- 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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- 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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- Design, synthesis, and functional assessment of Cmpd-15 derivatives as negative allosteric modulators for the β2-adrenergic receptor
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The β2-adrenergic receptor (β2AR), a G protein-coupled receptor, is an important therapeutic target. We recently described Cmpd-15, the first small molecule negative allosteric modulator (NAM) for the β2AR. Herein we report in details the design, synthesis and structure-activity relationships (SAR) of seven Cmpd-15 derivatives. Furthermore, we provide in a dose-response paradigm, the details of the effects of these derivatives in modulating agonist-induced β2AR activities (G-protein-mediated cAMP production and β-arrestin recruitment to the receptor) as well as the binding affinity of an orthosteric agonist in radio-ligand competition binding assay. Our results show that some modifications, including removal of the formamide group in the para-formamido phenylalanine region and bromine in the meta-bromobenzyl methylbenzamide region caused dramatic reduction in the functional activity of Cmpd-15. These SAR results provide valuable insights into the mechanism of action of the NAM Cmpd-15 as well as the basis for future development of more potent and selective modulators for the β2AR based on the chemical scaffold of Cmpd-15.
- Meng, Kaicheng,Shim, Paul,Wang, Qingtin,Zhao, Shuai,Gu, Ting,Kahsai, Alem W.,Ahn, Seungkirl,Chen, Xin
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p. 2320 - 2330
(2018/03/29)
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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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- 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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- 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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p. 7343 - 7347
(2016/10/30)
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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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- 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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- 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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- 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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scheme or table
p. 493 - 506
(2011/04/16)
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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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- Endothelin antagonist
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The instant invention relates to some tripeptide derivatives having activity against endothelin a process for preparing them, pharmaceutical composition containing the same and their use in prevention or treatment of some diseases associated with endothelin.
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- Highly efficient catalytic synthesis of α-amino acids under phase-transfer conditions with a novel catalyst/substrate pair
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A facile and fast enantioselective synthesis of α-amino acids with high ee values was achieved by the asymmetric alkylation of the glycine derivative 1 under phase-transfer conditions with (R)-2-amino-2′-hydrozy-1,1′-binaphthyl (NOBIN; see sceme). The ee value of the amino acid products. This occures as a results of a significant positive nonlinear effect in the alkylation reaction.
- Belokon, Yuri N.,Kochetkov, Konstantin A.,Churkina, Tatiana D.,Ikonnikov, Nikolai S.,Larionov, Oleg V.,Harutyunyan, Syuzanna R.,Vyskocil, Stepan,North, Michael,Kagan, Henri B.
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p. 1948 - 1951
(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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- 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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- 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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p. 117 - 120
(2007/10/02)
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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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p. 1479 - 1485
(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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