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Direct monitoring of biocatalytic deacetylation of amino acid substrates by1H NMR reveals fine details of substrate specificity
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.
supporting information
p. 4904 - 4909
(2021/06/16)

Saccharochelins A-H, Cytotoxic Amphiphilic Siderophores from the Rare Marine Actinomycete Saccharothrix sp. D09
Siderophores are secreted by microorganisms to survive in iron-depleted conditions, and they also possess tremendous therapeutic potential. Genomic-inspired isolation facilitated the identification of eight amphiphilic siderophores, saccharochelins A-H (1-8), from a rare marine-derived Saccharothrix species. Saccharochelins feature a series of fatty acyl groups appended to the same tetrapeptide skeleton. With the help of gene disruption and heterologous expression, we identified the saccharochelin biosynthetic pathway. The diversity of saccharochelins originates from the flexible specificity of the starter condensation (CS) domain at the beginning of the nonribosomal peptide synthetase (NRPS) toward various fatty acyl substrates. Saccharochelins showed cytotoxicity against several human tumor cell lines, with IC50 values ranging from 2.3 to 17 μM. Additionally, the fatty acid side chains of the saccharochelins remarkably affected the cytotoxicity, suggesting changing the N-terminal acyl groups of lipopeptides may be a promising approach to produce more potent derivatives.
Bian, Xiaoying,Dai, Guangzhi,Jiao, Nianzhi,Liu, Yang,Ravichandran, Vinothkannan,Ren, Xiangmei,Shen, Qiyao,Sui, Haiyan,Zhang, Youming,Zhong, Lin,Zhou, Haibo
p. 2149 - 2156
(2021/08/20)

COMBINING BETA-DIPEPTIDES AND AMINO ACIDS FOR OPTIMAL NUTRITIONAL SUPPLEMENTATION
The invention relates to anutritional supplement comprising a combination of one or more β-aspartyl-containing dipeptides,oroligomers thereof, or salts thereof, wherein each of the β-dipeptides comprises β-L-aspartyl as a first amino acid residue and an amino acid selected from arginine, lysine, ornithine, and citrulline as the second amino acid residue, and the respective second amino acid(s) or salts thereof. The invention further relates to the use of the combination for nutritional supplementation and to the combination for use in amino acid therapy.
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(2020/02/23)

Natural Hydroxamate-Containing Siderophore Acremonpeptides A-D and an Aluminum Complex of Acremonpeptide D from the Marine-Derived Acremonium persicinum SCSIO 115
Four new hydroxamate-containing natural product cyclopeptides designated acremonpeptides A-D (1-4), together with Al(III)-acremonpeptide D (5) were obtained from the marine fungus Acremonium persicinum SCSIO 115. The planar structures of 1-5 were established on the basis of HRMS as well as 1D and 2D NMR data sets. Moreover, the amino acid absolute configurations were determined using Marfey's method. Compounds 1-5 all feature three 2-amino-5-(N-hydroxyacetamido)pentanoic acid (N5-hydroxy-N5-acetyl-l-ornithine) metal ion chelating moieties. Beyond their discovery and structure elucidation, in vitro bioassays revealed acremonpeptides A (1), B (2), and Al(III)-acremonpeptide D (5) as moderate antiviral agents for herpes simplex virus 1 with EC50 values of 16, 8.7, and 14 μM, respectively.
Chen, Ziming,Huang, Hongbo,Ju, Jianhua,Luo, Minghe,Song, Xiaoxian,Wang, Xin,Zang, Ruochen
p. 2594 - 2600
(2019/10/11)

Catenulobactins A and B, Heterocyclic Peptides from Culturing Catenuloplanes sp. with a Mycolic Acid-Containing Bacterium
The production of two new heterocyclic peptide isomers, catenulobactins A (1) and B (2), in cultures of Catenuloplanes sp. RD067331 was significantly increased when it was cocultured with a mycolic acid-containing bacterium. The planar structures and absolute configurations of the catenulobactins were determined based on NMR/MS and chiral-phase GC-MS analyses. Catenulobactin B (2) displayed Fe(III)-chelating activity and moderate cytotoxicity against P388 murine leukemia cells.
Hoshino, Shotaro,Ozeki, Masahiro,Awakawa, Takayoshi,Morita, Hiroyuki,Onaka, Hiroyasu,Abe, Ikuro
supporting information
p. 2106 - 2110
(2018/09/12)

A new ureido-substituted amino acid from the tubers of Gymnadenia conopsea
A new ureido-substituted amino acid, conopsamide A (1), has been isolated from an ethanolic extract of the tubers of Gymnadenia conopsea. Its structure was elucidated by extensive spectroscopic analysis, and the absolute configuration was assigned by Marfey's method. The new compound was evaluated for in vitro assay for HDAC1 (Histone Deacetylase 1) inhibitory activity.
Lin, Peng-Cheng,Yao, Jing,Wu, Jiang,Tian, Jin,Bao, Yi,Lin, Sheng
p. 257 - 259
(2017/01/28)

Daryamide Analogues from a Marine-Derived Streptomyces species
Three new cyclohexene amine derivatives, daryamides D-F (1-3), a new arylamine derivative, carpatamide D (4), and a new ornithine lactamization derivative, ornilactam A (5), were isolated from the marine-derived Streptomyces strain SNE-011. Their structures, including absolute configurations, were elucidated on the basis of spectroscopic analysis and chemical methods. The carpatamide skeleton could be considered as the biosynthetic precursor of the daryamides.
Fu, Peng,La, Scott,MacMillan, John B.
p. 1096 - 1101
(2017/05/05)

Characterization of a thermostable arginase from Rummeliibacillus pycnus SK31.001
L-arginase from Rummeliibacillus pycnus SK31.001 is newly discovered. A 906 bp complete open reading frame, which encodes a 301 amino acid protein, was identified using degenerate PCR and inverse PCR techniques. The arginase was found to have a conserved active site with 6 amino acid residues binding to 2 manganese ions: D123, H125, D228, D230, H100 and D127. Bioinformatics analysis revealed that R. pycnus arginase is a hexamer with a subunit molecular mass of 33 kDa and whole molecular mass of 195 kDa. R. pycnus arginase is thermostable with an optimal temperature of 80 °C and maintains 85% of its initial activity after 24 h of incubation at 40 or 50 °C. An arginase activity assay showed that R. pycnus arginase has an optimum pH of 9.5 and a preference for Mn2+. Using arginine as the substrate, the Michaelis-Menten constant (Km) and catalytic efficiency (kcat/Km) were measured to be 0.212 mM and 2970 mM?1s?1, respectively. The biosynthesis yield of L-ornithine by the purified enzyme was 144.4 g/L, and the molar yield was 95.2%.
Huang, Kai,Zhang, Tao,Jiang, Bo,Mu, Wanmeng,Miao, Ming
p. S68 - S75
(2018/04/13)

Variochelins, Lipopeptide Siderophores from Variovorax boronicumulans Discovered by Genome Mining
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
p. 865 - 872
(2016/05/24)

FUNCTIONALIZED FLUORINE CONTAINING PHTHALOCYANINE MOLECULES
Functionalized fluorine containing phthalocyanine molecules, methods of making, and methods of use in diagnostic applications and disease treatment are disclosed herein. In some embodiments, the fluorine containing phthalocyanine molecules are functionalized with a reactive functional group or at least one cancer-targeting ligand (CTL). The CTL can facilitate more efficient binding and/or internalization to a cancer cell than to a healthy cell. The CTL can inhibit expression of oncoprotein in some embodiments. The pthalocyanine moiety can be used in diagnostic applications, such as fluorescence labeling of a cancer cell, and/or treatment applications, such as catalyzing formation of a reactive oxygen species (ROS) which can contribute to cell death of a cancer cell.
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(2015/03/16)

Enzymatic production of l-ornithine from l-arginine with recombinant thermophilic arginase
In this study, to develop a simple and efficient enzymatic production process for the environment-friendlysynthesis of l-ornithine from l-arginine, the Escherichia coli BL21 (DE3) strain overexpressing arginase(ARG) from Bacillus caldovelox was chosen as the potential biocatalyst. The biochemical properties ofthe recombinant ARG were characterized and compared with those of the native enzyme. The maximalconversion rate of l-arginine to l-ornithine was 87.1% with a final l-ornithine concentration of 112.3 g/Lunder the following optimal conditions: 170 g/L l-arginine, 12 g/L whole-cell biocatalyst, 10 μM Mn2+,60°C, pH 9.0, and 4 h of incubation. When compared with a recent work, the biocatalytic process describedin the present study achieved higher average l-ornithine synthesis rate of 26.2 g/L/h, and thus has greatpotential for large-scale production of l-ornithine.
Song, Wei,Niu, Panqing,Chen, Xiulai,Liu, Liming
p. 1 - 7
(2015/01/08)

Immunomodulatory peptides
The invention relates to peptides derivatized with a hydrophilic polymer which, in some embodiments, bind to human FcRn and inhibit binding of the Fc portion of an IgG to an FcRn, thereby modulating serum IgG levels. The disclosed compositions and methods may be used in some embodiments, for example, in treating autoimmune diseases and inflammatory disorders. The invention also relates, in further embodiments, to methods of using and methods of making the peptides of the invention.
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(2014/12/12)

Developing an irreversible inhibitor of human DDAH-1, an enzyme upregulated in melanoma
Inhibitors of the human enzyme dimethylarginine dimethylaminohydrolase-1 (DDAH-1) can raise endogenous levels of asymmetric dimethylarginine (ADMA) and lead to a subsequent inhibition of nitric oxide synthesis. In this study, N 5-(1-imino-2-chloroethyl)-L-ornithine (Cl-NIO) is shown to be a potent time- and concentration-dependent inhibitor of purified human DDAH-1 (KI=1.3±0.6 μM; kinact=0.34±0.07 min -1), with >500-fold selectivity against two arginine-handling enzymes in the same pathway. An activity probe is used to measure the in cell IC50 value (6.6±0.2 μM) for Cl-NIO inhibition of DDAH-1 artificially expressed within cultured HEK293T cells. A screen of diverse melanoma cell lines reveals that a striking 50/64 (78 %) of melanoma lines tested showed increased levels of DDAH-1 relative to normal melanocyte control lines. Treatment of the melanoma A375 cell line with Cl-NIO shows a subsequent decrease in cellular nitric oxide production. Cl-NIO is a promising tool for the study of methylarginine-mediated nitric oxide control and a potential therapeutic lead compound for other indications with elevated nitric oxide production, such as septic shock and idiopathic pulmonary fibrosis. Inactivator of DDAH-1: The enzyme DDAH-1 regulates nitric oxide production by catabolizing endogenous inhibitors of nitric oxide synthases. Here, we develop a potent irreversible inactivator of DDAH-1 and demonstrate its use with purified enzymes, with DDAH-1 artificially expressed in cultured cells, and with DDAH-1 that we found to be overexpressed in ～80 % of cultured melanoma cell lines tested.
Wang, Yun,Hu, Shougang,Gabisi Jr., Abdul M.,Er, Joyce A. V.,Pope, Arthur,Burstein, Gayle,Schardon, Christopher L.,Cardounel, Arturo J.,Ekmekcioglu, Suhendan,Fast, Walter
supporting information
p. 792 - 797
(2014/05/06)

Microorganisms and methods for the biosynthesis of adipate, hexamethylenediamine and 6-aminocaproic acid
The invention provides a non-naturally occurring microbial organism having a 6-aminocaproic acid, caprolactam, hexametheylenediamine or levulinic acid pathway. The microbial organism contains at least one exogenous nucleic acid encoding an enzyme in the respective 6-aminocaproic acid, caprolactam, hexametheylenediamine or levulinic acid pathway. The invention additionally provides a method for producing 6-aminocaproic acid, caprolactam, hexametheylenediamine or levulinic acid. The method can include culturing a 6-aminocaproic acid, caprolactam or hexametheylenediamine producing microbial organism, where the microbial organism expresses at least one exogenous nucleic acid encoding a 6-aminocaproic acid, caprolactam, hexametheylenediamine or levulinic acid pathway enzyme in a sufficient amount to produce the respective product, under conditions and for a sufficient period of time to produce 6-aminocaproic acid, caprolactam, hexametheylenediamine or levulinic acid.
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(2013/03/26)

Identification of new peptide amides as selective cathepsin L inhibitors: The first step towards selective irreversible inhibitors?
A small library of peptide amides was designed to profile the cathepsin L active site. Within the cathepsin family of cysteine proteases, the first round of selection was on cathepsin L and cathepsin B, and then selected hits were further evaluated for binding to cathepsin K and cathepsin S. Five highly selective sequences with submicromolar affinities towards cathepsin L were identified. An acyloxymethyl ketone warhead was then attached to these sequences. Although these original irreversible inhibitors inactivate cathepsin L, it appears that the nature of the warhead drastically impact the selectivity profile of the resulting covalent inhibitors.
Torkar, Ana,Lenar?i?, Brigita,Lah, Tamara,Dive, Vincent,Devel, Laurent
supporting information
p. 2968 - 2973
(2013/06/27)

Structure and function of non-native metal clusters in human arginase i
Various binuclear metal ion clusters and complexes have been reconstituted in crystalline human arginase I by removing the Mn2+2 cluster of the wild-type enzyme with metal chelators and subsequently soaking the crystalline apoenzyme in buffer solutions containing NiCl2 or ZnCl2. X-ray crystal structures of these metal ion variants are correlated with catalytic activity measurements that reveal differences resulting from metal ion substitution. Additionally, treatment of crystalline Mn2+2-human arginase I with Zn2+ reveals for the first time the structural basis for inhibition by Zn2+, which forms a carboxylate-histidine-Zn2+ triad with H141 and E277. The imidazole side chain of H141 is known to be hyper-reactive, and its chemical modification or mutagenesis is known to similarly compromise catalysis. The reactive substrate analogue 2(S)-amino-6-boronohexanoic acid (ABH) binds as a tetrahedral boronate anion to Mn2+2, Co2+ 2, Ni2+2, and Zn2+2 clusters in human arginase I, and it can be stabilized by a third inhibitory Zn2+ ion coordinated by H141. Because ABH binds as an analogue of the tetrahedral intermediate and its flanking transition states in catalysis, this implies that the various metallo-substituted enzymes are capable of some level of catalysis with an actual substrate. Accordingly, we establish the following trend for turnover number (kcat) and catalytic efficiency (k cat/KM): Mn2+ > Ni2+ ≈ Co 2+ ? Zn2+. Therefore, Mn2+ is required for optimal catalysis by human arginase I.
D'Antonio, Edward L.,Hai, Yang,Christianson, David W.
p. 8399 - 8409,11
(2020/09/16)

GALACTOSE CLUSTER-PHARMACOKINETIC MODULATOR TARGETING MOIETY FOR siRNA
The present invention is directed compositions for targeted delivery of RNA interference (RNAi) polynucleotides to cell in vivo. The pharmacokinetic modulator improve in vivo targeting compared to the targeting ligand alone. Targeting ligand-pharmacokinetic modulator targeting moiety targeted RNAi polynucleotides can be administered in vivo alone or together with co-targeted delivery polymers.
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(2012/06/30)

Lysine racemase from a lactic acid bacterium, Oenococcus oeni: Structural basis of substrate specificity
Oenococcus oeni, a lactic acid bacterium, possesses a lysine racemase, which has a specific activity towards basic amino acids. A comparison of amino acid residues around the active site suggested that Ile222 and Tyr354 of the Geobacillus stearothermophilus alanine racemase, which shares 60% sequence similarity with lysine racemase, were replaced by Thr224 and Trp355 in the O. oeni lysine racemase. T224I/W355Y double mutations significantly decreased the activity of lysine racemase, whereas I222T/Y354W double mutations endowed alanine racemase with lysine racemization activity. These results suggest that the two residues play an important role in lysine racemization.
Kato, Shiro,Hemmi, Hisashi,Yoshimura, Tohru
p. 505 - 508
(2013/02/25)

METHODS OF MAKING L-ORNITHINE PHENYL ACETATE
Disclosed herein are processes for making L-ornithine phenyl acetate. The process may include, for example, intermixing a halide salt of L-ornithine with silver phenyl acetate. The process may also include forming a phenyl acetate salt in situ. The present application also relates to various compositions obtained from these processes, including crystalline forms.
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(2012/04/23)

Molecular insights into the biosynthesis of guadinomine: A type III secretion system inhibitor
Guadinomines are a recently discovered family of anti-infective compounds produced by Streptomyces sp. K01-0509 with a novel mode of action. With an IC50 of 14 nM, guadinomine B is the most potent known inhibitor of the type III secretion system (TTSS) of Gram-negative bacteria. TTSS activity is required for the virulence of many pathogenic Gram-negative bacteria including Escherichia coli, Salmonella spp., Yersinia spp., Chlamydia spp., Vibrio spp., and Pseudomonas spp. The guadinomine (gdn) biosynthetic gene cluster has been cloned and sequenced and includes 26 open reading frames spanning 51.2 kb. It encodes a chimeric multimodular polyketide synthase, a nonribosomal peptide synthetase, along with enzymes responsible for the biosynthesis of the unusual aminomalonyl-acyl carrier protein extender unit and the signature carbamoylated cyclic guanidine. Its identity was established by targeted disruption of the gene cluster as well as by heterologous expression and analysis of key enzymes in the biosynthetic pathway. Identifying the guadinomine gene cluster provides critical insight into the biosynthesis of these scarce but potentially important natural products.
Holmes, Tracy C.,May, Aaron E.,Zaleta-Rivera, Kathia,Ruby, J. Graham,Skewes-Cox, Peter,Fischbach, Michael A.,Derisi, Joseph L.,Iwatsuki, Masato,Omura, Satoshi,Khosla, Chaitan
supporting information
p. 17797 - 17806
(2013/01/15)

Structure and biosynthetic assembly of cupriachelin, a photoreactive siderophore from the bioplastic producer cupriavidus necator H16
The bacterium Cupriavidus necator H16 produces a family of linear lipopeptides when grown under low iron conditions. The structural composition of these molecules, exemplified by the main metabolite cupriachelin, is reminiscent of siderophores that are excreted by marine bacteria. Comparable to marine siderophores, the ferric form of cupriachelin exhibits photoreactive properties. Exposure to UV light induces an oxidation of its peptidic backbone and a concomitant reduction of the coordinated Fe(III). Here, we report the genomics-inspired isolation and structural characterization of cupriachelin as well as its encoding gene cluster, which was identified by insertional mutagenesis. Based upon the functional characterization of adenylation domain specificity, a model for cupriachelin biosynthesis is proposed.
Kreutzer, Martin F.,Kage, Hirokazu,Nett, Markus
experimental part
p. 5415 - 5422
(2012/05/20)

Stabilized and immobilized bacillus subtilis arginase for the biobased production of nitrogen-containing chemicals
L-Ornithine could serve as an intermediate in the biobased production of 1,4-diaminobutane from L-arginine. Using the concept of biorefinery, Larginine could become widely available from biomass waste streams via the nitrogen storage polypeptide cyanophycin. Selective hydrolysis of L-arginine to L-ornithine is difficult to perform chemically, therefore the stabilization and immobilization of Bacillus subtilis arginase (EC 3.5.3.1) was studied in a continuously stirred membrane reactor system. Initial pH of the substrate solution, addition of L-aspartic acid and reducing agents all appeared to have an effect on the operational stability of B. subtilis arginase. A remarkably good operational stability (total turnover number, TTN = 1. 13-108) at the pH of arginine free base (pH 11.0) was observed, which was further improved with the addition of sodium dithionite to the substrate solution (TTN > 1.109). B. subtilis arginase was successfully immobilized on three commercially available epoxy-activated supports. Immobilization on Sepabeads EC-EP was most promising, resulting in a recovered activity of 75% and enhanced thermostability. In conclusion, the stabilization and immobilization of B. subtilis arginase has opened up possibilities for its application in the biobased production of nitrogen-containing chemicals as an alternative to the petrochemical production.
Koenst, Paul M.,Turras, Pedro M. C. C. D.,Franssen, Maurice C. R.,Scott, Elinor L.,Sanders, Johan P. M.
experimental part
p. 1493 - 1502
(2010/08/20)

Thermokinetic studies on the activation of arginase by glycine
The activation of bovine liver arginase, which catalyzes the hydrolysis of L-arginine to L-ornithine and urea, by glycine was studied by thermokinetic methods at 37 °C in 40 mmol?L-1 sodium barbiturate-HCl buffer solution (pH 9.4). Results of this experiment indicate that an appropriate concentration of glycine can enhance the activity of arginase, and the relative activation rate reached its maximum value, 74%, when the concentration of glycine in reaction system was 1 mmol?L-1 and the initial concentration of arginine was 5 mmol?L-1. With the increase of substrate concentration, the relative activation rate decreased in a definite glycine concentration. Michealis constant Km of reaction decreased from 5.53 to 3.31 mmol?L-1 and inhibition constant of product L-ornithine Kp increased from 1.18 to 3.73 mmol?L-1 when glycine concentration was 1 mmol?L-1. For these reasons one possible activation mechanism of arginase by glycine was suggested that the activation effect results from the competition of glycine and arginine to enzyme activity position. When one or two of the activity positions of arginase are occupied by glycine, it is propitious for the enzyme to complex with substrate and obstruct L-ornithine from combining with enzyme, and when all of the activity positions are occupied by glycine, the activation effect vanishs and the inhibition effect appears.
Xie, Xiuyin,Wang, Cunxin,Wang, Zhiyong
body text
p. 928 - 932
(2010/11/04)

Crystal structure of arginase from plasmodium falciparum and implications for l -arginine depletion in malarial infection
The 2.15 A resolution crystal structure of arginase from Plasmodium falciparum, the parasite that causes cerebral malaria, is reported in complex with the boronic acid inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) (K d = 11 μM). This is the first crystal structure of a parasitic arginase. Various protein constructs were explored to identify an optimally active enzyme form for inhibition and structural studies and to probe the structure and function of two polypeptide insertions unique to malarial arginase: a 74-residue low-complexity region contained in loop L2 and an 11-residue segment contained in loop L8. Structural studies indicate that the low-complexity region is largely disordered and is oriented away from the trimer interface; its deletion does not significantly compromise enzyme activity. The loop L8 insertion is located at the trimer interface and makes several intra- and intermolecular interactions important for enzyme function. In addition, we also demonstrate that arg- Plasmodium berghei sporozoites show significantly decreased liver infectivity in vivo. Therefore, inhibition of malarial arginase may serve as a possible candidate for antimalarial therapy against liver-stage infection, and ABH may serve as a lead for the development of inhibitors.
Dowling, Daniel P.,Ilies, Monica,Olszewski, Kellen L.,Portugal, Silvia,Mota, Maria M.,Llinas, Manuel,Christianson, David W.
experimental part
p. 5600 - 5608
(2011/04/16)

NOVEL MULTIMERIC MOLECULES, A PROCESS FOR PREPARING THE SAME AND THE USE THEREOF FOR MANUFACTURING MEDICINAL DRUGS
The invention relates to a compound of the formula (I): in which k and j are independently 0 or 1, Y is a macrocycle in which the cycle includes 9 to 36 carbon atoms and is functionalised by three amino functions and by a chain for attaching the spacer arm Z via an X bond, Rc is a binding pattern with a receptor of the TNF superfamily, X is a chemical function for binding the Y group to the space arm, and Z is a bi-, tri- or tetra-functional spacer arm.
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(2010/06/16)

NOVEL MULTIMERIC CD40 LIGANDS, METHOD FOR PREPARING SAME AND USE THEREOF FOR PREPARING DRUGS
The invention concerns a compound of formula (I), wherein Y represents a macrocycle whereof the cycle comprises 9 to 36 atoms, and is functionalized by three amine or COOH functions; Rc represents a group of formula H—Xa—Xb—Xc—Xd—Xe—(Xf)i—, wherein i represents 0 or 1, Xn is in particular selected among lysine, arginine, ornithine residues, Xb is in particular selected among glycine, asparagine, L-proline or D-proline residues, Xc et Xd are in particular selected among tyrosine, phenylalanine or 3-nitrotyrosine residues, Xe et Xf are in particular selected among the following amino acid residues: NH2—(CH2)n—COOH, n ranging from 1 to 10 or NH2—(CH2—CH2—O)m—CH2CH2COOH, m ranging from 3 to 6, provided that one at least of the amino acid residues Xa, Xb, Xc and Xd is different from the corresponding amino acid in the sequence of the natural CD40 143Lys-Gly-Tyr-Tyr146 fragment
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(2010/08/07)

Cyclic tripeptides from the halotolerant fungus Aspergillus sclerotiorum PT06-1
Eleven new aspochracin-type cyclic tripeptides, sclerotiotides A-K (1-11), together with three known compounds, JBIR-15 (12), aspochracin (13), and penicillic acid, were isolated from the ethyl acetate extract of the fermentation broth of the halotolerant Aspergillus sclerotiorum PT06-1 in a hypersaline nutrient-rich medium. Their structures were elucidated by spectroscopic analysis and chemical methods. Chemical transformations of 12 and 13 proved that sclerotiotides D-K (4-11) were artifacts probably formed during the fermentation or subsequent isolation steps. All 13 cyclic tripeptides have been evaluated for their antimicrobial and cytotoxic effects. Only sclerotiotides A (1), B (2), F (6), and I (9) and JBIR-15 (12) showed selective antifungal activity against Candida albicans with MIC values of 7.5, 3.8, 30, 6.7, and 30 μM, respectively.
Zheng, Jinkai,Xu, Zhihong,Wang, Yi,Hong, Kui,Liu, Peipei,Zhu, Weiming
experimental part
p. 1133 - 1137
(2010/09/10)

Substrate-selective supramolecular tandem assays: Monitoring enzyme inhibition of arginase and diamine oxidase by fluorescent dye displacement from calixarene and cucurbituril macrocycles
A combination of moderately selective host-guest binding with the impressive specificity of enzymatic transformations allows the real-time monitoring of enzymatic reactions in a homogeneous solution. The resulting enzyme assays ("supramolecular tandem assays") exploit the dynamic binding of a fluorescent dye with a macrocyclic host in competition with the binding of the substrate and product. Two examples of enzymatic reactions were investigated: the hydrolysis of arginine to ornithine catalyzed by arginase and the oxidation of cadaverine to 5-aminopentanal by diamine oxidase, in which the substrates have a higher affinity to the macrocycle than the products ("substrate-selective assays"). The depletion of the substrate allows the fluorescent dye to enter the macrocycle in the course of the enzymatic reaction, which leads to the desired fluorescence response. For arginase, p-sulfonatocalix[4]arene was used as the macrocycle, which displayed binding constants of 6400 M-1 with arginine, 550 M-1 with ornithine, and 60 000 M-1 with the selected fluorescent dye (1-aminomethyl-2,3-diazabicyclo[2.2.2]oct-2-ene); the dye shows a weaker fluorescence in its complexed state, which leads to a switch-off fluorescence response in the course of the enzymatic reaction. For diamine oxidase, cucurbit[7]uril (CB7) was used as the macrocycle, which showed binding constants of 4.5 × 106 M-1 with cadaverine, 1.1 × 105 M-1 with 1-aminopentane (as a model for the thermally unstable 1-aminopentanal), and 2.9 × 105 M-1 with the selected fluorescent dye (acridine orange, AO); AO shows a stronger fluorescence in its complexed state, which leads to a switch-on fluorescence response upon enzymatic oxidation. It is demonstrated that tandem assays can be successfully used to probe the inhibition of enzymes. Inhibition constants were estimated for the addition of known inhibitors, i.e., S-(2-boronoethyl)-L- cysteine and 2(S)-amino-6-boronohexanoic acid for arginase and potassium cyanide for diamine oxidase. Through the sequential coupling of a "product- selective" with a "substrate-selective" assay it was furthermore possible to monitor a multistep biochemical pathway, namely the decarboxylation of lysine to cadaverine by lysine decarboxylase followed by the oxidation of cadaverine by diamine oxidase. This "domino tandem assay" was performed in the same solution with a single reporter pair (CB7/AO).
Nau, Werner M.,Ghale, Garima,Hennig, Andreas,Bakirci, Hueseyin,Bailey, David M.
experimental part
p. 11558 - 11570
(2011/03/21)

Cyclic dipeptide of D-ornithine obtained from the dobsonfly, Protohermes grandis thunberg
A new compound was isolated from the water-soluble fraction of a methyl alcohol extract obtained from the larva of the dobsonfly (Protohermes grandis Thunberg). The novel compound had a 12-membered ring and was confirmed to be a cyclic dipeptide of D-orni
Tanaka, Ryuichiro,Oda, Masashi
body text
p. 1669 - 1670
(2010/03/24)

L-ORNITHINE-CITRIC ACID SALT CRYSTAL
The present invention provides a crystal of a salt of L-ornithine and citric acid, the crystal of the salt of L-ornithine and citric acid in which pH of the 5 weight % aqueous solution is 3 to 6, the crystal of the salt of L-ornithine and citric acid in which a composition ratio of L-ornithine and citric acid is 2: 1 (molar ratio), a process for producing the crystals of the salt of L-ornithine and citric acid which comprises dissolving L-ornithine and citric acid in water, and precipitating the crystal from the resulting aqueous solution, the process for producing the crystal of the salt of L-ornithine and citric acid in which the pH of the aqueous solution is 3 to 6, and the like.
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Page/Page column 4-6

(2008/06/13)

Process for producing alpha 2,3/ alpha 2,8-sialyltransferase and sialic acid-containing complex sugar
The present invention can provide a process for producing a protein having α2,3/α2,8-sialyltransferase activity using a transformant comprising a DNA encoding a protein having α2,3/α2,8-sialyltransferase activity derived from a microorganism belonging to the genus Pasteurella and a process for producing a sialic acid-containing complex carbohydrate using a transformant capable of producing a protein having α2,3/α2,8-sialyltransferase activity derived from a microorganism.
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(2008/06/13)

Fluorescent sensors for diamines
A series of seven diamine sensors was prepared using dimers of a quinolone aldehyde chromophore. Binding to six different diamine guests was explored by a combination of NMR, absorption and fluorescence spectroscopy. It was shown that the dimeric sensors bound the diamine guests by formation of a bis-iminium ion which produced large changes in the fluorescence of the quinolone core. Issues of selectivity between guests are discussed. The Royal Society of Chemistry 2005.
Secor, Kristen,Plante, Jeffrey,Avetta, Christopher,Glass, Timothy
p. 4073 - 4077
(2007/10/03)

STABLE ISOTOPE-LABELED AMINO ACID, METHOD OF INTEGRATING THE SAME INTO TARGET PROTEIN, METHOD OF NMR STRUCTURAL ANALYSIS OF PROTEIN AND PROCESS FOR PRODUCING SITE-SELECTIVE STABLE ISOTOPE-LABELED FUMARIC ACID AND TARTARIC ACID
The present invention provides a stable isotope-labeled amino acid which is at least one of amino acids constituting a protein and which has at least one of the following labeling patterns:(a) hydrogen atoms except at least one hydrogen atom in one or more methylene groups are deuterated,(b) hydrogen atoms in one of prochiral gem-methyl groups are completely deuterated,(c) hydrogen atoms in prochiral methyl groups are partially deuterated, and(d) all hydrogen atoms except one of them in methyl group are deuterated and hydrogen atoms in the aromatic ring are partially deuterated. With the stable isotope-labeled amino acid, the deuteration of protein can be attained without damaging the NMR sensitivity of remaining hydrogen nucleus and, in addition, the rapid, accurate analysis of NMR spectrum of a high-molecular protein which is beyond the limitation in the prior art and the determination of the stereo-structure can be performed at the same time.
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Page 25

(2010/02/08)

20(S) camptothecin glycoconjugates
The present invention relates to glycoconjugates of 20(S)-camptothecin, in which a 3-O-methylated β-L-fucose unit is linked to the 20-hydroxyl group of a camptothecin derivative via a thiourea-modified peptide spacer. The invention furthermore relates to processes for the preparation of the compounds according to the invention and to their use as medicaments, in particular in connection with oncoses.
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(2008/06/13)

Gene recombinant antibody and antibody fragment thereof
A recombinant antibody or the antibody fragment thereof which specifically reacts with an extracellular domain of human CCR4; a DNA which encodes the recombinant antibody or the antibody fragment thereof; a method for producing the recombinant antibody or the antibody fragment thereof; a method for immunologically detecting CCR4, a method for immunologically detecting a cell which expressed CCR4 on the cell surface, a method for depleting a cell which expresses CCR4 on the cell surface, and a method for inhibiting production of Th2 cytokine, which comprise using the recombinant antibody according or antibody fragment thereof; a therapeutic or diagnostic agent for Th2-mediated immune diseases; and a therapeutic or diagnostic agent for a blood cancer.
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(2008/06/13)

Polyamine transport inhibitors
Described herein are novel specific, pure competitive inhibitors of natural polyamine transport in mammalian cells. Despite their low molecular weight, the inhibitors of the present invention stay virtually impermeant to the cell and display minor non-specific effects while exhibiting a very high affinity for the carrier. More specifically described are synthetic derivatives of original polyamines, wherein the original polyamine is modified to comprise an amido group immediately linked to the polyamine backbone. A side chain may be anchored to the amido group and provide for the formation of dimeric synthetic derivatives or its labelling and subsequent usage as a marker for the polyamine transporter. The use of such novel inhibitors of polyamine transport to evaluate the antitumor efficacy of polyamine depletion strategies with minimal systemic cytotoxic effects or to control and treat disorders involving unrestrained cell proliferation and/or cell differentiation wherein polyamine transport is required as well as pharmaceutical composition thereof are also described.
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(2008/06/13)

Substituted quinoxaline-2-ones as glutamate receptor antagonists
A novel series of substituted quinoxaline 2-ones useful as neuroprotective agents are taught. Novel intermediates, processes of preparation, and pharmaceutical compositions containing the compounds are also taught. The compounds are glutamate receptor antagonists and are useful in the treatment of stroke, cerebral ischemia, or cerebral infarction resulting from thromboembolic or hemorrhagic stroke, cerebral vasospasms, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia, seizure disorders, pain, Alzheimer's, Parkinson's, and Huntington's Diseases.
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(2008/06/13)

Amino acid conjugates of cyclohexapeptidyl amines
Novel amino acid conjugates of cyclohexa-peptidyl amines having the formula STR1 and having antifungal and antiparasital properties are described. The compounds exhibit less acute toxicity than the free amines.
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(2008/06/13)

Rhodopeptins, novel cyclic tetrapeptides with antifungal activities from Rhodococcus sp.. II. Structure elucidation
The structures of rhodopeptins, novel antifungal peptides, were determined on the basis of physico-chemical analyses of the intact molecules and their acid hydrolysates. The structures of rhodopeptins C1, C2, C3, C4 and B5 were determined to be cyclo (-Gly-L-Orn-L-Val-3-amino-10 -methyldodecanoyl-), cyclo (-Gly-L-Orn-L-Ile-3-amino-10-methyldodecanoyl-), cyclo (-Gly-L-Orn-L-Val-3 -amino-12-methyltridecanoyl-), cyclo (-Gly-L-Orn-L-Val-3-amino-l2-methyltetradecanoyl-) and cyclo (-Gly-L-Lys-L-Val-3-amino-13-methyltetradecanoyl-), respectively. They are novel cyclic tetrapeptides containing a lipophilic β-amino acid.
Chiba, Hiroyuki,Agematu, Hitosi,Dobashi, Kazuyuki,Yoshioka, Takeo
p. 700 - 709
(2007/10/03)

Parenteral nutrition therapy with amino acids
Parenteral nutrition aqueous solutions are provided which preferably contain glutamine together with other organic nitrogen containing compounds. The respective concentrations of the compounds present in any given such solution are typically approximately multiples of the concentration of the same compounds as found in normal human plasma, and the respective mole ratios of various such compounds in any given such solution relative to one another are approximately the same mole ratio associated with the same compounds as found in normal human plasma. Processes for using such solutions are provided.
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(2008/06/13)

Peptides with an insulin-like action
Peptides with an insulin-like action, of formula I: STR1 in which G is a hydrogen atom, an amino add residue, or a monosubstituted or polysubstituted amino acid; D is an amino acid residue, a phosphoamino acid residue, a monosaccharide residue, or a covalent bond; E is --NH--(CH2)n --NR52, a glycerol residue, or --NH--(CH2)p --R6 --R7 ; R1 is (C1 -C4)-alkyl or =O; R2 is a sulfhydryl protecting group, (C1 -C3)-alkyl, or a hydrogen atom; R3 and R4, independently of one another, are a hydrogen atom or methyl; R5, each being identical or different, is a hydrogen atom, 1 to 6 monosaccharide residues, or 1 to 6 monosubstituted or polysubstituted monosaccharide residues; R6 is O PO4 H, PO2 H, NHCOO, S or OCOO; R7 is a hydrogen atom, 1 to 6 monosaccharide residues, or 1 to 6 monosubstituted or polysubstituted monosaccharide residues; w is an integer 1 or 2; their preparation and use for treatment of diabetes mellitus or insulin-independent diabetes.
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(2008/06/13)

Cosmetic composition
A composition suitable for topical application to mammalian skin and hair for inducing, maintaining or increasing hair growth comprises a hair growth promoter chosen from glutamine derivatives and salts thereof. The composition preferably also comprises an activity enhancer which may be chosen from hair growth stimulants, penetration enhancers and cationic polymers.
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(2008/06/13)

Long-wavelength water soluble chlorin photosensitizers useful for photodynamic therapy and diagnosis of tumors
Novel photosensitizers useful for photodynamic therapy and diagnosis of tumors. Photosensitizers are derived from chlorophyll-a of photosynthetic plants and algae, possess long wavelength absorption between 600 and 800 nm, are stable, and water soluble. A process of preparation of these compounds and method of use for diagnostic and therapeutic purposes.
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(2008/06/13)

Optically active ester derivatives, preparation process thereof, liquid crystal materials and a light switching element
Disclosed are herein optically active ester derivatives represented by the formula (I): STR1 (wherein R1 represents an alkyl group having 3 to 20 carbon atoms; R2 represents an optically active alkyl or alkoxyalkyl group having 3 to 15 carbon atoms optionally substituted by halogen atoms; Y represents --O--, --COO-- or --OCO--; X represents --COO-- or --OCO--; l represents a number of 1 or 2; k and m each represents a number of 0 or 1; n represents a number of 1 to 6), preparation processes therefor, liquid crystal materials containing such ester derivatives as active ingredient, and a light switching element using said liquid crystal materials as liquid crystal element.
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(2008/06/13)

Chemoenzymatische Synthesen von D-ω-Ureidoaminisaeuren
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Drauz, Karlheinz,Kottenhahn, Matthias,Makryaleas, Kyriakos,Klenk, Herbert,Bernd, Michael
p. 704 - 706
(2007/10/02)

Process for making an optically active mixture of an n-acyl-amino acid or ester containing at least two chiral centers
In the process of hydrocarboxylating an α-enamide with CO and H2O or an organic hydroxyl compound to produce an N-acyl-α-amino acid or ester, respectively, the improvement comprising using as the α-enamide reactant, an α-enamide which has a chiral center that is essentially all L or D, thereby producing a reaction mixture containing diastereomeric N-acyl-α-amino acids or esters having two chiral centers, said mixture having essentially no enantiomeric pairs.
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(2008/06/13)

Novel spergualin-related compounds and compositions
The present invention relates to novel spergualin-related compounds represented by the general formula [I]: STR1 wherein X is --(CH2)1?5 or STR2 Y is a hydrogen atom or a residue obtained by removing a hydroxyl group from the carboxyl group of an amino acid or a peptide; m is 0, 1 or 2 and n is 1 or 2, with the proviso that Y is not a hydrogen atom when n is 2 and m is 0. This compounds are stable and exhibit a high immunosuppressive activity.
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(2008/06/13)

Process for making an optically active mixture of an N-acyl-amino acid or ester containing at least two chiral centers
In the process of hydrocarboxylating an α-enamide with CO and H2 O or an organic hydroxyl compound to produce an N-acyl-α-amino acid or ester, respectively, the improvement comprising using as the α-enamide reactant, an α-enamide which has a chiral center that is essentially all L or D, thereby producing a reaction mixture containing diastereomeric N-acyl-α-amino acids or esters having two chiral centers, said mixture having essentially no enantiomeric pairs.
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(2008/06/13)

New Pyoverdin-Type Siderophores from Pseudomonas fluorescens
The structures of two new pyoverdins (GM-I and GM-II) isolated from the culture medium of Pseudomonas fluorescens have been elucidated by spectroscopic methods and degradation studies.The pyoverdins consist of a chromophore which could be identified as (1S)-5-amino-2,3-dihydro-8,9-dihydroxy-1H-pyrimidoquinoline-1-carvoxylic acid substituted at the amino group with 3-carboxypropanoyl or a siccinamoyl residue and at the carboxy group with the N-terminus of D-Ala-D-Lys-Gly-Gly-D-threo-(OH)Asp-D-Glu-D-Ser-L-Ala-D-Ala-L-Ala-L-N5-(OH)Orn.According to the "short-hand" nomenclatur proposed in the two compounds should be characterized as pyoverdin-X-akGGd'qsAaaAO'*-SUCA and pyoverdin-Q-akGGD'qaAaaAO'*-SUC.
Mohn, G.,Taraz, K.,Budzikiewicz, H.
p. 1437 - 1450
(2007/10/02)

Stereoselective Synthesis of 2,4-Diamino Acids by Asymmetric Hydrogenation
A stereoselective synthesis of unusual basic amino acids, ornithine, 2,4-diaminopentanoic acid, and 2,4-diamino-6-methylheptanoic acid, was achieved by the hydrogenation of cyclic α,β-dehydro dipeptides obtained by the condensation of cyclo(-Gly-L(or D)-aminoacyl-) and protected linear or chiral amino aldehydes.The degree of chiral induction greatly depended on the bulkiness of the side chains of α,β-dehydro amino acids.The Rf values on paper chromatography of (2S,4S or 2R,4S)-diaminopentanoic acid prepared by the present method were different from the reported values of a compound which had been obtained from metabolic products of Clostridium sticklandii and estimated to be 2,4-diaminopentanoic acid.
Park, Nam Gyu,Lee, Sannamu,Maeda, Hiroshi,Aoyagi, Haruhiko,Kato, Tetsuo
p. 2315 - 2319
(2007/10/02)