- Mechanism-inspired engineering of phenylalanine aminomutase for enhanced β-regioselective asymmetric amination of cinnamates
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Turn to switch: A mutant of phenylalanine aminomutase was engineered that can catalyze the regioselective amination of cinnamate derivatives (see scheme, red) to, for example, β-amino acids. This regioselectivity, along with the X-ray crystal structures, suggests two distinct carboxylate binding modes differentiated by Cβi£Cipso bond rotation, which determines if β- (see scheme) or α-addition takes place. Copyright
- Wu, Bian,Szymanski, Wiktor,Wybenga, Gjalt G.,Heberling, Matthew M.,Bartsch, Sebastian,Dewildeman, Stefaan,Poelarends, Gerrit J.,Feringa, Ben L.,Dijkstra, Bauke W.,Janssen, Dick B.
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- Bio-inspired enantioselective full transamination using readily available cyclodextrin
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The mimics of vitamin B6-dependent enzymes that catalyzed an enantioselective full transamination in the pure aqueous phase have been realized for the first time through the establishment of a new “pyridoxal 5′-phosphate (PLP) catalyzed non-covalent cyclodextrin (CD)-keto acid inclusion complexes” system, and various optically active amino acids have been obtained.
- Zhang, Shiqi,Li, Guangxun,Liu, Hongxin,Wang, Yingwei,Cao, Yuan,Zhao, Gang,Tang, Zhuo
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- THE INCLUSION OF THE ENANTIOMERS OF N-TRIFLUOROACETYL-4-FLUOROPHENYLALANINE AND N-TRIFLUOROACETYLPHENYLALANINE BY CYCLOMALTOHEXAOSE: A 2H- AND 19F-N.M.R. STUDY
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19F-N.m.r. studies show that N-trifluoroacetyl-D- and -L-4-fluorophenylalanine and N-trifluoroacetyl-D- and -L-phenylalanine form 1:1 inclusion complexes with cyclomaltohexaose (α-cyclodextrin) characterised by stability constants of 11.44 +/- 1.13, 11.40 +/- 1.09, 6.15 +/- 0.59, and 6.37 +/- 0.81 M-1, respectively, in aqueous 0.1M NaCl at pH 6.5 and 25 deg C.Under similar conditions, the correlation time of N-trifluoroacetyl-phenylalanine changed from 65 +/- 4 ps in the free state to 320 +/- 40 ps in the complex, consistent with there being little freedom of movement of the guest in the inclusion complex.
- Smith, Nicholas J.,Spotswood, Thomas M.,Lincoln, Stephen F.
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- Acylase I catalysed hydrolysis of para-substituted (S)-phenylalanine derivatives from mixtures of the racemic ortho- and para-substituted isomers
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para-Substituted (S)-phenylalanines may be obtained by treatment of the corresponding mixtures of ortho- and para-substituted N-acetyl-(RS)- phenylalanines with Acylase I from porcine kidney. The selectivity of the enzyme may be attributed to its evolution to digest peptide derivatives of (S)-phenylalanine and (S)-tyrosine.
- Easton, Christopher J.,Harper, Jason B.
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- A new approach to the efficient method for the asymmetric synthesis of (S)-O-, M-, P-fluorophenylalanines and their 2-methyl-substituted analogs
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The reactions of asymmetric C-alkylation of glycine and alanine in NiII complexes of their Schiff's bases with modified chiral auxiliaries (S)-2-N-[(N0-2-chlorobenzylprolyl)- amino]benzophenone and (S)-2-N-[N′-(3, 4-dimethylbenzylprolyl)amino]benzophenone by fluorine-substituted benzyl halogenides have been studied. As a result, a highly stereoselective and relatively rapid method for the asymmetric synthesis of (S)-o-, m-, p-fluorophenylalanines and their 2-methyl substituted analogs has been developed.
- Saghiyan, Ashot S.,Petrosyan, Satenik G.,Manasyan, Luiza L.,Dadayan, Slavik A.,Geolchanyan, Arpine V.,Panosyan, Henry A.,Maleev, Victor I.,Khrustalev, Victor N.
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- Asymmetric synthesis of organoelement analogues of natural products; Part 12: General method for the asymmetric synthesis of fluorine-containing phenylalanines and α-methyl(phenyl)alanines via alkylation of the chiral nickel(II) Schiff's base complexes of
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Nickel(II) complexes of Schiff's bases derived from (S)-o-[(N-benzyl]prolyl)amino]benzophenone [N-(2-benzoylphenyl)-1-benzylpyrrolidine-2-carboxamide] (BBP) and glycine or alanine have been used for asymmetric synthesis of fluoro (S)-phenylalanines and (S
- Kukhar,Belokon,Soloshonok,Svistunova Yu.,Rozhenko,Kuz'mina
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- ASYMMETRIC SYNTHESIS OF HETEROORGANIC ANALOGS OF NATURAL COMPOUNDS. 2. A CONVENIENT PREPARATIVE METHOD FOR THE SYNTHESIS OF ENANTIOMERICALLY PURE (S)-(-)-o-, m-, and p-FLUOROPHENYLALANINES AND THEIR 2-METHYL-SUBSTITUTED ANALOGS.
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A convenient preparative method for the synthesis of the enantiomerically pure o-, m-, and p-fluorophenylalanines and their α-methyl-substituted analogs by means of the alkylation with the corresponding fluorine-containing benzyl chlorides of glycine and
- Soloshonok, V. A.,Belokon', Yu. N.,Kukhar', V. P.,Chernoglazova, N. I.,Saporovskaya, M. B.,et al.
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- Biocatalytic stereoinversion of d-: Para -bromophenylalanine in a one-pot three-enzyme reaction
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Halogenated derivatives of phenylalanine can be used as cross-coupling reagents for making drug-like molecules, and pure enantiomers of these precursors are therefore highly desirable. In our exploration of enzymatic routes to simplify the deracemisation process, the application of two enzymes, d-amino acid transaminase and phenylalanine dehydrogenase, both from Lysinibacillus sphaericus, has given promising results for the stereo-inversion of d-enantiomers of para-bromophenylalanine as the model substrate and also p-chloro/fluorophenylalanine and tyrosine. The addition of a coenzyme recycling system using ethanol and alcohol dehydrogenase reduced the amount of coenzyme needed for the reaction catalysed by phenylalanine dehydrogenase, reducing cost and permitting efficient and complete conversion of the racemic amino acids to the l-enantiomer. Relative proportions of the enzymes were optimized. The high purity of the l-enantiomer, with an ee over 99%, and the ease of the process make it an ideal alternative for deracemisation of the studied compounds.
- Khorsand, Fahimeh,Murphy, Cormac D.,Whitehead, Andrew J.,Engel, Paul C.
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- Engineering of phenylalanine ammonia lyase from Rhodotorula graminis for the enhanced synthesis of unnatural L-amino acids
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Phenylalanine ammonia lyase (PAL) catalyses the reversible non-oxidative deamination of phenylalanine to trans-cinnamic acid and ammonia. Analogues of L-phenylalanine are incorporated as pharmacophores in several peptidomimetic drug molecules and are therefore of particular interest to the fine chemical industry. PAL from Rhodotorula graminis (RgrPAL) has shown an ability to accept analogues of L-phenylalanine. Our aim was to increase enzymatic activity with directed evolution towards a specific non-natural substrate through the cloning and over-production of PAL in Escherichia coli. The identified variants of RgrPAL with significantly showed more catalytic efficient compared to the wild-type enzyme. These variants were used in a preparative scale biotransformation resulting in a 94% conversion to L-4-Br-phenylalanine (>99% ee).
- Rowles, Ian,Groenendaal, Bas,Binay, Baris,Malone, Kirk J.,Willies, Simon C.,Turner, Nicholas J.
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- A novel phenylalanine ammonia-lyase from Pseudozyma antarctica for stereoselective biotransformations of unnatural amino acids
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A novel phenylalanine ammonia-lyase of the psychrophilic yeast Pseudozyma antarctica (PzaPAL) was identified by screening microbial genomes against known PAL sequences. PzaPAL has a significantly different substrate binding pocket with an extended loop (26 aa long) connected to the aromatic ring binding region of the active site as compared to the known PALs from eukaryotes. The general properties of recombinant PzaPAL expressed in E. coli were characterized including kinetic features of this novel PAL with L-phenylalanine (S)-1a and further racemic substituted phenylalanines rac-1b-g,k. In most cases, PzaPAL revealed significantly higher turnover numbers than the PAL from Petroselinum crispum (PcPAL). Finally, the biocatalytic performance of PzaPAL and PcPAL was compared in the kinetic resolutions of racemic phenylalanine derivatives (rac-1a-s) by enzymatic ammonia elimination and also in the enantiotope selective ammonia addition reactions to cinnamic acid derivatives (2a-s). The enantiotope selectivity of PzaPAL with o-, m-, p-fluoro-, o-, p-chloro- and o-, m-bromo-substituted cinnamic acids proved to be higher than that of PcPAL.
- Varga, Andrea,Csuka, Pál,Sonesouphap, Orlavanah,Bánóczi, Gergely,To?a, Monica Ioana,Katona, Gabriel,Molnár, Zsófia,Bencze, László Csaba,Poppe, László,Paizs, Csaba
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p. 185 - 194
(2020/04/28)
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- Synthesis, in vitro biological activity, hydrolytic stability and docking of new analogs of BIM-23052 containing halogenated amino acids
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One of the potent somatostatin analogs, BIM-23052 (DC-23-99) d-Phe-Phe-Phe-d-Trp-Lys-Thr-Phe-Thr-NH2, has established in vitro growth hormone inhibitory activity in nM concentrations. It is also characterized by high affinity to some somatostatin receptors which are largely distributed in the cell membranes of many tumor cells. Herein, we report the synthesis of a series of analogs of BIM-23052 containing halogenated Phe residues using standard solid-phase peptide method Fmoc/OtBu-strategy. The cytotoxic effects of the compounds were tested in vitro against two human tumor cell lines—breast cancer cell line and hepatocellular cancer cell line, as well as on human non-tumorigenic epithelial cell line. Analogs containing fluoro-phenylalanines are cytotoxic in μM range, as the analog containing Phe (2-F) showed better selectivity against human hepatocellular cancer cell line. The presented study also reveals that accumulation of halogenated Phe residues does not increase the cytotoxicity according to tested cell lines. The calculated selective index reveals different mechanisms of antitumor activity of the parent compound BIM-23052 and target halogenated analogs for examined breast tumor cell lines. All peptides tested have high antitumor activity against the HepG2 cell line (IC50 ≈ 100?μM and SI > 5) compared to breast cells. This is probably due to the high permeability of the cell membrane and the higher metabolic activity of hepatocytes. In silico docking studies confirmed that all obtained analogs bind well with the somatostatin receptors with preference to ssrt3 and ssrt5. All target compounds showed high hydrolytic stability at acid and neutral pH, which mimic physiological condition in stomach and human plasma.
- Danalev, Dancho,Borisova, Desislava,Yaneva, Spaska,Georgieva, Maya,Balacheva, Anelia,Dzimbova, Tatyana,Iliev, Ivan,Pajpanova, Tamara,Zaharieva, Zdravka,Givechev, Ivan,Naydenova, Emilia
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p. 1581 - 1592
(2020/11/23)
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- Asymmetric synthesis, biological activity and molecular docking studies of some unsaturated α-amino acids, derivatives of glycine, allylglycine and propargylglycine
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New enantiomerically enriched unsaturated tailor-made amino acids have been obtained. As a starting amino acid synthon for the asymmetric synthesis of tailor-made unsaturated amino acids, Ni(II) square-planar complexes of Schiff's bases of propargylglycine, allylglycine and glycine with chiral auxiliary (S)-2-N-(N’-benzylprolyl)-aminobenzophenone ((S)-BPB) were used. The Cα-alkylation of propargylglycine, allylglycine and glycine moieties resulted in the asymmetric synthesis of novel (S)-α-propargylglycine, (S)-α-allylglycine and glycine derivatives containing an aromatic group in the side chain (de 80–95,5%). After purification and cleavage of the metal complexes, the amino acids were isolated in high enantiomeric purity (ee >99%). Of the obtained seven tailor-made amino acids four showed inhibitory activity to collagenase G. The amino acid with an acetylene bond in the side chain (IC50 = 1.29 ± 0.02 mM) had the best result. Molecular docking showed that the amino acids with activity to collagenase G contained hydrogen and π-π bonds with the enzyme.
- Hayriyan, Liana A.,Karapetyan, Ani J.,Minasyan, Ella V.,Mkrtchyan, Anna F.,Paloyan, Ani M.,Panosyan, Henrik A.,Poghosyan, Artavazd S.,Saghyan, Ashot S.,Sahakyan, Lusine Yu.,Sargsyan, Armen S.,Tovmasyan, Anna S.,Tsaturyan, Avetis H.
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- ANTIBACTERIALS AND/OR MODULATORS OF BIOFILM FORMATION AND METHODS OF USING THE SAME
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Amides substituted with aromatic groups were synthesized and some were purified to create enantiomer pure compounds. The compounds were tested to determine their ability to inhibit the growth of bacteria and the formation of biofilms created by bacteria. Some of these compounds were found to be effective antibacterials and to effectively inhibit the formation of biofilms.
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Paragraph 0122
(2017/04/11)
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- Kinetic Resolution of Aromatic β-Amino Acids Using a Combination of Phenylalanine Ammonia Lyase and Aminomutase Biocatalysts
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An enzymatic strategy for the preparation of (R)-β-arylalanines employing phenylalanine aminomutase and ammonia lyase (PAM and PAL) enzymes has been demonstrated. Candidate PAMs with the desired (S)-selectivity from Streptomyces maritimus (EncP) and Bacillus sp. (PabH) were identified via sequence analysis using a well-studied template sequence. The newly discovered PabH could be linked to the first ever proposed biosynthesis of pyloricidin-like secondary metabolites and was shown to display better β-lyase activity in many cases. In spite of this, a method combining the higher conversion of EncP with a strict α-lyase from Anabaena variabilis (AvPAL) was found to be more amenable, allowing kinetic resolution of five racemic substrates and a preparative-scale reaction with >98% (R) enantiomeric excess. This work represents an improved and enantiocomplementary method to existing biocatalytic strategies, allowing simple product separation and modular telescopic combination with a preceding chemical step using an achiral aldehyde as starting material. (Figure presented.).
- Weise, Nicholas J.,Ahmed, Syed T.,Parmeggiani, Fabio,Turner, Nicholas J.
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p. 1570 - 1576
(2017/05/05)
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- Telescopic one-pot condensation-hydroamination strategy for the synthesis of optically pure L-phenylalanines from benzaldehydes
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A chemo-enzymatic telescopic approach was designed for the synthesis of L-arylalanines in high yield and optical purity, starting from commercially available and inexpensive substituted benzaldehydes. The method exploits a chemical Knoevenagel–Doebner condensation (optimised to give complete conversions in a short reaction time, employing microwave irradiation) and a biocatalytic phenylalanine ammonia lyase mediated hydroamination (for the stereoselective addition of ammonia). The two reactions can be run sequentially in one pot, bringing together the advantages of chemical and biological catalysis. The preparative applicability was demonstrated with the synthesis of five L-dihalophenylalanines (71–84% yield, 98–99% ee) of relevance as molecular probes, for medicinal chemistry and for the synthesis of pharmaceutical ingredients.
- Parmeggiani, Fabio,Ahmed, Syed T.,Weise, Nicholas J.,Turner, Nicholas J.
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p. 7256 - 7262
(2016/10/26)
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- A new type of chiral-pyridoxamines for catalytic asymmetric transamination of α-keto acids
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A new type of chiral pyridoxamines bearing an adjacent chiral stereocenter has been developed via multi-step synthesis. The pyridoxamines displayed catalytic activity in asymmetric transamination of α-keto acids to give a variety of optically active amino acids in 27–78% yields with 34–62% ee's under very mild conditions. This work provides a synthetic strategy to construct new chiral pyridoxamines using bromopyridine 7 as a key synthon and also represents an early example of the applications of chiral pyridoxamines in asymmetric catalysis.
- Chen, Jianfeng,Zhao, Junyu,Gong, Xing,Xu, Dongfang,Zhao, Baoguo
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supporting information
p. 4612 - 4615
(2016/09/23)
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- Influence of the aromatic moiety in α- And β-arylalanines on their biotransformation with phenylalanine 2,3-aminomutase from: Pantoea agglomerans
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In this study enantiomer selective isomerization of various racemic α- and β-arylalanines catalysed by phenylalanine 2,3-aminomutase from Pantoea agglomerans (PaPAM) was investigated. Both α- and β-arylalanines were accepted as substrates when the aryl moiety was relatively small, like phenyl, 2-, 3-, 4-fluorophenyl or thiophen-2-yl. While 2-substituted α-phenylalanines bearing bulky electron withdrawing substituents did not react, the corresponding substituted β-aryl analogues were converted rapidly. Conversion of 3- and 4-substituted α-arylalanines happened smoothly, while conversion of the corresponding β-arylalanines was poor or non-existent. In the range of pH 7-9 there was no significant influence on the conversion of racemic α- or β-(thiophen-2-yl)alanines, whereas increasing the concentration of ammonia (ammonium carbonate from 50 to 1000 mM) inhibited the isomerization progressively and decreased the amount of the by-product (i.e. (E)-3-(thiophen-2-yl)acrylic acid was detected). In all cases, the high ee values of the products indicated excellent enantiomer selectivity and stereospecificity of the isomerization except for (S)-2-nitro-α-phenylalanine (ee 92%) from the β-isomer. Substituent effects were rationalized by computational modelling revealing that one of the main factors controlling biocatalytic activity was the energy difference between the covalent regioisomeric enzyme-substrate complexes.
- Varga, Andrea,Bánóczi, Gergely,Nagy, Botond,Bencze, László Csaba,To?a, Monica Ioana,Gellért, ákos,Irimie, Florin Dan,Rétey, János,Poppe, László,Paizs, Csaba
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p. 56412 - 56420
(2016/07/06)
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- Intensified biocatalytic production of enantiomerically pure halophenylalanines from acrylic acids using ammonium carbamate as the ammonia source
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An intensified, industrially-relevant strategy for the production of enantiopure halophenylalanines has been developed using the novel combination of a cyanobacterial phenylalanine ammonia lyase (PAL) and ammonium carbamate reaction buffer. The process boasts STYs up to >200 g L-1 d-1, ees ≥ 98% and simplified catalyst/reaction buffer preparation and work up.
- Weise, Nicholas J.,Ahmed, Syed T.,Parmeggiani, Fabio,Siirola, Elina,Pushpanath, Ahir,Schell, Ursula,Turner, Nicholas J.
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p. 4086 - 4089
(2016/07/06)
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- Synthesis of D- and L-Phenylalanine Derivatives by Phenylalanine Ammonia Lyases: A Multienzymatic Cascade Process
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The synthesis of substituted D-phenylalanines in high yield and excellent optical purity, starting from inexpensive cinnamic acids, has been achieved with a novel one-pot approach by coupling phenylalanine ammonia lyase (PAL) amination with a chemoenzymatic deracemization (based on stereoselective oxidation and nonselective reduction). A simple high-throughput solid-phase screening method has also been developed to identify PALs with higher rates of formation of non-natural D-phenylalanines. The best variants were exploited in the chemoenzymatic cascade, thus increasing the yield and ee value of the D-configured product. Furthermore, the system was extended to the preparation of those L-phenylalanines which are obtained with a low ee value using PAL amination.
- Parmeggiani, Fabio,Lovelock, Sarah L.,Weise, Nicholas J.,Ahmed, Syed T.,Turner, Nicholas J.
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p. 4608 - 4611
(2015/04/14)
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- The bacterial ammonia lyase EncP: A tunable biocatalyst for the synthesis of unnatural amino acids
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Enzymes of the class I lyase-like family catalyze the asymmetric addition of ammonia to arylacrylates, yielding high value amino acids as products. Recent examples include the use of phenylalanine ammonia lyases (PALs), either alone or as a gateway to deracemization cascades (giving (S)- or (R)-α-phenylalanine derivatives, respectively), and also eukaryotic phenylalanine aminomutases (PAMs) for the synthesis of the (R)-β-products. Herein, we present the investigation of another family member, EncP from Streptomyces maritimus, thereby expanding the biocatalytic toolbox and enabling the production of the missing (S)-β-isomer. EncP was found to convert a range of arylacrylates to a mixture of (S)-α- and (S)-β-arylalanines, with regioselectivity correlating to the strength of electron-withdrawing/-donating groups on the ring of each substrate. The low regioselectivity of the wild-type enzyme was addressed via structure-based rational design to generate three variants with altered preference for either α- or β-products. By examining various biocatalyst/substrate combinations, it was demonstrated that the amination pattern of the reaction could be tuned to achieve selectivities between 99:1 and 1:99 for β:α-product ratios as desired.
- Weise, Nicholas J.,Parmeggiani, Fabio,Ahmed, Syed T.,Turner, Nicholas J.
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supporting information
p. 12977 - 12983
(2015/10/28)
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- Phenylalanine ammonia lyase catalyzed synthesis of amino acids by an MIO-cofactor independent pathway
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Phenylalanine ammonia lyases (PALs) belong to a family of 4-methylideneimidazole-5-one (MIO) cofactor dependent enzymes which are responsible for the conversion of L-phenylalanine into trans-cinnamic acid in eukaryotic and prokaryotic organisms. Under conditions of high ammonia concentration, this deamination reaction is reversible and hence there is considerable interest in the development of PALs as biocatalysts for the enantioselective synthesis of non-natural amino acids. Herein the discovery of a previously unobserved competing MIO-independent reaction pathway, which proceeds in a non-stereoselective manner and results in the generation of both L- and D-phenylalanine derivatives, is described. The mechanism of the MIO-independent pathway is explored through isotopic-labeling studies and mutagenesis of key active-site residues. The results obtained are consistent with amino acid deamination occurring by a stepwise E1cB elimination mechanism. All manner of things: A competing MIO-independent (MIO=4-methylideneimidazole-5-one) reaction pathway has been identified for phenylalanine ammonia lyases (PALs), which proceeds in a non-stereoselective manner, resulting in the generation of D-phenylalanine derivatives. The mechanism of D-amino acid formation is explored through isotopic-labeling studies and mutagenesis of key active-site residues.
- Lovelock, Sarah L.,Lloyd, Richard C.,Turner, Nicholas J.
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supporting information
p. 4652 - 4656
(2014/05/20)
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- Enzymatic synthesis of chiral phenylalanine derivatives by a dynamic kinetic resolution of corresponding amide and nitrile substrates with a multi-enzyme system
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Mutant α-amino-ε-caprolactam (ACL) racemase (L19V/L78T) from Achromobacter obae with improved substrate specificity toward phenylalaninamide was obtained by directed evolution. The mutant ACL racemase and thermostable mutant D-amino acid amidase (DaaA) from Ochrobactrum anthropi SV3 co-expressed in Escherichia coli (pACLmut/pDBFB40) were utilized for synthesis of (R)-phenylalanine and non-natural (R)-phenylalanine derivatives (4-OH, 4-F, 3-F, and 2-F-Phe) by dynamic kinetic resolution (DKR). Recombinant E. coli with DaaA and mutant ACL racemase genes catalyzed the synthesis of (R)-phenylalanine with 84% yield and 99% ee from (RS)-phenylalaninamide (400 mM) in 22 h. (R)-Tyrosine and 4-fluoro-(R)-phenylalanine were also efficiently synthesized from the corresponding amide compounds. We also co-expresed two genes encoding mutant ACL racemase and L-amino acid amidase from Brevundimonas diminuta in E. coli and performed the efficient production of various (S)-phenylalanine derivatives. Moreover, 2-aminophenylpropionitrile was converted to (R)-phenylalanine by DKR using a combination of the non-stereoselective nitrile hydratase from recombinamt E. coli and mutant ACL racemase and DaaA from E. coli encoding mutant ACL racemase and DaaA genes. Copyright
- Yasukawa, Kazuyuki,Asano, Yasuhisa
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p. 3327 - 3332
(2013/01/15)
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- COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
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The present invention relates to derivatized cyclofructan compounds, compositions comprising derivatized cyclofructan compounds, and methods of using compositions comprising derivatized cyclofructan compounds for chromatographic separations of chemical species, including enantiomers. Said compositions may comprise a solid support and/or polymers comprising derivatized cyclofructan compounds.
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Page/Page column 45-49; 60
(2010/12/31)
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- Use of whole cell culture of Aeromonas sp. as enantioselective scavenger: A facile preparation of l-amino acid derivatives in high enantiomeric excess
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The bacterium Aeromonas sp. (CGMCC 2226) can enantioselectively scavenge d-isomer, making l-amino acid derivatives (AADs) in high ee. The enantioselective scavenger (ES) has shown a broad substrate scope. Eleven l-AADs, Phe derivatives substituted with methyl-, mono- and dichloro-, bromo-, and nitro-group, were produced in high ee from corresponding racemates.
- Zhang, Zizhang
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experimental part
p. 1129 - 1131
(2009/09/04)
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- Phenylalanine aminomutase-catalyzed addition of ammonia to substituted cinnamic acids: A route to enantiopure α- and β-amino acids
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(Chemical Equation Presented) An approach is described for the synthesis of aromatic α- and β-amino acids that uses phenylalanine aminomutase to catalyze a highly enantioselective addition of ammonia to substituted cinnamic acids. The reaction has a broad scope and yields substituted α- and β-phenylalanines with excellent enantiomeric excess. The regioselectivity of the conversion is determined by substituents present at the aromatic ring. A box model for the enzyme active site is proposed, derived from the influence of the hydrophobicity of substituents on the enzyme affinity toward various substrates.
- Szymanski, Wiktor,Wu, Bian,Weiner, Barbara,De Wildeman, Stefaan,Feringa, Ben L.,Janssen, Dick B.
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supporting information; experimental part
p. 9152 - 9157
(2010/03/01)
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- Resolution of non-protein amino acids via the microbial protease-catalyzed enantioselective hydrolysis of their N-unprotected esters
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In the Aspergillus oryzae protease-catalyzed ester hydrolysis, substitution of N-unprotected amino acid esters for the corresponding N-protected amino acid esters resulted in a large enhancement of the hydrolysis rate, while the enantioselectivity was deteriorated strikingly when the substrates employed were the conventional methyl esters. This difficulty was overcome by employing esters bearing a longer alkyl chain such as the isobutyl ester. Utilizing this ester, amino acids carrying an aromatic side chain were resolved with excellent enantioselectivities (E=50 to >200). With amino acids bearing an aliphatic side chain also, good results in terms of the hydrolysis rate and enantioselectivity were obtained by employing such an ester as the isobutyl ester. Moreover, the enantioselectivity proved to be enhanced further by conducting the reaction at low temperature. This procedure was applicable to the case where the enantioselectivity was not high enough even by the use of the isobutyl ester.
- Miyazawa, Toshifumi,Imagawa, Kiwamu,Minowa, Hiroe,Miyamoto, Toyoko,Yamada, Takashi
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p. 10254 - 10261
(2007/10/03)
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- Enantioselective synthesis of non-natural amino acids using phenylalanine dehydrogenases modified by site-directed mutagenesis
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The substrate scope of three mutants of phenylalanine dehydrogenase as biocatalysts for the transformation of a series of 2-oxo acids, structurally related to phenylpyruvic acid, to the analogous -amino acids, non-natural analogues of phenylalanine, has been investigated. The mutant enzymes are more tolerant than the wild type enzyme of the non-natural substrates, especially those with substituents at the 4-position on the phenyl ring. Excellent enantiocontrol resulted in all cases.
- Busca, Patricia,Paradisi, Francesca,Moynihan, Eamonn,Maguire, Anita R.,Engel, Paul C.
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p. 2684 - 2691
(2007/10/03)
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- Phenylalanine ammonia-lyase: The use of its broad substrate specificity for mechanistic investigations and biocatalysis - Synthesis of L-arylalanines
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Several fluoro-and chlorophenylalanines were found to be good substrates of phenylalanine ammonialyase (PAL/EC 4.3.1.5) from parsley. The enantiomerically pure L-amino acids were obtained in good yields by reaction of the corresponding cinnamic acids with 5M ammonia solution (buffered to pH 10) in the presence of PAL. The kinetic constants for nine different fluoro-and chlorophenylalanines do not provide a rigorous proof for but are consistent with the previously proposed mechanism comprising an electrophilic attack of the methylidene-imidazolone cofactor of PAL at the aromatic nucleus as a first chemical step. In the resulting Friedel-Crafts-type σ complex the β-protons are activated for abstraction and consequently the pro-S is abstracted by an enzymic base. Results from semi-empirical calculations combined with a proposed partial active site model showed a correlation between the experimental kinetic constants and the change in polarization of the pro-S Cβ-H bond and heat of formation of the σ complexes, thus making the electrophilic attack at the neutral aromatic ring plausible. Furthermore, while 5-pyrimidinylalanine was found to be a moderately good substrate of PAL, 2-pyrimidinylalanine was an inhibitor.
- Gloge, Andreas,Zon, Jerzy,Koevari, Agnes,Poppe, Laszlo,Retey, Janos
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p. 3386 - 3390
(2007/10/03)
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- Resolution of non-protein amino acids via microbial protease-catalyzed ester hydrolysis: Marked enhancement of enantioselectivity by the use of esters with longer alkyl chains and at low temperature
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In the microbial protease-catalyzed hydrolysis of amino acid esters with the free α-amino group, the enantioselectivity can be enhanced greatly by employing esters with longer alkyl chains such as the isobutyl ester instead of the conventional methyl ester and by conducting the reaction at low temperature.
- Miyazawa, Toshifumi,Minowa, Hiroe,Miyamoto, Toyoko,Imagawa, Kiwamu,Yanagihara, Ryoji,Yamada, Takashi
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p. 367 - 370
(2007/10/03)
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- Schiff bases of amino acid esters as new substrates for the enantioselective enzymatic hydrolysis and accompanied asymmetric transformations in aqueous organic solvents
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The enzyme (lipases and chymotrypsin)-catalyzed hydrolysis of Schiff bases derived from racemic amino acid esters and aromatic aldehydes has been investigated. The reactions were successfully carried out in different aqueous organic solvents at ambient temperature, but the aqueous acetonitrile (5.4% water content by volume) was the solvent of choice. The L-amino acid (ee 98%) precipitated out from the solution as the reaction progressed, and the liberated aldehyde and unhydrolyzed D-ester (ee 40-98%) remained in the solution. The range of substrates included amino acids having different types of side chains. The addition of an organic base (DABCO) into the solution resulted in the racemization of the remaining D-ester and the additional hydrolysis of the substrate, thus leading to the effective asymmetric transformation of the initial ester. Upto 87.5% of the initial racemate was converted into the L-enantiomer.
- Parmar, Virinder S.,Singh, Amarjit,Bisht, Kirpal S.,Kumar, Naresh,Belokon,Kochetkov,Ikonnikov,Orlova,Tararov,Saveleva
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p. 1223 - 1226
(2007/10/03)
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- Enzymatic peptide synthesis in frozen aqueous systems: Use of N(α)-unprotected unusual acyl donors
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α-Chymotrypsin (EC 3.4.21.1) was used for catalyzing the reaction of various N(α)-unprotected non-coded phenylalanine ester derivatives with H-Leu-NH2 and H-Arg-NH2 in frozen aqueous solution at -15°C. Compared with reactions at room temperature, a significant yield increasing effect could be established. The kinetic parameters of ester hydrolysis show that most of the unusual acyl donors (compared with the coded phenylalanine methyl ester) are well accepted substrates for α-chymotrypsin.
- Gerisch,Jakubke,Kreuzfeld
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p. 3039 - 3045
(2007/10/03)
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- HOMOCHIRAL HETEROORGANIC ANALOGS OF NATURAL COMPOUNDS. III. BIOCATALYTIC METHOD OF OBTAINING HOMOCHIRAL FLUORINE-CONTAINING (R)- AND (S)-PHENYLALANINES AND (S,R)- AND (R,S)-PHENYLSERINES
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A convenient biocatalytic method of obtaining homochiral (S)- and (R)-threo-β-(4-fluorophenyl)serine and -2-, -3-, and 4-fluoro- and -2,3,4,5,6-pentafluorophenylalanines by the enantioselective hydrolysis of their racemic N-phenylacetyl derivatives under the action of Escherichia coli penicillin acylase is proposed.
- Soloshonok, V. A.,Shvyadas, V. K.,Kukhar, V. P.,Galaev, I. Yu.,Kozlova, E. V.,Svistunova, N. Yu.
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p. 236 - 240
(2007/10/02)
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- Synthesis of Nonproteinogenic (R)- or (S)-Amino Acids. - Analogues of Phenylalanine, Isotopically Labelled and Cyclic Amino Acids from tert-Butyl 2-(tert-Butyl)-3-methyl-4-oxo-1-imidazolidinecarboxylate (Boc-BMI)
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The enantiomerically pure glycine derivatives (R)- and (S)-Boc-BMI, commercially available on a kg scale, are used as starting materials (Scheme 1) for the preparation of (i) open-chain amino acids such as α-deuterio amino acids (4,5), β-arylalanines (2), aspartic acid derivatives (6, 7a, 8), or ω-halo amino acids (7b,c, 12, 13, 16, 17, 19, 22), (ii) of α-aminocycloalkanecarboxylic acids (9, 11), and (iii) of heterocyclic α-amino acids (14, 15, 18, 20) containing azetidine, pyrrolidine, piperidine or perhydroazepine rings.Inversion by deprotonation/protonation ordeuteration allows to prepare either enantiomer of an amino acid from the same Boc-BMI enantiomer (Scheme 5).Effects of additives such as the cyclic urea DMPU, lithium salts, or secondeary amines upon the reactivity of lithium enolates are discussed and, in part, exploited.
- Seebach, Dieter,Dziadulewicz, Edward,Behrendt, Linda,Cantoreggi, Sergio,Fitzi, Robert
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p. 1215 - 1232
(2007/10/02)
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- Method of treating nausea and vomiting with certain substituted-phenylalkylamino (and aminoacid) derivatives and other serotonin depleting agents
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A method for the treatment of emesis in a mammal, which method comprises administering to said mammal an emesis inhibiting amount of a compound which depletes serotonin in the brain of mammals; among which are compounds having the formula: STR1 wherein, R is selected from hydrogen, loweralkyl, trifluoromethyl, carboxyl, or loweralkoxycarbonyl; R1 and R2 are hydrogen or loweralkyl; Z is trifluoromethyl or halogen; the optical isomers and pharmaceutically acceptable salts thereof; two of the preferred compounds of the invention are fenfluramine and norfenfluramine.
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- Drug Latentiation by γ-Glutamyl Transpeptidase
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The N-γ-glutamyl derivatives of L-thiazolidine-4-carboxylic acid, 4-aminobutyric acid, 1-aminocyclopentanecarboxylic acid, 2-aminophenol, and p-fluoro-L-phenylalanine (compounds 6, 8, 9, 10, and 12 respectively) were synthesized using the synthom phthaloylglutamic anhydride.Their relative rates of cleavage by the enzyme γ-glutamyl transpeptidase (γ-GT) were determined in order to evaluate the possibility for their selective release by this enzyme which is elevated in certain pathological conditions.Compounds 6, 8, and 9 were not readily solvolyzed by γ-GT, but compounds 10 and 12, as well as the N-γ-glutamylated derivatives of 3- and 4-aminophenol, were readily cleaved.
- Magnan, Sanne D. J.,Shirota, Frances N.,Nagasawa, Herbert T.
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p. 1018 - 1021
(2007/10/02)
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- Pharmacologically active peptides
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Compounds of the formula STR1 and pharmaceutically acceptable non-toxic acid addition salts thereof, in which L and D define the chirality; R1 is hydrogen or C1 -C3 primary alkyl; R2 is C1 -C4/s
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