- Identification of Cyclopropane Formation in the Biosyntheses of Hormaomycins and Belactosins: Sequential Nitration and Cyclopropanation by Metalloenzymes
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Hormaomycins and belactosins are peptide natural products that contain unusual cyclopropane moieties. Bioinformatics analysis of the corresponding biosynthetic gene clusters showed that two conserved genes, hrmI/belK and hrmJ/belL, were potential candidates for catalyzing cyclopropanation. Using in vivo and in vitro assays, the functions of HrmI/BelK and HrmJ/BelL were established. HrmI and BelK, which are heme oxygenase-like dinuclear iron enzymes, catalyze oxidation of the ?-amino group of l-lysine to afford l-6-nitronorleucine. Subsequently, HrmJ and BelL, which are iron- and α-ketoglutarate-dependent oxygenases, effectively convert l-6-nitronorleucine into 3-(trans-2-nitrocyclopropyl)-alanine through C4?C6 bond installation. These observations disclose a novel pathway of cyclopropane ring construction and exemplify the new chemistry involving metalloenzymes in natural product biosynthesis.
- Chang, Wei-chen,Dairi, Tohru,Li, Xiaojun,Ogasawara, Yasushi,Shimaya, Ryo
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supporting information
(2021/12/30)
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- METHODS OF PREPARING N6-((2-AZIDOETHOXY)CARBONYL)LYSINE
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Disclosed herein are methods of preparing N6-((2-azidoethoxy)carbonyl)lysine, N6-((2-azidoethoxy)carbonyl)-L-lysine, and N6-((2-azidoethoxy)carbonyl)-D-lysine. Also disclosed herein are the compounds tert-butyl N2-(tert-butoxycarbonyl)-N6-((2-chloroethoxy)carbonyl)-L-lysinate and tertbutyl N6-((2-azidoethoxy)carbonyl)-N2-(tert-butoxycarbonyl)-L-lysinate, and uses thereof.
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- Short self-assembling peptides with a urea bond: A new type of supramolecular peptide hydrogel materials
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There is an increasing need to develop short self-assembling peptides (SAPs) that can form hydrogels for cell engineering and biomedical applications. In this study, we proposed new short self-assembling peptides with a symmetric structure via a urea bond
- Tsutsumi, Hiroshi,Tanaka, Kunifumi,Chia, Jyh Yea,Mihara, Hisakazu
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- Non-natural amino acid and application thereof in protein site-specific modification and protein interaction
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The invention relates to a non-natural amino acid compound represented by a general formula (I) and a preparation method thereof, and applications of the non-natural amino acid compound in fixed-pointmodification of bio-macro-molecular proteins, protein i
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Paragraph 0125-0126; 0128
(2021/02/13)
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- Biofunctional supramolecular hydrogels fabricated from a short self-assembling peptide modified with bioactive sequences for the 3D culture of breast cancer MCF-7 cells
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Self-assembling peptides are a type of molecule with promise as scaffold materials for cancer cell engineering. We have reported a short self-assembling peptide, (FFiK)2, that had a symmetric structure connected via a urea bond. In this study, we functionalized (FFiK)2 by conjugation with various bioactive sequences for the 3D culture of cancer cells. Four sequences, RGDS and PHSRN derived from fibronectin and AG73 and C16 derived from laminin, were selected as bioactive sequences to promote cell adhesion, proliferation or migration. (FFiK)2, and its derivatives could co-assemble into supramolecular nanofibers displaying bioactive sequences and form hydrogels. MCF-7 cells were encapsulated in functionalized peptide hydrogels without significant cytotoxicity. Encapsulated MCF-7 cells proliferated under 3D culture conditions. MCF-7 cells proliferated with spheroid formation in hydrogels that displayed RGDS or PHSRN sequences, which will be able to be applied to drug screening targeting cancer stem cells. On the other hand, since MCF-7 cells migrated in a 3D hydrogel that displayed AG73, we could construct the metastatic model of breast cancer cells, which is helpful for the elucidation of breast cancer cells and drug screening against cancer cells under metastatic state. Therefore, functionalized (FFiK)2 hydrogels with various bioactive sequences can be used to regulate cancer cell function for tumor engineering and drug screening.
- Chia, Jyh Yea,Miki, Takayuki,Mihara, Hisakazu,Tsutsumi, Hiroshi
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supporting information
(2021/08/21)
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- SWCNT-porphyrin nano-hybrids selectively activated by ultrasound: an interesting model for sonodynamic applications
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Sonodynamic therapy (SDT) is an innovative anticancer approach, based on the excitation of a given molecule (usually a porphyrin) by inertial acoustic cavitation that leads to cell deathviathe production of reactive oxygen species (ROS). This study aims t
- Arpicco, Silvia,Barge, Alessandro,Bosca, Federica,Canaparo, Roberto,Corazzari, Ingrid,Cravotto, Giancarlo,Dosio, Franco,Durando, Gianni,Foglietta, Federica,Pastero, Linda,Serpe, Loredana,Tagliapietra, Silvia,Turci, Francesco,Zonari, Daniele
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p. 21736 - 21744
(2020/07/03)
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- Bioorthogonal Ligation and Cleavage by Reactions of Chloroquinoxalines with ortho-Dithiophenols
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A bioorthogonal ligation and cleavage method via reactions of chloroquinoxalines (CQ) and ortho-dithiophenols (DT) is presented. Double nucleophilic substitutions of ortho-dithiophenols to chloroquinoxalines provide conjugates containing tetracyclic benzo[5,6][1,4]dithiino[2,3-b]quinoxaline with strong built-in fluorescence together with release of the other functional molecules. Three cleavable linkers were designed and successfully used in release of the molecules containing biotin from the protein conjugates. The CQ-DT bioorthogonal reactions can be applied for the bioorthogonal ligations, bioorthogonal cleavages, and trans-tagging of proteins, and show advantages of readily accessible unnatural orthogonal groups, appealing reaction kinetics (k2≈1.3 m?1 s?1), excellent biocompatibility of orthogonal groups, and high stability of conjugates. This complements previous bioorthogonal reactions and is a new route for protein-fishing applications and in-gel fluorescence analysis.
- Fu, Hua,Li, Hongyun,Li, Youshan,Lou, Zhenbang,Yang, Haijun,Zhao, Yufen
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supporting information
p. 3671 - 3677
(2020/02/04)
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- Antitumor agents 7. Synthesis, antiproliferative activity and molecular modeling of new L-lysine-conjugated pyridophenoxazinones as potent DNA-binding ligands and topoisomerase IIα inhibitors
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A series of L-lysine-conjugated pyridophenoxazinones 2–5 and 2′-5′ were designed and synthesized for developing compounds with multimodal anticancer potentialities. All compounds inhibited the proliferation of a panel of human liquid and solid neoplastic
- Pedatella, Silvana,Cerchia, Carmen,Manfra, Michele,Cioce, Anna,Bolognese, Adele,Lavecchia, Antonio
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- Structural Basis for Genetic-Code Expansion with Bulky Lysine Derivatives by an Engineered Pyrrolysyl-tRNA Synthetase
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Yanagisawa et al. analyzed the Y306A/Y384F mutant of Methanosarcina mazei pyrrolysyl-tRNA synthetase (PylRS) with 17 non-natural, bulky oxycarbonyllysine derivatives for tRNAPyl aminoacylation and site-specific incorporation into proteins. Fourteen crystal structures of the amino acid-bound PylRS mutant revealed the structural bases of the binding. This information facilitates the structure-based design of novel amino acids. Pyrrolysyl-tRNA synthetase (PylRS) and tRNAPyl have been extensively used for genetic-code expansion. A Methanosarcina mazei PylRS mutant bearing the Y306A and Y384F mutations (PylRS(Y306A/Y384F)) encodes various bulky non-natural lysine derivatives by UAG. In this study, we examined how PylRS(Y306A/Y384F) recognizes many amino acids. Among 17 non-natural lysine derivatives, N?-(benzyloxycarbonyl)lysine (ZLys) and 10 ortho/meta/para-substituted ZLys derivatives were efficiently ligated to tRNAPyl and were incorporated into proteins by PylRS(Y306A/Y384F). We determined crystal structures of 14 non-natural lysine derivatives bound to the PylRS(Y306A/Y384F) catalytic fragment. The meta- and para-substituted ZLys derivatives are snugly accommodated in the productive mode. In contrast, ZLys and the unsubstituted or ortho-substituted ZLys derivatives exhibited an alternative binding mode in addition to the productive mode. PylRS(Y306A/Y384F) displayed a high aminoacylation rate for ZLys, indicating that the double-binding mode minimally affects aminoacylation. These precise substrate recognition mechanisms by PylRS(Y306A/Y384F) may facilitate the structure-based design of novel non-natural amino acids.
- Yanagisawa, Tatsuo,Kuratani, Mitsuo,Seki, Eiko,Hino, Nobumasa,Sakamoto, Kensaku,Yokoyama, Shigeyuki
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p. 936 - 13,949
(2019/07/17)
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- Preparation method of furosine and salt thereof
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The invention relates to a preparation method of furosine and salt thereof. The method comprises steps as follows: 1) a compound in a formula (V) and alcohol react, and a compound in a formula (VI) isobtained; 2) the compound in the formula (VI) reacts with 2-halogenated acetylfuran, and a compound in a formula (III) is obtained; 3) the compound in the formula (III) is subjected to acid hydrolysis, and furosine or salt thereof is obtained, wherein R is C1-6 alkyl, R1 is an amino protection group (such as t-butyloxycarbonyl Boc) and X is halogen. The method is simple and convenient and raw materials are easy to obtain.
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Paragraph 0030; 0031; 0032
(2018/04/21)
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- Analysis of Advanced Glycation Endproducts in Rat Tail Collagen and Correlation to Tendon Stiffening
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Methylglyoxal is a major 1,2-dicarbonyl compound in vivo and leads to nonenzymatic protein modifications, known as advanced glycation endproducts. Especially long-lived proteins like collagen are prone to changes of the mechanical or biological function,
- Jost, Tobias,Zipprich, Alexander,Glomb, Marcus A.
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p. 3957 - 3965
(2018/04/23)
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- METHOD FOR PRODUCING DESMOSINE, ISODESMOSINE AND DERIVATIVES THEREOF
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A process for preparing a compound represented by the following general formula (I) or a salt thereof, which comprises reacting lysine or a protective product thereof or a salt thereof with allysine or a protective product thereof in the presence of a spe
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Paragraph 0133-0134
(2015/12/19)
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- Pr(OTf)3-promoted Chichibabin pyridine synthesis of isodesmosine in H2O/MeOH
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1,2,3,5-Tetrasubstituted pyridinium amino acid isodesmosine is a crosslinking amino acid of elastin and is an attractive biomarker for the diagnosis of chronic obstructive pulmonary disease (COPD). Herein, we report an application of the Chichibabin pyrid
- Sugimura, Takanori,Komatsu, Akira,Koseki, Yohei,Usuki, Toyonobu
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supporting information
p. 6343 - 6346
(2015/02/19)
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- Structure-activity relationships in nucleotide oligomerization domain 1 (Nod1) agonistic γ-glutamyldiaminopimelic acid derivatives
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N-Acyl-γ-glutamyldiaminopimelic acid is a prototype ligand for Nod1. We report a detailed SAR of C12-γ-d-Glu-DAP. Analogues with glutaric or γ-aminobutyric acid replacing the glutamic acid show greatly attenuated Nod1-agonistic activity. Substitution of the meso-diaminopimelic (DAP) acid component with monoaminopimelic acid, l- or d-lysine, or cadaverine also results in reduced activity. The free amine on DAP is crucial. However, the N-acyl group on the d-glutamyl residue can be substituted with N-alkyl groups with full preservation of activity. The free carboxylates on the DAP and Glu components can also be esterified, resulting in more lipophilic but active analogues. Transcriptomal profiling showed a dominant up-regulation of IL-19, IL-20, IL-22, and IL-24, which may explain the pronounced Th2-polarizing activity of these compounds and also implicate cell signaling mediated by TREM-1. These results may explain the hitherto unknown mechanism of synergy between Nod1 and TLR agonists and are likely to be useful in designing vaccine adjuvants.
- Agnihotri, Geetanjali,Ukani, Rehman,Malladi, Subbalakshmi S.,Warshakoon, Hemamali J.,Balakrishna, Rajalakshmi,Wang, Xinkun,David, Sunil A.
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p. 1490 - 1510
(2011/04/24)
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- Synthesis and evaluation of macrocyclic amino acid derivatives for tumor imaging by gallium-68 positron emission tomography
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68Ga PET imaging in clinical oncology represents a notable development because the availability of 68Ga is not dependent on a cyclotron. Furthermore, labeled amino acid derivatives have been proven to be useful for the imaging many t
- Shetty, Dinesh,Jeong, Jae Min,Ju, Chang Hwan,Kim, Young Ju,Lee, Ji-Youn,Lee, Yun-Sang,Lee, Dong Soo,Chung, June-Key,Lee, Myung Chul
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experimental part
p. 7338 - 7347
(2010/12/25)
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- Heterocycle-amino acid derivatives for targeting cancer tissue and radioactive or non-radioactive labeled compounds thereof
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The present invention relates to novel amino acid derivatives containing heterocyclic chelating residues thereof; radioactive or nonradioactive metal complexes thereof; methods for preparation thereof; and apyrogenic and sterile preparative kits of the co
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Page/Page column 19-20
(2010/11/03)
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- A pyrrolysine analogue for protein click chemistry
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(Chemical Equation Presented) Ignoring the STOP sign: A pyrrolysine analogue bearing a terminal alkyne was site-specifically incorporated into recombinant calmodulin (CaM) through a UAG codon. The resulting protein was labeled with an azide-containing dye using a copper(I)-catalyzed click reaction. Subsequent application of an orthogonal cysteine tagging method yielded a CaM labeled with two distinct fluorophores that enabled its study by FRET spectroscopy.
- Fekner, Tomasz,Li, Xin,Lee, Marianne M.,Chan, Michael K.
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supporting information; experimental part
p. 1633 - 1635
(2009/06/30)
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- Synthesis of the unnatural amino acid Nα-Nε-(ferrocene-1-acetyl)-l-lysine: A novel organometallic nuclease
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The synthesis of a new unnatural amino acid, Nα-Nε-(ferrocene-1-acetyl)-l-lysine, was achieved by coupling a ferroceneacetic acid molecule onto the side chain amine of a lysine. The structure of the compound provides options for inco
- Gellett, Amanda M.,Huber, Paul W.,Higgins, Pamela J.
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p. 2959 - 2962
(2008/12/22)
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- Synthesis and precursor-directed biosynthesis of new hormaomycin analogues
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Several new analogues of hormaomycin (1), a peptide lactone with interesting biological activities, were prepared by total synthesis or by precursor-directed biosynthesis. The new analogues 2a-c, 3a-c, O-MOM-1 and epi-O-MOM-1 as well as the model acyl tri
- Zlatopolskiy, Boris D.,Radzom, Markus,Zeeck, Axel,De Meijere, Armin
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p. 1525 - 1534
(2007/10/03)
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- Examination of N-hydroxylation as a prerequisite mechanism of nitric oxide synthase inactivation
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L-N5-(1-Hydroxyiminoethyl)-ornithine (L-NHIO) and L-N6-(1-hydroxyiminoethyl)-lysine (L-NHIL) were synthesized and tested as potential intermediates in the mechanism-based inactivation of nitric oxide synthase (NOS) by L-N5-iminoethyl-ornithine (L-NIO) and L-N6-iminoethyllysine (L-NIL). Although these compounds were determined to be competitive inhibitors, mechanism-based inactivation was not observed. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Maurer, Tristan S.,Pan, Jianping,Booth, Brian P.,Kalman, Thomas I.,Fung, Ho-Leung
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p. 1077 - 1080
(2007/10/03)
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- Synthesis of reagents for the construction of hypusine and deoxyhypusine peptides and their application as peptidic antigens
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Two new synthetic methods which allow access to (2S)-deoxyhypusine, natural (2S,9R)-hypusine, (2S,9S)-hypusine, and deoxyhypusine- and hypusine- containing peptides are described. The methods involve both the construction of a deoxyhypusine reagent in which the α-nitrogen protecting group is orthogonal to the N-7 and N-12 protecting groups and an alternate synthesis of our previous hypusine reagent, a synthesis which provides for better stereochemical control at C-9. Synthetic hypusine and deoxyhypusine can be generated from these reagents. The hypusine-containing hexapeptide (Cys-Thr- Gly-Hpu-His-Gly) is conjugated to ovalbumin (OVA), keyhole limpet hemocyanin (KLH), and a bis-maleimide; KLH conjugates are also made with the deoxyhypusine- and lysine-containing hexapeptides. Monoclonal antibodies are generated to the hypusine-containing hexapeptide-OVA conjugate in mice. These are isolated and screened against the hypusine-containing hexapeptide-KLH and hypusine-containing hexapeptide-bis-maleimide conjugates, as well as against the deoxyhypusine-containing and lysine-containing hexapeptide-KLH conjugates. These antibodies may be useful in localizing intracellular hypusine-containing peptides as well as peptides containing hypusine analogues.
- Bergeron, Raymond J.,Weimar, William R.,Müller, Ralf,Zimmerman, Curt O.,McCosar, Bruce H.,Yao, Hua,Smith, Richard E.
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p. 3888 - 3900
(2007/10/03)
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