng,Peng, Fangfang,Liu, Mingyang,Liu, Huizhen,Yang, Guanying,Han, Buxing
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p. 5683 - 5689
(2020/09/21)
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- Iheyamides A-C, Antitrypanosomal Linear Peptides Isolated from a Marine Dapis sp. Cyanobacterium
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Iheyamides A (1), B (2), and C (3), new linear peptides, were isolated from a marine Dapis sp. cyanobacterium. Their structures were elucidated by spectroscopic analyses and degradation reactions. Iheyamide A (1) showed moderate antitrypanosomal activities against Trypanosoma brucei rhodesiense and Trypanosoma brucei brucei (IC50 = 1.5 μM), but the other two analogues, iheyamides B (2) and C (3), did not (IC50 > 20 μM, respectively). The structure-activity relationship clarified that an isopropyl-O-Me-pyrrolinone moiety was necessary for the antitrypanosomal activity. Furthermore, the cytotoxicity of 1 against normal human cells, WI-38, was 10 times weaker than its antitrypanosomal activity (IC50 = 18 μM).
- Kurisawa, Naoaki,Iwasaki, Arihiro,Jeelani, Ghulam,Nozaki, Tomoyoshi,Suenaga, Kiyotake
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p. 1684 - 1690
(2020/06/08)
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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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- Highly Diastereoselective Metal-Free Catalytic Synthesis of Drug-Like Spiroimidazolidinone
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A four-step procedure has been developed for the synthesis of (S)-3-isopropyl-1-[(R)-1-phenylethyl)- 1,4-diazaspiro[4.5]decan-2-one with high diastereoselectivity (up to 95% de) from (S)-α-aminoisovaleric acid (L-valine). Quantum chemical computations of the synthesized compound have been performed using Gaussian 09 software package.
- Jassem,Raheemah,Radhi,Alid,Jaber
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p. 1598 - 1603
(2019/12/28)
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- Chemical structure of cichorinotoxin, a cyclic lipodepsipeptide that is produced by Pseudomonas cichorii and causes varnish spots on lettuce
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Pseudomonas cichorii, which causes varnish spots on lettuce and seriously damages lettuce production during the summer season in the highland areas of Japan (e.g., Nagano and Iwate prefectures) was isolated. The structure of a toxin produced by this organism was analyzed based on the detailed evaluation of its 2D NMR and FABMS spectra, and this compound has not been reported previously. We propose the name cichorinotoxin for this toxin. In conjunction with the D or L configurations of each amino acid, which were determined by Marfey’s method, we propose the structure of cichorinotoxin to be as follows: 3-hydroxydecanoyl-(Z)-dhThr1-D-Pro2-D-Ala3-D-Ala4-D-Ala5-D-Val6-D-Ala7-(Z)-dhThr8-Ala9-Val10-D-Ile11-Ser12-Ala13-Val14-Ala15-Val16-(Z)-dhThr17-D-alloThr18-Ala19-L-Dab20-Ser21-Val22, and an ester linkage is present between D-alloThr18 and Val22 (dhThr: 2-aminobut-2-enoic acid; Dab: 2,4-diaminobutanoic acid). Thus, the toxin is a lipodepsipeptide with 22 amino acids. The mono- and tetraacetate derivatives and two alkaline hydrolysates, compounds A and B, were prepared. We discuss here the structure–activity relationships between the derivatives and their necrotic activities toward lettuce.
- Komatsu, Hidekazu,Shirakawa, Takashi,Uchiyama, Takeo,Hoshino, Tsutomu
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p. 299 - 309
(2019/02/20)
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- Artificial Biocatalytic Cascade with Three Enzymes in One Pot for Asymmetric Synthesis of Chiral Unnatural Amino Acids
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Two biocatalytic reactions, transamination catalyzed by transaminases and reductive amination catalyzed by amino acid dehydrogenases, can be used for asymmetric synthesis of optically pure unnatural amino acids. However, although transaminases show a great diversity and broad substrate spectrum, most transaminase reactions are reversible, while amino acid dehydrogenases catalyze reductive amination irreversibly but with strict substrate specificity. Accordingly, herein we developed a tri-enzyme one-pot reaction system to exploit the respective advantages of transaminases and amino acid dehydrogenases, while overcoming the disadvantages of each. In this work, representatives of all four subgroups of transaminases coupled with different amino acid dehydrogenases to produce five l- and four d- unnatural amino acid products, using ammonia and the co-enzyme NAD(P)H, which is regenerated by a robust alcohol dehydrogenase with 2-propanol as cheap cosubstrate. The complete conversion and high enantiopurity (ee > 99 %) of the products, demonstrated it as an ideal alternative for asymmetric synthesis of chiral amino acid compounds.
- Zhou, Haisheng,Meng, Lijun,Yin, Xinjian,Liu, Yayun,Xu, Gang,Wu, Jianping,Wu, Mianbin,Yang, Lirong
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supporting information
p. 6470 - 6477
(2019/11/02)
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- Discovery of Amantamide, a Selective CXCR7 Agonist from Marine Cyanobacteria
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CXCR7 plays an emerging role in several physiological processes. A linear peptide, amantamide (1), was isolated from marine cyanobacteria, and the structure was determined by NMR and mass spectrometry. The total synthesis was achieved by solid-phase method. After screening two biological target libraries, 1 was identified as a selective CXCR7 agonist. The selective activation of CXCR7 by 1 could provide the basis for developing CXCR7-targeted therapeutics and deciphering the role of CXCR7 in different diseases.
- Liang, Xiao,Luo, Danmeng,Yan, Jia-Lei,Rezaei, Mohammad A.,Salvador-Reyes, Lilibeth A.,Gunasekera, Sarath P.,Li, Chenglong,Ye, Tao,Paul, Valerie J.,Luesch, Hendrik
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supporting information
p. 1622 - 1626
(2019/03/07)
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- Kyanamide, a new Ahp-containing depsipeptide from marine cyanobacterium Caldora penicillata
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Kyanamide (1), a new depsipeptide containing 3-amino-6-hydroxy-2-piperidone moiety, was isolated from the Caldora penicillata marine cyanobacterium collected in Okinawa. Its structure was determined by spectroscopic analysis and Marfey's analysis of acid hydrolysate. Kyanamide exhibited moderate cytotoxicity against HeLa S3 cells. 1 also exhibited potent protease inhibitory activity against elastase and chymotrypsin with IC50 values of 0.13 nM and 1.1 μM.
- Ozaki, Kaori,Iwasaki, Arihiro,Suenaga, Kiyotake,Teruya, Toshiaki
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p. 3382 - 3386
(2019/05/15)
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- Induction of cryptic metabolites of the endophytic fungus: Trichocladium sp. through OSMAC and co-cultivation
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The endophytic fungus Trichocladium sp. isolated from roots of Houttuynia cordata was cultured on solid rice medium, yielding a new amidepsine derivative (1) and a new reduced spiro azaphilone derivative (3) together with eight known compounds (4-11). Co-cultivation of Trichocladium sp. with Bacillus subtilis resulted in induction of a further new compound (2) and a 10-fold increase of 11 compared to the axenic fungal culture. Moreover, when the fungus was cultivated on peas instead of rice, a new sesquiterpene derivative (13) and two known compounds (12 and 14) were obtained. Addition of 2% tryptophan to rice medium led to the isolation of a new bismacrolactone (15). The structures of the new compounds were elucidated by HRESIMS, 1D and 2D NMR as well as by comparison with the literature. A combination of TDDFT-ECD, TDDFT-SOR, DFT-VCD and DFT-NMR calculations were applied to determine the absolute and relative configurations of 13 and 15. Compounds 7, 11 and 15 exhibited strong cytotoxicity against the L5178Y mouse lymphoma cell line with IC50 values of 0.3, 0.5 and 0.2 μM, respectively.
- Tran-Cong, Nam Michael,Mándi, Attila,Kurtán, Tibor,Müller, Werner E.G.,Kalscheuer, Rainer,Lin, Wenhan,Liu, Zhen,Proksch, Peter
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p. 27279 - 27288
(2019/09/12)
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- Isolation and Total Synthesis of Mabuniamide, a Lipopeptide from an Okeania sp. Marine Cyanobacterium
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The bioassay-guided fractionation of an Okeania sp. marine cyanobacterium collected in Okinawa led to the isolation of the lipopeptide mabuniamide (1). The gross structure of 1 was determined by spectroscopic analyses, and its absolute configuration was determined using Marfey's analysis of the acid hydrolysate of 1. The absolute configuration of 1 was confirmed by total synthesis. Mabuniamide (1) stimulated glucose uptake in cultured rat L6 myotubes. In addition, mabuniamide (1) and its stereoisomer (2) exhibited moderate antimalarial activity.
- Ozaki, Kaori,Iwasaki, Arihiro,Sezawa, Dai,Fujimura, Haruka,Nozaki, Tomoyoshi,Saito-Nakano, Yumiko,Suenaga, Kiyotake,Teruya, Toshiaki
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p. 2907 - 2915
(2019/10/16)
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- Decorated single-enantiomer phosphoramide-based silica/magnetic nanocomposites for direct enantioseparation
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The nano-composites Fe3O4SiO2(-O3Si[(CH2)3NH])P(O)(NH-R(+)CH(CH3)(C6H5))2 (Fe3O4SiO2PTA(+)) and Fe3O4SiO2(-O3Si[(CH2)3NH])P(O)(NH-S(-)CH(CH3)(C6H5))2 (Fe3O4SiO2PTA(-)) were prepared and used for the chiral separation of five racemic mixtures (PTA = phosphoric triamide). The separation results show chiral recognition ability of these materials with respect to racemates belonging to different families of compounds (amine, acid, and amino-acid), which show their feasibility to be potential adsorbents in chiral separation. The nano-composites were characterized by FTIR, TEM, SEM, EDX, XRD, and VSM. The VSM curves of nano-composites indicate their superparamagnetic property, which is stable after their use in the separation process. Fe3O4, Fe3O4SiO2, Fe3O4SiO2PTA(+) and Fe3O4SiO2PTA(-) are regularly spherical with uniform shape and the average sizes of 17-20, 18-23, 36-47 and 43-52 nm, respectively.
- Karimi Ahmadabad, Fatemeh,Pourayoubi, Mehrdad,Bakhshi, Hadi
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p. 27147 - 27156
(2019/09/12)
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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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- Driving Transamination Irreversible by Decomposing Byproduct Α-Ketoglutarate into Ethylene Using Ethylene-Forming Enzyme
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The transformations of transaminases have been extensively studied as an approach to the production of chiral amino moieties. However, the low equilibrium conversion of the reaction is a critical disadvantage to transaminase application, and a strategy for shifting the reaction equilibrium is essential. Herein, we have developed a novel method to effectively prevent the reversibility of transamination by fully decomposing byproduct α-ketoglutarate into ethylene and carbon dioxide in situ using ethylene-forming enzyme (EFE). Two transaminases and one EFE were expressed in E. coli and purified to be used in the cascade reaction. After optimal reaction conditions were determined based on the enzymatic properties, a cascade reaction coupling transaminase with EFE was conducted and showed high efficiency in the synthesis of l-phosphinothricin. Finally, using this approach with only an equivalent amount of amino donor l-glutamate increased the conversions of various keto acids from 99%. This strategy shows great potential for transamination using glutamate as the amino donor.
- Meng, Li-Jun,Liu, Ya-Yun,Zhou, Hai-Sheng,Yin, Xin-Jian,Wu, Jian-Ping,Wu, Mian-Bin,Xu, Gang,Yang, Li-Rong
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p. 3309 - 3314
(2018/10/02)
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- Organocatalytic Enantioselective Addition of α-Aminoalkyl Radicals to Isoquinolines
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With a dual organocatalytic system involving a chiral phosphoric acid and a dicyanopyrazine-derived chromophore (DPZ) photosensitizer and under the irradiation with visible light, an enantioselective Minisci-type addition of α-amino acid-derived redox-active esters (RAEs) to isoquinolines has been developed. A variety of prochiral α-aminoalkyl radicals generated from RAEs were successfully introduced on isoquinolines, providing a range of valuable α-isoquinoline-substituted chiral secondary amines in high yields with good to excellent enantioselectivities.
- Liu, Xiangyuan,Liu, Yang,Chai, Guobi,Qiao, Baokun,Zhao, Xiaowei,Jiang, Zhiyong
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supporting information
p. 6298 - 6301
(2018/10/09)
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- Accessing d-Valine Synthesis by Improved Variants of Bacterial Cyclohexylamine Oxidase
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Chemoenzymatic deracemization was applied to prepare d-valine from racemic valine ethyl ester or l-valine ethyl ester in high yield (up to 95 %) with excellent optical purity (>99 % ee) by employing a newly evolved cyclohexylamine oxidase (CHAO) variant Y321I/M226T exhibiting catalytic efficiency that was 30 times higher than that of the wildtype CHAO. Interestingly, CHAO and its variants showed opposite enantioselectivity for valine ethyl ester and phenylalanine ethyl ester.
- Gong, Rui,Yao, Peiyuan,Chen, Xi,Feng, Jinhui,Wu, Qiaqing,Lau, Peter C. K.,Zhu, Dunming
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p. 387 - 390
(2017/12/26)
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- Structure-guided engineering of: Meso -diaminopimelate dehydrogenase for enantioselective reductive amination of sterically bulky 2-keto acids
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meso-Diaminopimelate dehydrogenase (DAPDH) and mutant enzymes are an excellent choice of biocatalysts for the conversion of 2-keto acids to the corresponding d-amino acids. However, their application in the enantioselective reductive amination of bulky 2-keto acids, such as phenylglyoxylic acid, 2-oxo-4-phenylbutyric acid, and indole-3-pyruvic acid, is still challenging. In this study, the structure-guided site-saturation mutagenesis of a Symbiobacterium thermophilum DAPDH (StDAPDH) gave rise to a double-site mutant W121L/H227I, which showed dramatically improved enzyme activities towards various 2-keto acids including these sterically bulky substrates. Several d-amino acids were prepared in optically pure form. The molecular docking of substrates into the active sites of wild-type and mutant W121L/H227I enzymes revealed that the substrate binding cavity of the mutant enzyme was reshaped to accommodate these bulky substrates, thus leading to higher enzyme activity. These results lay a foundation for further shaping the substrate binding pocket and manipulating the interactions between the substrate and binding sites to access highly active d-amino acid dehydrogenases for the preparation of synthetically challenging d-amino acids.
- Cheng, Xinkuan,Chen, Xi,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming
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p. 4994 - 5002
(2018/10/17)
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- Catalytic amino acid production from biomass-derived intermediates
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Amino acids are the building blocks for protein biosynthesis and find use in myriad industrial applications including in food for humans, in animal feed, and as precursors for bio-based plastics, among others. However, the development of efficient chemical methods to convert abundant and renewable feedstocks into amino acids has been largely unsuccessful to date. To that end, here we report a heterogeneous catalyst that directly transforms lignocellulosic biomass-derived α-hydroxyl acids into α-amino acids, including alanine, leucine, valine, aspartic acid, and phenylalanine in high yields. The reaction follows a dehydrogenation-reductive amination pathway, with dehydrogenation as the rate-determining step. Ruthenium nanoparticles supported on carbon nanotubes (Ru/CNT) exhibit exceptional efficiency compared with catalysts based on other metals, due to the unique, reversible enhancement effect of NH3 on Ru in dehydrogenation. Based on the catalytic system, a two-step chemical process was designed to convert glucose into alanine in 43% yield, comparable with the well-established microbial cultivation process, and therefore, the present strategy enables a route for the production of amino acids from renewable feedstocks. Moreover, a conceptual process design employing membrane distillation to facilitate product purification is proposed and validated. Overall, this study offers a rapid and potentially more efficient chemical method to produce amino acids from woody biomass components.
- Deng, Weiping,Wang, Yunzhu,Zhang, Sui,Gupta, Krishna M.,Hülsey, Max J.,Asakura, Hiroyuki,Liu, Lingmei,Han, Yu,Karp, Eric M.,Beckham, Gregg T.,Dyson, Paul J.,Jiang, Jianwen,Tanaka, Tsunehiro,Wang, Ye,Yan, Ning
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p. 5093 - 5098
(2018/05/23)
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- Structural Diversity and Anticancer Activity of Marine-Derived Elastase Inhibitors: Key Features and Mechanisms Mediating the Antimetastatic Effects in Invasive Breast Cancer
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Three new 3-amino-6-hydroxy-2-piperidone (Ahp)-containing cyclic depsipeptides, named loggerpeptins A–C (1–3), along with molassamide (4), were discovered from a marine cyanobacterium, extending the structural diversity of this prevalent scaffold of cyanobacterial serine protease inhibitors. Molassamide, which contains a 2-amino-butenoic (Abu) unit in the cyclic core, was the most potent and selective analogue against human neutrophil elastase (HNE). Given the growing evidence supporting the role of HNE in breast cancer progression and metastasis, we assessed the cellular effects of compounds 3 and 4 in the context of targeting invasive breast cancer. Both compounds inhibited cleavage of the elastase substrate CD40 in biochemical assays; however, only 4 exhibited significant cellular activity. As CD40 and other receptor proteolytic processing culminates in NFκB activation, we assessed the effects of 4 on the expression of target genes, including ICAM-1. ICAM-1 is also a direct target of elastase and, in our studies, compound 4 attenuated both elastase-induced ICAM-1 gene expression and ICAM-1 proteolytic processing by elastase, revealing a potential dual effect on migration through modulation of gene expression and proteolytic processing. Molassamide also specifically inhibited the elastase-mediated migration of highly invasive triple-negative breast cancer cells.
- Al-Awadhi, Fatma H.,Paul, Valerie J.,Luesch, Hendrik
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p. 815 - 825
(2018/03/27)
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- Kakeromamide A, a new cyclic pentapeptide inducing astrocyte differentiation isolated from the marine cyanobacterium Moorea bouillonii
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Kakeromamide A (1), a new cyclic pentapeptide encompassing a thiazole ring moiety and a β-amino acid, was isolated from the marine cyanobacterium Moorea bouillonii. Its structure was elucidated by the spectral analysis and the modified Marfey's method. Compound 1 induced differentiation of neural stem cells into astrocytes at the concentration of 10 μM.
- Nakamura, Fumiaki,Maejima, Hiroshi,Kawamura, Midori,Arai, Daisuke,Okino, Tatsufumi,Zhao, Meng,Ye, Tao,Lee, Jungyeol,Chang, Young-Tae,Fusetani, Nobuhiro,Nakao, Yoichi
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supporting information
p. 2206 - 2209
(2018/05/25)
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- Izenamides A and B, Statine-Containing Depsipeptides, and an Analogue from a Marine Cyanobacterium
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Izenamides A, B, and C (1-3), new linear depsipeptides, were isolated from a taxonomically distinct marine cyanobacterium. Izenamides A and B contain a statine moiety [(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid] and inhibited the activity of cathepsin D, an aspartic peptidase. Meanwhile, izenamides did not show growth-inhibitory activity against HeLa, HL60, or MCF-7 cells at up to 10 μM.
- Kanamori, Yuki,Iwasaki, Arihiro,Sumimoto, Shimpei,Matsubara, Teruhiko,Sato, Toshinori,Suenaga, Kiyotake
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supporting information
p. 1673 - 1681
(2018/08/04)
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- Natalenamides A–C, cyclic tripeptides from the termite-associated Actinomadura sp. RB99
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In recent years, investigations into the biochemistry of insect-associated bacteria have increased. When combined with analytical dereplication processes, these studies provide a powerful strategy to identify structurally and/or biologically novel compounds. Non-ribosomally synthesized cyclic peptides have a broad bioactivity spectrum with high medicinal potential. Here, we report the discovery of three new cyclic tripeptides: natalenamides A–C (compounds 1–3). These compounds were identified from the culture broth of the fungus-growing termite-associated Actinomadura sp. RB99 using a liquid chromatography (LC)/ultraviolet (UV)/mass spectrometry (MS)-based dereplication method. Chemical structures of the new compounds (1–3) were established by analysis of comprehensive spectroscopic methods, including one-dimensional (1H and13C) and two-dimensional (1H-1H-COSY, HSQC, HMBC) nuclear magnetic resonance spectroscopy (NMR), together with high-resolution electrospray ionization mass spectrometry (HR-ESIMS) data. The absolute configurations of the new compounds were elucidated using Marfey’s analysis. Through several bioactivity tests for the tripeptides, we found that compound 3 exhibited significant inhibitory effects on 3-isobutyl-1-methylxanthine (IBMX)-induced melanin production. The effect of compound 3 was similar to that of kojic acid, a compound extensively used as a cosmetic material with a skin-whitening effect.
- Lee, Seoung Rak,Lee, Dahae,Yu, Jae Sik,Benndorf, René,Lee, Sullim,Lee, Dong-Soo,Huh, Jungmoo,Wilhelm de Beer,Kim, Yong Ho,Beemelmanns, Christine,Kang, Ki Sung,Kim, Ki Hyun
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- Discovery of new A- and B-type laxaphycins with synergistic anticancer activity
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Two new cyclic lipopeptides termed laxaphycins B4 (1) and A2 (2) were discovered from a collection of the marine cyanobacterium Hormothamnion enteromorphoides, along with the known compound laxaphycin A. The planar structures were solved based on a combined interpretation of 1D and 2D NMR data and mass spectral data. The absolute configurations of the subunits were determined by chiral LC-MS analysis of the hydrolysates, advanced Marfey's analysis and 1D and 2D ROESY experiments. Consistent with similar findings on other laxaphycin A- and B-type peptides, laxaphycin B4 (1) showed antiproliferative effects against human colon cancer HCT116 cells with IC50 of 1.7 μM, while laxaphycins A and A2 (2) exhibited weak activities. The two major compounds isolated from the sample, laxaphycins A and B4, were shown to act synergistically to inhibit the growth of HCT116 colorectal cancer cells.
- Cai, Weijing,Matthew, Susan,Chen, Qi-Yin,Paul, Valerie J.,Luesch, Hendrik
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p. 2310 - 2319
(2018/04/02)
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- The optical activity of the valine compound and its production method
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The invention relates to an optically active valine compound and a production method thereof. The optically active valine compound is composed of 1 mole of L-valine and 1 mole of N-benzoyl-L-alanine. The production method comprises the steps of reacting the N-benzoyl-L-alanine selectively with L-valine in the presence of D-valine, other amino acids, impurities generated in the DL-valine synthesis process and a crude product L-valine obtained by hydrolyzing or fermenting proteins, thereby forming a novel crystal compound. The optically active L-valine and N-benzoyl-L-alanine can be taken as intermediates for optically decomposing DL-valine and purifying L-valine.
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Paragraph 0068; 0069; 0070
(2017/04/21)
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