- Identification and characterization of γ-glutamylamine cyclotransferase, an enzyme responsible for γ-glutamyl-ε-lysine catabolism
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γ-Glutamylamine cyclotransferase (GGACT) is an enzyme that converts γ-glutamylamines to free amines and 5-oxoproline. GGACT shows high activity toward γ-glutamyl-ε-lysine, derived from the breakdown of fibrin and other proteins cross-linked by transglutaminases. The enzyme adopts the newly identified cyclotransferase fold, observed in γ- glutamylcyclotransferase (GGCT), an enzyme with activity toward γ-glutamyl-α-amino acids (Oakley, A. J., Yamada, T., Liu, D., Coggan, M., Clark, A. G., and Board, P. G. (2008) J. Biol. Chem. 283, 22031-22042). Despite the absence of significant sequence identity, several residues are conserved in the active sites of GGCTand GGACT, including a putative catalytic acid/base residue (GGACT Glu82). The structure of GGACT in complex with the reaction product 5-oxoproline provides evidence for a commoncatalytic mechanism in both enzymes. The proposed mechanism, combined with the three-dimensional structures, also explains the different substrate specificities of these enzymes. Despite significant sequence divergence, there are at least three subfamilies in prokaryotes and eukaryotes that have conserved the GGCT fold and GGCT enzymatic activity.
- Oakley, Aaron J.,Coggan, Marjorie,Board, Philip G.
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Read Online
- Massive Glutamine Cyclization to Pyroglutamic Acid in Human Serum Discovered Using NMR Spectroscopy
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Glutamine is one of the most abundant metabolites in blood and is a precursor as well as end product central to numerous important metabolic pathways. A number of surprising and unexpected roles for glutamine, including cancer cell glutamine addiction discovered recently, stress the importance of accurate analysis of glutamine concentrations for understanding its role in health and numerous diseases. Utilizing a recently developed NMR approach that offers access to an unprecedented number of quantifiable blood metabolites, we have identified a surprising glutamine cyclization to pyroglutamic acid that occurs during protein removal. Intact, ultrafiltered and protein precipitated samples from the same pool of human serum were comprehensively investigated using 1H NMR spectroscopy at 800 MHz to detect and quantitatively evaluate the phenomenon. Interestingly, although glutamine cyclization occurs in both ultrafiltered and protein precipitated serum, the cyclization was not detected in intact serum. Strikingly, due to cyclization, the apparent serum glutamine level drops by up to 75% and, concomitantly, the pyroglutamic acid level increases proportionately. Further, virtually under identical conditions, the magnitude of cyclization is vastly different for different portions of samples from the same pool of human serum. However, the sum of glutamine and pyroglutamic acid concentrations in each sample remains the same for all portions. These unexpected findings indicate the importance of considering the sum of apparent glutamine and pyroglutamic acid levels, obtained from the contemporary analytical methods, as the actual blood glutamine level for biomarker discovery and biological interpretations. (Graph Presented)
- Gowda, G. A. Nagana,Gowda, Yashas N.,Raftery, Daniel
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- Crystal structure and functional analysis of the glutaminyl cyclase from Xanthomonas campestris
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Glutaminyl cyclases (QCs) (EC 2.3.2.5) catalyze the formation of pyroglutamate (pGlu) at the N-terminus of many proteins and peptides, a critical step for the maturation of these bioactive molecules. Proteins having QC activity have been identified in animals and plants, but not in bacteria. Here, we report the first bacterial QC from the plant pathogen Xanthomonas campestris (Xc). The crystal structure of the enzyme was solved and refined to 1.44-A resolution. The structure shows a β-propeller and exhibits a scaffold similar to that of papaya QC (pQC), but with some sequence deletions and conformational changes. In contrast to the pQC structure, the active site of XcQC has a wider substrate-binding pocket, but its accessibility is modulated by a protruding loop acting as a flap. Enzyme activity analyses showed that the wild-type XcQC possesses only 3% QC activity compared to that of pQC. Superposition of those two structures revealed that an active-site glutamine residue in pQC is substituted by a glutamate (Glu45) in XcQC, although position 45 is a glutamine in most bacterial QC sequences. The E45Q mutation increased the QC activity by an order of magnitude, but the mutation E45A led to a drop in the enzyme activity, indicating the critical catalytic role of this residue. Further mutagenesis studies support the catalytic role of Glu89 as proposed previously and confirm the importance of several conserved amino acids around the substrate-binding pocket. XcQC was shown to be weakly resistant to guanidine hydrochloride, extreme pH, and heat denaturations, in contrast to the extremely high stability of pQC, despite their similar scaffold. On the basis of structure comparison, the low stability of XcQC may be attributed to the absence of both a disulfide linkage and some hydrogen bonds in the closure of β-propeller structure. These results significantly improve our understanding of the catalytic mechanism and extreme stability of type I QCs, which will be useful in further applications of QC enzymes.
- Huang, Wei-Lin,Wang, Yu-Ruei,Ko, Tzu-Ping,Chia, Cho-Yun,Huang, Kai-Fa,Wang, Andrew H.-J.
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Read Online
- Preparation method of (S)-1 - (benzyloxycarbonyl) -5 -oxo-pyrrolidine -2 - formic acid
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The invention discloses a preparation method of (S)-1 - (benzyloxycarbonyl) -5 -oxo-pyrrolidine -2 - formic acid, which mainly solves the complexity in the original process, and is long in period and high in cost. The method specifically comprises first steps of preparing L - benzyloxycarbonyl N - glutamic acid from - L - glutamic acid and a benzyloxycarbonyl donor, second steps of intramolecular condensation cyclization N - benzyloxycarbonyl - L - glutamic acid to obtain the N -benzyloxycarbonyl - L - glutamic acid crude product. The third The crude N - benzyloxycarbonyl - L - glutamic acid crude product and the organic amine base are mixed, and the organic amine salt form is prepared by the solubility of the product in a solvent, fourth (N -) - L - (benzyloxycarbonyl) S oxopyrrolidine -1 - formic acid is prepared by desalinating -5 - benzyloxycarbonyl -2 - glutamic acid. To the method, the high-purity product is prepared, and the yield and the quality are greatly improved.
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Paragraph 0044
(2021/09/01)
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- A colorimetric assay method for measuring D-glutamate cyclase activity
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In mammals, metabolism of free D-glutamate is regulated by D-glutamate cyclase (DGLUCY), which reversibly converts D-glutamate to 5-oxo-D-proline and H2O. Metabolism of these D-amino acids by DGLUCY is thought to regulate cardiac function. In this study, we established a simple, accurate, and sensitive colorimetric assay method for measuring DGLUCY activity. To this end, we optimized experimental procedures for derivatizing 5-oxo-D-proline with 2-nitrophenylhydrazine hydrochloride. 5-Oxo-D-proline was derivatized with 2-nitrophenylhydrazine hydrochloride in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide as a catalyst to generate the acid hydrazides, whose levels were then determined using a colorimetric method. Under optimized conditions, we examined the sensitivity and accuracy of the colorimetric method and compared our technique with other methods by high-performance liquid chromatography with ultraviolet–visible or fluorescence detection. Moreover, we assessed the suitability of this colorimetric method for measuring DGLUCY activity in biological samples. Our colorimetric method could determine DGLUCY activity with adequate validity and reliability. This method will help to elucidate the relationship among DGLUCY activity, the physiological and pathological roles of D-glutamate and 5-oxo-D-proline, and cardiac function.
- Ariyoshi, Makoto,Hamase, Kenji,Homma, Hiroshi,Katane, Masumi,Matoba, Satoaki,Mita, Masashi,Miyamoto, Tetsuya,Motoda, Risa,Nakayama, Kazuki,Saitoh, Yasuaki,Sakai-Kato, Kumiko,Sekine, Masae,Tateishi, Shuhei
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- Designed proteinoid polymers and nanoparticles encapsulating risperidone for enhanced antipsychotic activity
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Background: Nanoparticles (NPs) incorporating drug formulations can be used to facilitate passage through biological barriers including the blood–brain barrier (BBB) and increase drug delivery and bioavailability. Hence, NP-based administration may enhance the efficiency of current antipsychotics. Encapsulation within NPs can resolve aqueous solubility problems that not only reduce permeability through the BBB but also affect targeting. The present study describes a new drug delivery system based on proteinoid NPs to explore the possibility of improving drug efficacy. Risperidone (RSP) is a commonly used atypical antipsychotic medication, and was therefore selected for encapsulation by proteinoid NPs. Results: Proteinoid polymers with high molecular weight and low polydispersity were synthesized from l-amino acids and poly-l-lactic acid (PLLA) by thermal step-growth polymerization mechanism. RSP-loaded proteinoid NPs were then prepared using a self-assembly process in the presence of RSP, followed by PEGylation. The optimal PEGylated RSP-loaded NPs were characterized in terms of diameter and size distribution, drug loading, ζ-potential, cytotoxicity, biodistribution, and psychopharmacological effects. The findings indicate significantly higher antipsychotic activity of drug-loaded proteinoid NPs compared to free RSP. Conclusions: Proteinoid NPs enhance RSP delivery and may potentially increase drug efficiency by reducing dosage and side effects.[Figure not available: see fulltext.].
- Einat, H.,Grinberg, I.,Lugasi, L.,Margel, S.,Okun, E.,Rudnick-Glick, S.
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- Organocatalytic Decarboxylation of Amino Acids as a Route to Bio-based Amines and Amides
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Amino acids obtained by fermentation or recovered from protein waste hydrolysates represent an excellent renewable resource for the production of bio-based chemicals. In an attempt to recycle both carbon and nitrogen, we report here on a chemocatalytic, metal-free approach for decarboxylation of amino acids, thereby providing a direct access to primary amines. In the presence of a carbonyl compound the amino acid is temporarily trapped into a Schiff base, from which the elimination of CO2 may proceed more easily. After evaluating different types of aldehydes and ketones on their activity at low catalyst loadings (≤5 mol%), isophorone was identified as powerful organocatalyst under mild conditions. After optimisation many amino acids with a neutral side chain were converted in 28–99 % yield in 2-propanol at 150 °C. When the reaction is performed in DMF, the amine is susceptible to N-formylation. This consecutive reaction is catalysed by the acidity of the amino acid reactant itself. In this way, many amino acids were efficiently transformed to the corresponding formamides in a one-pot catalytic system.
- Claes, Laurens,Janssen, Michiel,De Vos, Dirk E.
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p. 4297 - 4306
(2019/08/26)
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- Substrate Specificity and Chemical Mechanism for the Reaction Catalyzed by Glutamine Kinase
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Campylobacter jejuni, a leading cause of gastroenteritis worldwide, has a unique O-methyl phosphoramidate (MeOPN) moiety attached to its capsular polysaccharide. Investigations into the biological role of MeOPN have revealed that it contributes to the pathogenicity of C. jejuni, and this modification is important for the colonization of C. jejuni. Previously, the reactions catalyzed by four enzymes (Cj1418-Cj1415) from C. jejuni that are required for the biosynthesis of the phosphoramidate modification have been elucidated. Cj1418 (l-glutamine kinase) catalyzes the formation of the initial phosphoramidate bond with the ATP-dependent phosphorylation of the amide nitrogen of l-glutamine. Here we show that Cj1418 catalyzes the phosphorylation of l-glutamine through a three-step reaction mechanism via the formation of covalent pyrophosphorylated (Enz-X-Pβ-Pγ) and phosphorylated (Enz-X-Pβ) intermediates. In the absence of l-glutamine, the enzyme was shown to catalyze a positional isotope exchange (PIX) reaction within β-[18O4]-ATP in support of the formation of the Enz-X-Pβ-Pγintermediate. In the absence of ATP, the enzyme was shown to catalyze a molecular isotope exchange (MIX) reaction between l-glutamine phosphate and [15N-amide]-l-glutamine in direct support of the Enz-X-Pβintermediate. The active site nucleophile has been identified as His-737 based on the lack of activity of the H737N mutant and amino acid sequence comparisons. The enzyme was shown to also catalyze the phosphorylation of d-glutamine, γ-l-glutamyl hydroxamate, γ-l-glutamyl hydrazide, and β-l-aspartyl hydroxamate, in addition to l-glutamine.
- Taylor, Zane W.,Chamberlain, Alexandra R.,Raushel, Frank M.
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- Substrate Specificity and Chemical Mechanism for the Reaction Catalyzed by Glutamine Kinase
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Campylobacter jejuni, a leading cause of gastroenteritis worldwide, has a unique O-methyl phosphoramidate (MeOPN) moiety attached to its capsular polysaccharide. Investigations into the biological role of MeOPN have revealed that it contributes to the pathogenicity of C. jejuni, and this modification is important for the colonization of C. jejuni. Previously, the reactions catalyzed by four enzymes (Cj1418-Cj1415) from C. jejuni that are required for the biosynthesis of the phosphoramidate modification have been elucidated. Cj1418 (l-glutamine kinase) catalyzes the formation of the initial phosphoramidate bond with the ATP-dependent phosphorylation of the amide nitrogen of l-glutamine. Here we show that Cj1418 catalyzes the phosphorylation of l-glutamine through a three-step reaction mechanism via the formation of covalent pyrophosphorylated (Enz-X-Pβ-Pγ) and phosphorylated (Enz-X-Pβ) intermediates. In the absence of l-glutamine, the enzyme was shown to catalyze a positional isotope exchange (PIX) reaction within β-[18O4]-ATP in support of the formation of the Enz-X-Pβ-Pγintermediate. In the absence of ATP, the enzyme was shown to catalyze a molecular isotope exchange (MIX) reaction between l-glutamine phosphate and [15N-amide]-l-glutamine in direct support of the Enz-X-Pβintermediate. The active site nucleophile has been identified as His-737 based on the lack of activity of the H737N mutant and amino acid sequence comparisons. The enzyme was shown to also catalyze the phosphorylation of d-glutamine, γ-l-glutamyl hydroxamate, γ-l-glutamyl hydrazide, and β-l-aspartyl hydroxamate, in addition to l-glutamine.
- Taylor, Zane W.,Chamberlain, Alexandra R.,Raushel, Frank M.
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p. 5447 - 5455
(2018/09/25)
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- Method for preparing hydrobromic acid teneligliptin
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The invention provides a method for preparing hydrobromic acid teneligliptin. The method includes steps of preparing L-hydroxyproline; mixing the L-hydroxyproline and sodium bicarbonate with each other to obtain mixtures, dissolving the mixtures in water, adding acetone into the water, dropping di-tert-butyl dicarbonate into the water, carrying out room-temperature reaction overnight and then treating reaction products to obtain t-butyloxycarboryl-N-hydroxyproline; preparing t-butyloxycarboryl-N-4-oxo-proline from the t-butyloxycarboryl-N-hydroxyproline; preparing (2S)-4-oxo-2-(3-thiazolidine carbonyl)-1-pyrrolidine carboxylic acid tert-butyl ester from the t-butyloxycarboryl-N-4-oxo-proline; preparing compounds III from compounds IV; preparing compounds II from the compounds III; preparing compounds 1-(3-methyl-1-phenyl-1H-pyrazole-5-base) piperazine from the compounds II; preparing intermediates I; preparing the hydrobromic acid teneligliptin from the intermediates I. The method has the advantages that the method is low in cost, and the cost of the method is only two-thirds of the cost of an existing method in the prior art; the yield of the hydrobromic acid teneligliptin is higher than 95%, and the purity of the hydrobromic acid teneligliptin is higher than 98%.
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Paragraph 0043; 0044
(2017/07/01)
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- Bio-based N-alkyl-2-pyrrolidones by Pd-catalyzed reductive N-alkylation and decarboxylation of glutamic acid
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Environmental regulations boost the search for new safer and less toxic bio-based solvents to replace controversial high-boiling solvents such as N-methyl-2-pyrrolidone and N,N-dimethylformamide in the chemical industry. Recently, N-alkyl-2-pyrrolidones and 5-methyl-N-alkyl-2-pyrrolidones were proposed as attractive alternative solvents for many applications. Here, we report a bio-based two-step chemocatalytic system for the synthesis of a broad range of N-alkyl-2-pyrrolidones starting from glutamic acid and C3-C5 carbonyl compounds. In the first step N-mono-alkylated derivatives of glutamic acid were synthesized in high yields (>85%) by a mild and efficient Pd-catalyzed reductive N-alkylation. Subsequently, thermally induced lactamization to the corresponding N-alkylpyroglutamic acid followed by Pd-catalyzed decarboxylation at 250 °C under inert atmosphere resulted in N-alkyl-2-pyrrolidones. Hydrolytic degradation was partially counteracted by the neutralization of the N-alkylpyroglutamic acid substrate with a base, resulting in yields up to 82%. Finally, both reaction steps were successfully combined in a one-pot process using the same Pd/Al2O3 catalyst in different conditions of gas atmosphere and temperature.
- De Schouwer, Free,Adriaansen, Sander,Claes, Laurens,De Vos, Dirk E.
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p. 4919 - 4929
(2017/10/19)
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- Design of fluorogenic probes and fluorescent-tagged inhibitors for γ-glutamyl cyclotransferase
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A tumor-related protein, human chromosome 7 ORF 24 (C7orf24), is involved in regulation of the glutathione homeostasis cycle as a γ-glutamyl cyclotransferase (GGCT). The singular substrate preference of this enzyme had long hampered its chemical probe development. That is, substrate of GGCT is definitely ‘γ-Glu-Xaa’, where Xaa is an L-α-amino acid. Based on the structure of substrates and GGCT fluorogenic probes, LISA-4/101, we succesfully developed a fluorescent-tagged inhibitor, gKFA. These chemical tools will assist cancer-related researches in the future.
- Yoshiya, Taku,Ii, Hiromi,Tsuda, Shugo,Mochizuki, Masayoshi,Kageyama, Susumu,Yoshiki, Tatsuhiro
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p. 618 - 623
(2017/08/15)
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- Process for preparing hyperpolarized substrates and method for MRI
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The present invention generally relates to a process for the preparation of aqueous solutions of hyperpolarized molecules ready for use in in-vivo MR diagnostic imaging, the use thereof as MRI contrast agent in investigation methods for producing diagnostic MR images of a human or non-human animal body organ, region or tissue.
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Page/Page column 32
(2017/08/01)
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- L-pyrrolidine carboxylic acid new process for the synthesis of (by machine translation)
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The invention relates to a new synthetic process of L-pyrrolidone carboxylic acid. The process comprises the steps of adding an organic solvent and L-glutamic acid into a reactor, heating to 50-60 DEG C, stirring, dropping a dehydrating agent, performing heat preservation reaction for 1-5 hours, then naturally cooling, performing after-treatment on a product, and performing vacuum drying to obtain a white solid product. Under the condition of normal pressure and in presence of the dehydrating agent, a technical scheme of synthesizing L-pyrrolidone carboxylic acid at relatively low temperature is provided; the technical scheme is mild in synthesis condition, short in reaction time, convenient in production operation and simple in equipment requirement; L-pyrrolidone carboxylic acid obtained by adopting the technical scheme is relatively high in product purity, and is beneficial for industrial production.
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Paragraph 0018; 0019; 0020; 0021; 0022
(2016/12/01)
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- Preparation method for L-hydroxyproline
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The invention provides a preparation method for L-hydroxyproline. The preparation method comprises the following steps: preparing pyroglutamic acid; preparing pyroglutamate; preparing pyroglutamic acid alcohol; preparing (3R,7aS)-3-phenyltetrahydropyrrolo[1,2]oxazole-5(3H)-one; and preparing L-hydroxyproline. Compared with the prior art, the invention has the following beneficial effects: the method overcomes the problems that a traditional manner of extraction of L-hydroxyproline from an animal donor has potential safety hazards and that production of L-hydroxyproline is limited as biological raw materials are utilized, and can synthesize L-hydroxyproline under the condition of shortage of biological raw materials; synthetic methods for L-hydroxyproline are enriched; the added value of L-hydroxyproline is increased; the application scope of L-hydroxyproline can be further broadened; prepared L-hydroxyproline is high in yield and purity, so the synthesis purity of atazanavir is indirectly improved; and common raw materials can be selected in preparation of L-hydroxyproline, so production cost is low.
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Paragraph 0071; 0072
(2016/10/10)
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- A method for preparing butanediimide (by machine translation)
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The present invention provides a method for preparing butanediimide, including: in the pyroglutamic acid and burnt glutanic acid salt of one or two, with an aqueous solution of a silver salt, persulfate mixed, succinimide obtained after the reaction. In this application in the process of preparing butanediimide, to pyroglutamic acid or burnt glutanic acid salt as raw materials, using the nitrogen source for the amino acid itself, avoid the corrosion resistance caused by the additional nitrogen source, therefore the mild condition of the preparation butanediimide; and this application uses wide raw material sources, the only role of silver salts and persulphate butanediimide can be obtained, therefore the preparation method is simple. (by machine translation)
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Paragraph 0033; 0034
(2017/03/17)
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- A L-villaggio glu preparation method (by machine translation)
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The invention discloses a preparation method of an L-pyroglutamic acid. The preparation method comprises the following steps: 1, melting, namely melting a L-glutamic acid serving as a raw material at a temperature ranging from 170 DEG C to 180 DEG C and under the pressure ranging from 0.45MP to 0.55MP; 2, cooling, namely after the temperature of the melt falls, feeding the melt into a cooling tank until the melt is completely coagulated into a block; 3, decoloring, namely putting the cooled block into mother liquor, increasing the temperature to the range of 70 DEG C to 75 DEG C and then adding activated carbon for decoloring; 4, filtering, namely filtering by use of a plate frame and remaining the filtrate for crystallization; 5, cooling the filtrate and separating out crystals; and 6, separating, namely putting the solid-liquid mixture after crystallization into a centrifugal separator to separate out the finished product L-pyroglutamic acid. Due to the adopted technical scheme of the preparation method of the L-pyroglutamic acid, the reaction temperature is reduced, and DL-pyroglutamic acid and other impurities are reduced; the production efficiency is improved; the production steps are reduced so that the cost is reduced; the quality and yield of the product are obviously improved and increased, and large-scale production can be realized.
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Paragraph 0026-0027; 0032; 0039
(2017/04/11)
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- A GGCT fluorogenic probe: Design, synthesis and application to cancer-related cells
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Cancer-related γ-glutamyl cyclotransferase (GGCT) specifically converts γ-glutamyl amino acids (γ-Glu-Xaa) into pyroglutamate and the corresponding amino acids (Xaa). Here we report a novel GGCT fluorogenic probe LISA-101 containing a masked O-acylated fluorophore resorufin on the side chain of the P′1 amino acid (Xaa). Upon GGCT treatment, the P′1 amino acid was liberated and spontaneously released the intact fluorophore. Thus, the fluorescence was regained. LISA-101 will expand the strategies for cancer studies.
- Yoshiya, Taku,Ii, Hiromi,Tsuda, Shugo,Kageyama, Susumu,Yoshiki, Tatsuhiro,Nishiuchi, Yuji
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supporting information
p. 3182 - 3185
(2015/03/18)
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- Synthesis of tertiary and quaternary amine derivatives from wood resin as chiral NMR solvating agents
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Chiral tertiary and quaternary amine solvating agents for NMR spectroscopy were synthesized from the wood resin derivative (+)-dehydroabietylamine (2). The resolution of enantiomers of model compounds [Mosher's acid (3) and its n-Bu4N salt (4)] (guests) by (+)-dehydroabietyl-N,N-dimethylmethanamine (5) and its ten different ammonium salts (hosts) was studied. The best results with 3 were obtained using 5 while with 4 the best enantiomeric resolution was obtained using (+)-dehydroabietyl-N,N-dimethylmethanaminium bis(trifluoromethane-sulfonimide) (6). The compounds 5 and 6 showed a 1:1 complexation behaviour between the host and guest. The capability of 5 and 6 to recognize the enantiomers of various α-substituted carboxylic acids and their n-Bu4N salts in enantiomeric excess (ee) determinations was demonstrated. A modification of the RES-TOCSY NMR pulse sequence is described, allowing the enhancement of enantiomeric discrimination when the resolution of multiplets is insufficient.
- Laaksonen, Tiina,Heikkinen, Sami,W?h?l?, Kristiina
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supporting information
p. 20873 - 20886
(2015/12/23)
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- Peptide Tyrosinase Activators
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Peptides that increase melanin synthesis are provided. These peptides include pentapeptides YSSWY, YRSRK, and their variants. The peptides may activate the enzymatic activity of tyrosinase to increase melanin synthesis. The pharmaceutical, cosmetic, and other compositions including the peptides are also provided. The methods of increasing melanin production in epidermis of a subject are provided where the methods include administering compositions comprising an amount of one or more peptides effective to increase the melanin production. The methods also include treating vitiligo or other hypopigmentation disorders with compositions including one or more peptides.
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- Facile synthesis of α-hydroxy carboxylic acids from the corresponding α-amino acids
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An effective and improved procedure is developed for the synthesis of α-hydroxy carboxylic acids by treatment of the corresponding protonated α-amino acid with tert-butyl nitrite in 1,4-dioxane-water. The amino moiety must be protonated and located α to a carboxylic acid function in order to undergo initial diazotization and successive hydroxylation, since neither β-amino acids nor acid derivatives such as esters and amides undergo hydroxylations. The method is successfully applied for the synthesis of 18 proteinogenic amino acids.
- Stuhr-Hansen, Nicolai,Padrah, Shahrokh,Str?mgaard, Kristian
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p. 4149 - 4151
(2015/02/02)
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- Straightforward synthesis of non-natural l-chalcogen and l-diselenide N-Boc-protected-γ-amino acid derivatives
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The synthesis of new chiral seleno-, telluro-, and thio-N-Boc-γ-amino acids is described herein. These new compounds were prepared through a simple and short synthetic route, from the inexpensive and commercially-available amino acid l-glutamic acid. The products, with a highly modular character, were obtained in good to excellent yields, via hydrolysis of chalcogen pyroglutamic derivatives with overall retention of the l-glutamic acid stereochemistry. Also, an l-diselenide-N-Boc-γ-amino acid was prepared in good yield. This new synthetic route represents an efficient method for preparing new l-chalcogen- and l-diselenide-γ-amino acids with biological potential.
- Kawasoko, Cristiane Y.,Foletto, Patricia,Rodrigues, Oscar E. D.,Dornelles, Luciano,Schwab, Ricardo S.,Braga, Antonio L.
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p. 5173 - 5183
(2013/08/15)
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- SUBSTITUTED PYRIDOXINE-LACTAM CARBOXYLATE SALTS
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The present invention provides salt adducts comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted, methods of their preparation, and pharmaceutical compositions and medicaments comprising them. Salt adducts of the invention and compositions comprising them may be used to in the treatment of diseases or disorders associated with or inflicted by alcohol consumption.
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Page/Page column 12
(2011/12/13)
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- 1-Acetylpyrene with dual functions as an environment-sensitive fluorophore and fluorescent photoremovable protecting group
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A series of new fluorescent ester conjugates of carboxylic acids including amino acids was synthesized by coupling with an environment-sensitive fluorophore 1-acetylpyrene. Interestingly, the fluorescence properties of the ester conjugates and 1-acetylpyrene were found to be highly sensitive to its surrounding environment. The results obtained from the photolysis of the ester conjugates indicated that various factors like solvent, irradiation wavelength, and the structure of the conjugates govern the rate of the photocleavage.
- Jana, Avijit,Atta, Sanghamitra,Sarkar, Sujan K.,Singh, N.D. Pradeep
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supporting information; experimental part
p. 9798 - 9807
(2011/02/22)
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- Discovery and structure-activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor
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A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X7 receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X7 antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.
- Abdi, Muna H.,Beswick, Paul J.,Billinton, Andy,Chambers, Laura J.,Charlton, Andrew,Collins, Sue D.,Collis, Katharine L.,Dean, David K.,Fonfria, Elena,Gleave, Robert J.,Lejeune, Clarisse L.,Livermore, David G.,Medhurst, Stephen J.,Michel, Anton D.,Moses, Andrew P.,Page, Lee,Patel, Sadhana,Roman, Shilina A.,Senger, Stefan,Slingsby, Brian,Steadman, Jon G.A.,Stevens, Alexander J.,Walter, Daryl S.
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scheme or table
p. 5080 - 5084
(2010/10/04)
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- Nonenzymatic, self-elimination degradation mechanism of glutathione
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In the present in vitro studies, evidence is provided showing that glutathione (GSH) can undergo spontaneous, nonenzymatic auto-degradation. The initial cleavage of the Glu-Cys bond involves nucleophilic attack of the N-terminal amino group of GSH at the
- Deshmukh, Manjeet,Kutscher, Hilliard,Stein, Stanley,Sinko, Patrick
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body text
p. 527 - 539
(2010/04/23)
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- Novel aminoglycosides and uses thereof in the treatment of genetic disorders
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A new class of paromomycin-derived aminoglycosides, which exhibit efficient stop-codon mutation suppression activity, low toxicity and high selectivity towards eukaryotic cells are provided. Also provided are chemical and chemo-enzymatic processes of preparing these paromomycin-derived aminoglycosides and intermediates thereof, as well as pharmaceutical compositions containing the same, and uses thereof in the treatment of genetic disorders.
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Page/Page column 54-56
(2009/04/24)
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- Hexafluoroacetone as protecting and activating reagent: An efficient strategy for activation of pyroglutamic acid and homologues
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Hexafluoroacetone-protected glutamic acid on treatment with thionyl chloride is transformed into a carboxy-activated pyroglutamic acid derivative. Likewise, the reaction sequence can be applied to aminoadipic acid and homologues.
- Pumpor, Ksenia,B?ttcher, Christoph,Fehn, Susanna,Burger, Klaus
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p. 259 - 269
(2007/10/03)
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- A new protocol for selective deprotection of N-tert-butoxycarbonyl protective group (t-Boc) with Sn(OTf)2
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A simple and efficient method for the selective removal of N-Boc group by employing tin(II) trifluoromethanesulfonate [Sn(OTf)2] in CH2Cl2 or solvent-free conditions was developed. The scope of this procedure is explored for the deprotection of a variety of amines, including amino acid derivatives.
- Bose, D. Subhas,Kumar, K. Kiran,Reddy, A.V. Narsimha
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p. 445 - 450
(2007/10/03)
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- Mapping the substrate selectivity of new hydrolases using colorimetric screening: Lipases from Bacillus thermocatenulatus and Ophiostoma piliferum, esterases from Pseudomonas fluorescens and Streptomyces diastatochromogenes
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Recent advances in biochemistry and molecular biology have simplified the discovery and preparation of new hydrolases. Although these hydrolases might solve problems in organic synthesis, measuring their selectivity, especially enantioselectivity, remains tedious and time consuming. Recently, we developed a colorimetric screening method to measure the enantioselectivity of hydrolases. Here we apply this rapid screening method to map the substrate selectivity of four new hydrolases: lipases from the thermophilic Bacillus thermocatenulatus (DSM 730, BTL2) and a filamentous fungus Ophiostoma piliferum (NRRL 18917, OPL) and esterases from two bacteria, Pseudomonas fluorescens (SIK-W1, esterase I, PFE) and Streptomyces diastatochromogenes (Tue 20, SDE). We screened a general library of 29 substrates and a chiral library of 23 pairs of enantiomers. All four hydrolases catalysed the hydrolysis of unnatural substrates, but the two lipases accepted a broader range of substrates than the two esterases. As expected, the two lipases favoured more hydrophobic substrates, while the two esterases showed a preference for smaller substrates. Several moderately enantioselective reactions were identified for the solketal esters: BTL2, butyrate, E = 7.9 (R); octanoate, E = 4.9 (R) and 3-bromo-2-methyl propionate methyl esters, PFE, E = 12 (S); SDE, E = 5.6 (S). OPL showed low enantioselectivity toward all substrates tested. The current colorimetric screen could not measure the selectivity for several slow-reacting substrates. Traditional screening identified high enantioselectivity of BTL2 and PFE toward one of these slow substrates, 1-phenylethyl acetate (E>50).
- Liu, Andrew Man Fai,Somers, Neil A.,Kazlauskas, Romas J.,Brush, Terry S.,Zocher, Frank,Enzelberger, Markus M.,Bornscheuer, Uwe T.,Horsman, Geoff P.,Mezzetti, Alessandra,Schmidt-Dannert, Claudia,Schmid, Rolf D.
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p. 545 - 556
(2007/10/03)
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- Highly diastereoselective alkylation of a pyroglutamate derivative with an electrophile obtained from indole. Synthesis of a potential intermediate for the preparation of the natural sweetener (-)-Monatin
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The synthesis of a potential intermediate for the preparation of the very intensive sweetening agent (-)-Monatin is described. The synthesis is based on a highly diastereoselective alkylation reaction of a pyroglutamate derivative with an electrophile obtained from indole.
- Oliveira, Davi De Jesus,Coelho, Fernando
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p. 2143 - 2159
(2007/10/03)
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- 1,5-dimethyl-4-phenylimidazolidin-2-one-derived iminic glycinimides: Useful new reagents for practical asymmetric synthesis of α-amino acids
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New 1,5-dimethyl-4-phenylimidazolidin-2-one-derived acyclic chiral iminic glycine reagents have been prepared and diastereoselectively alkylated with activated alkyl halides and electrophilic olefins in the presence of lithium chloride under (a) strong bases (LHMDS, KOBu(t)) and low temperature (-78 °C,) conditions; (b) solid-liquid phase-transfer catalysis reaction (LiOH, TBAB, -20 °C) conditions, and (c) in the presence of organic bases (DBU, BEMP, TMG, -20 °C). In the case of dielectrophiles C- and N-alkylation takes place to afford heterocyclic derivatives. Hydrolysis of alkylated products has been carried out (a) in two-step procedures with LiOOH or LiOH followed by acidic hydrolysis or Dowex purification, (b) in one single-step under refluxing water to give the corresponding α-amino acid, (c) in the presence of DBU in methanol to provide N-protected α-amino acids methyl esters, or (d) by a protection-hydrolysis procedure to afford N-Boc-protected α-amino acids. The chiral imidazolidinone has generally been recovered in good yield. This methodology has been shown to be useful for the synthesis of acyclic and heterocyclic (S)- and (R)-α-amino acids.
- Guillena,Najera
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p. 7310 - 7322
(2007/10/03)
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- Fleming-Tamao oxidation and masked hydroxyl functionality: Total synthesis of (+)-pramanicin and structural elucidation of the antifungal natural product (-)-pramanicin
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The total synthesis of (+)-pramanicin (41b) is reported, thereby establishing the relative and absolute stereochemistry of the naturally occurring antifungal agent. The key steps involve (i) conjugate addition of the diethyl((diethylamino)diphenylsilyl)zincate to a suitably protected γ- lactam 3 and quenching of the resultant enolate with the α,β-unsaturated γ,δ-epoxy aldehyde 2 (X = H), (ii) Ni(acac)2-catalyzed hydroxylation of a β-dicarbonyl array, and (iii) Fleming-Tamao oxidation to reveal the masked C-3 hydroxyl group.
- Barrett, Anthony G. M.,Head, John,Smith, Marie L.,Stock, Nicholas S.,White,Williams
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p. 6005 - 6018
(2007/10/03)
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- Easy microwave assisted deprotection of N-Boc derivatives
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A simple and efficient method for the cleavage of tert-butoxycarbonyl amides and amines is described, which takes place on silica gel under microwave irradiation.
- Siro, Jorge G.,Martín, Justina,García-Navío, José L.,Remui?an, Modesto J.,Vaquero, Juan J.
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p. 147 - 148
(2007/10/03)
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- Synthesis of aza-muricatacin : An analogue of the bioactive muricatacin an acetogenin of annonaceae
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Muricatacin is a hydroxy butanolide extracted from Annona muricata, and has shown cytotoxic activity. The threo and erythro aza-analogues, namely the hydroxy pyrrolidones have been synthesized through two different routes.
- Baussanne, Isabelle,Schwardt, Oliver,Royer, Jacques,Pichon, Marianne,Figadere, Bruno,Cave, Andre
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p. 2259 - 2262
(2007/10/03)
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- Synthesis of specially stable-isotope-labeled L-proline via L-glutamic acid
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(3,4-(13)C2)-L-proline and ((15)N)-L-proline were prepared from the correspondingly labeled L-glutamic acids via a single scheme in high yield and on a gram scale.The synthetic route is based on the ring closure of L-glutamic acid to L-5-oxoproline and the selective reduction of the 5-amide function, without interference with the 2-carboxylate function and the asymmetric center.The selective reduction is effected by first converting the amide into the corresponding thioamide and subsequently reducing the thioamide to the amine using tributyltin hydride, in combination with protection and deprotection steps.In earlier work we described the preparation of L-glutamic acid isotopically labeled at any position or combination of positions starting from simple highly enriched synthons.The synthetic scheme in this publication makes L-proline, (13)C- or (15)N-labeled at any position or combination of positions, easily available.The labeled L-prolines are charcterized by (1)H-, (13)C- and (15)N-NMR and mass spectrometry.
- Cappon, J. J.,Walle, G. A. M. van der,Verdegem, P. J. E.,Raap, J.,Lugtenburg, J.
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p. 517 - 523
(2007/10/02)
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- Chemoenzymatic synthesis of specifically stable-isotope labelled L-glutamic acid, L-glutamine and L-proline
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A synthetic scheme has been developed for the preparation of 13C- or 15N-enriched 2-oxoglutaric acid (1), L-glutamic acid (2), L-glutamine (3) and L-proline (4), from simple and commercially available highly enriched synthons.The products have been obtained with high isotope enrichment (>98percent) and high optical purity on a gram scale.The scheme allows the specific labelling of every C- or N-position and any combination of positions.The used combination of organic synthetic steps and enzymatic steps proves to be a very efficient way to obtain optically active biomolecules.
- Cappon, J J,Baart, J,Walle, G A M van der,Verdegem, P J E,Raap, J,Lugtenburg
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p. 813 - 816
(2007/10/02)
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- Characterization of the solution degradation products of histrelin, a gonadotropin releasing hormone (LH/RH) agonist
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The degradation products of histrelin (1, Glu-His-Trp-Ser-Tyr-(D-N(im)-bzl-His)-Leu-Arg-Pro-NHEt) were determined in aqueous solution at pH 5.4 and 87°C over an 18-day period (47% degradation). These degradation products (2-5) resulted from the cleavage of Glu-His and Trp-Ser peptide bonds, His-Trp diketopiperazine formation, and racemization of serine and histidine residues.
- Oyler,Naldi,Lloyd,Graden,Shaw,Cotter
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p. 271 - 275
(2007/10/02)
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- Action of Glutaminase in a Model System of a Soy Sauce Fermentation
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A model system was employed to investigate the role of glutaminase in soy sauce fermentation.In this system, a soybean protein was used as the starting material and a water extract of wheat bran koji was used as the enzyme preparation containing proteinases, peptidases, glutaminases and so on.A soybean protein was digested with the enzyme preparation. γ-Glutamylserine, γ-glutamylglutamic acid and γ-glutamylalanine were isolated from an acidic fraction of the soybean protein digest.The addition of the purified glutaminase from Aspergillus oryzae led to more production of glutamic acid and γ-glutamyl peptide and less production of glutamine and pyroglutamic acid. γ-Glutamyltranspeptidase activity and γ-glutamyl peptide(s) were also detected in a partical soy sauce mash.
- Tomita, Kenji,Yano, Toshihiro,Kitagata, Tatsuichiro,Ando, Nobuyuki,Kumagai, Hidehiko,Tochikura, Tatsurokuro
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p. 1873 - 1878
(2007/10/02)
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- Kinetic Resolution of Unnatural and Rarely Occuring Amino Acids: Enantioselective Hydrolysis of N-Acyl Amino Acids Catalyzed by Acylase I
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Acylase I (aminoacylase; N-acylamino-acid amidohydrolase, EC 3.5.1.14, from porcine kidney and the fungus Aspergillus) is broadly applicable enzymatic catalyst for the kinetic resolution of unnatural and rarely occuring α-amino acids.Its enantioselectivity for the hydrolysis of N-acyl L-α-amino acids is nearly absolute, yet it accepts substrates having a wide range of structure and functionality.This paper reports the initial rates of enzyme-catalyzed hydrolysis of over 50 N-acyl amino acids and analogues, the stabilities of the enzymes in aqueous and aqueous/organic solutions, and the effects of different acyl groups and metal ions on the rates of enzymatic hydrolysis.Eleven α-amino and α-methyl α-amino acids were resolved on a 2-29-g scale.Crude L- and D-amino acid products had generally >90percent ee.The utility of resolved amino acids as chiral synthons was illustrated by the preparation of (R)- and (S)-1-butene oxide and the diastereoselective (cis:trans, 7-8:1) iodolactonization of three 2-amino-4-alkenoic acid derivatives.
- Chenault, H. Keith,Dahmer, Juergen,Whitesides, George M.
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p. 6354 - 6364
(2007/10/02)
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- New peptide compounds having a lactone or cycloamide structure
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New peptide compounds having a lactone or cycloamide structure and containing a saturated bicyclic structure, pharmaceutically-acceptable acid addition salts thereof, method for the preparation thereof, pharmaceutical compositions containing the same, and use thereof for the stimulation of cyclic AMP in the cerebral tissue and consequently increasing the metabolic capacities of the brain, thereby making them of interest in the treatment of diseases of the central nervous system or disorders approximating normal or pathological aging, are disclosed.
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- A Novel Synthesis of L-Pyroglutamic Acid Derivatives from L-Proline: Utility of N-Protecting Groups for Ruthenium Tetroxide Oxidation of Cyclic α-Amino Acids
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The utility of four urethane type N-protecting groups, benzyloxycarbonyl (Z), p-nitrobenzyloxycarbonyl , trichloroethoxycarbonyl (Troc) and tert-butoxycarbonyl (Boc) groups, was tested in the ruthenium tetroxide (RuO4) oxidation of N-protected L-proline esters.Three groups, but not the Z group, which was decomposed by RuO4, were found to be stable during the oxidation and afforded high yields of the corresponding L-pyroglutamic acid esters.Removal of the protecting groups from the oxidation products was carried out successfully in the usual manner to give N-unsubstituted (NH-type) L-pyroglutamic acid derivatives without racemization.The first transformation of L-proline into L-pyroglutamic acid and its derivatives has been accomplished.Keywords - oxidation; ruthenium tetroxide oxidation; lactam synthesis; L-pyroglutamic acid synthesis; carboxamide N-protection; ruthenium tetroxide; L-proline; L-pyroglutamic acid; twophase method.
- Yoshifuji,Shigeyuki,Tanaka, Ken-ichi,Kawai, Tomoyuki,Nitta, Yoshihiro
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p. 3873 - 3878
(2007/10/02)
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- Intramolecular Aminolysis of Esters. O-Acetylserine and γ-Esters of Glutamic Acid
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The kinetics of the concurrent hydrolysis and intramolecular aminolysis of γ-ethyl glutamate have been studied in aqueous solution (40 deg C) in range of pH 7.6-10.4.While hydrolysis contributes only 3percent to the overall rate of reaction of γ-ethyl glutamate at pH 10.4, its importance relative to aminolysis increases with decreasing pH; at pH 8, the hydrolysis pathway accounts for 32percent of the rate of disapperance of the ester.The pH-rate profile for the aminolysis pathway indicates the presence of water and a hydroxide-catalyzed reaction and provides no evidence for intermediates.The conversion of diethyl glutamate to pyrrolidone-5-carboxylate may occur through either of two competing pathways: (a) rate-determining aminolysis to ethyl pyrrolidone-5-carboxylate, followed by rapid hydrolysis of the ester; (b) rate-determining hydrolysis to γ-ethylglutamate, followed by rapid cyclization.The pH-rate profile for the intramolecular aminolysis of O-acetylserine, determined at zero buffer concentration (30 deg C), has the complex appearance characteristic for acyl-transfer reactions involving neutral and anionic tetrahedral intermediates.Quantitative support for the interpretation of the pH-rate profile comes from the analysis of the nonlinear increases in the rate of aminolysis observed in the presence of increasing concentrations of phosphate buffers.The results of this and earlier studies suggest that there may not be major differences in the mechanisms of the intra- and intermolecular aminolysis of weakly acidic alcohols.
- Caswell, Michael,Chaturvedi, Rama K.,Lane, Stuart M.,Zvilichovsky, Bina,Schmir, Gaston L.
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p. 1585 - 1593
(2007/10/02)
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- FACILE SYNTHESIS OF γ-, δ-, AND ε-LACTAMS BY CYCLODEHYDRATION OF ο-AMINO ACIDS ON ALUMINA OR SILICA GEL
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It has been found that γ-, δ-, and ε-amino acids cyclodehydrate easily to their corresponding lactams by the action of alumina or silica gel in boiling toluene.
- Blade-Font, Artur
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p. 2443 - 2446
(2007/10/02)
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- Etude dans la serie des pyrrolidinones. IV. Formation de quelques derives de l'acide L methylene bis N-(oxo-5 pyrrolidine carboxylique-2)
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Starting from the readily available 5-oxo-2-carboxypyrrolidine, methylene-bis-(N-5-oxo-2-carboxypyrrolidine) was prepared and transformed into a diamine, then into two isomeric diols, which cyclised into one ether.The meso configuration has been assigned for this ether.The reduction of both diols and ether was complete and gave rise to methylene-bis-N-pyrrolidine.
- Miquel, Christian,Pigache, Pierre,Rigo, Benoit,Kolocouris, Nicolas
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p. 1447 - 1453
(2007/10/02)
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- PALLADIUM(II)-CATALYZED CYCLIZATION OF γ-BENZYL GLUTAMATE WITH FORMATION OF BENZALDEHYDE
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γ-Benzyl glutamate in water at neutral pH undergoes palldium(II)-catalyzed cyclization with oxidation of the ester bond to give pyroglutamic acid, benzaldehyde, and palladium metal.The reaction is specific for γ-benzyl glutamate and not observed for β-ben
- Odani, Akira,Yamauchi, Osamu
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- Pharmaceutical preparations having psychotropic activity and process for their manufacture
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Pharmaceutical preparations containing an L-pyroglutamic acid amide, processes for their preparation and methods of treating psychotic diseases with them.
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