80126-54-1Relevant articles and documents
A novel phenylalanine ammonia-lyase from Pseudozyma antarctica for stereoselective biotransformations of unnatural amino acids
Varga, Andrea,Csuka, Pál,Sonesouphap, Orlavanah,Bánóczi, Gergely,To?a, Monica Ioana,Katona, Gabriel,Molnár, Zsófia,Bencze, László Csaba,Poppe, László,Paizs, Csaba
, p. 185 - 194 (2020/04/28)
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.
Bi-enzymatic Conversion of Cinnamic Acids to 2-Arylethylamines
Weise, Nicholas J.,Thapa, Prasansa,Ahmed, Syed T.,Heath, Rachel S.,Parmeggiani, Fabio,Turner, Nicholas J.,Flitsch, Sabine L.
, p. 995 - 998 (2020/01/21)
The conversion of carboxylic acids, such as acrylic acids, to amines is a transformation that remains challenging in synthetic organic chemistry. Despite the ubiquity of similar moieties in natural metabolic pathways, biocatalytic routes seem to have been overlooked for this purpose. Herein we present the conception and optimisation of a two-enzyme system, allowing the synthesis of β-phenylethylamine derivatives from readily-available ring-substituted cinnamic acids. After characterisation of both parts of the reaction in a two-step approach, a set of conditions allowing the one-pot biotransformation was optimised. This combination of a reversible deaminating and irreversible decarboxylating enzyme, both specific for the amino acid intermediate in tandem, represents a general method by which new strategies for the conversion of carboxylic acids to amines could be designed.
Engineered Aminotransferase for the Production of d-Phenylalanine Derivatives Using Biocatalytic Cascades
Walton, Curtis J. W.,Parmeggiani, Fabio,Barber, Janet E. B.,McCann, Jenna L.,Turner, Nicholas J.,Chica, Roberto A.
, p. 470 - 474 (2017/12/15)
d-Phenylalanine derivatives are valuable chiral building blocks for a wide range of pharmaceuticals. Here, we developed stereoinversion and deracemization biocatalytic cascades to synthesize d-phenylalanine derivatives that contain electron-donating or -withdrawing substituents of various sizes and at different positions on the phenyl ring with a high enantiomeric excess (90 to >99 % ee) from commercially available racemic mixtures or l-amino acids. These whole-cell systems couple Proteus mirabilis l-amino acid deaminase with an engineered aminotransferase that displays native-like activity towards d-phenylalanine, which we generated from Bacillus sp. YM-1 d-amino acid aminotransferase. Our cascades are applicable to preparative-scale synthesis and do not require cofactor-regeneration systems or chemical reducing agents.
Organocatalytic Enantioselective Addition of α-Aminoalkyl Radicals to Isoquinolines
Liu, Xiangyuan,Liu, Yang,Chai, Guobi,Qiao, Baokun,Zhao, Xiaowei,Jiang, Zhiyong
supporting information, p. 6298 - 6301 (2018/10/09)
With a dual organocatalytic system involving a chiral phosphoric acid and a dicyanopyrazine-derived chromophore (DPZ) photosensitizer and under the irradiation with visible light, an enantioselective Minisci-type addition of α-amino acid-derived redox-active esters (RAEs) to isoquinolines has been developed. A variety of prochiral α-aminoalkyl radicals generated from RAEs were successfully introduced on isoquinolines, providing a range of valuable α-isoquinoline-substituted chiral secondary amines in high yields with good to excellent enantioselectivities.
One-Pot Enzymatic Synthesis of d-Arylalanines Using Phenylalanine Ammonia Lyase and l-Amino Acid Deaminase
Zhu, Longbao,Feng, Guoqiang,Ge, Fei,Song, Ping,Wang, Taotao,Liu, Yi,Tao, Yugui,Zhou, Zhemin
, p. 1 - 15 (2018/06/11)
The phenylalanine ammonia-lyase (AvPAL) from Anabaena variabilis catalyzes the amination of substituent trans-cinnamic acid (t-CA) to produce racemic d,l-enantiomer arylalanine mixture owing to its low stereoselectivity. To produce high optically pure d-arylalanine, a modified AvPAL with high d-selectivity is expected. Based on the analyses of catalytic mechanism and structure, the Asn347 residue in the active site was proposed to control stereoselectivity. Therefore, Asn347 was mutated to construct mutant AvPAL-N347A, the stereoselectivity of AvPAL-N347A for d-enantiomer arylalanine was 2.3-fold higher than that of wild-type AvPAL (WtPAL). Furthermore, the residual l-enantiomer product in reaction solution could be converted into the d-enantiomer product through stereoselective oxidation by PmLAAD and nonselective reduction by reducing agent NH3BH3. At optimal conditions, the conversion rate of t-CA and optical purity (enantiomeric excess (eeD)) of d-phenylalanine reached 82% and exceeded 99%, respectively. The two enzymes displayed activity toward a broad range of substrate and could be used to efficiently synthesize d-arylalanine with different groups on the phenyl ring. Among these d-arylalanines, the yield of m-nitro-d-phenylalanine was highest and reached 96%, and the eeD exceeded 99%. This one-pot synthesis using AvPAL and PmLAAD has prospects for industrial application.
Kinetic Resolution of Aromatic β-Amino Acids Using a Combination of Phenylalanine Ammonia Lyase and Aminomutase Biocatalysts
Weise, Nicholas J.,Ahmed, Syed T.,Parmeggiani, Fabio,Turner, Nicholas J.
, p. 1570 - 1576 (2017/05/05)
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.).
Single-Biocatalyst Synthesis of Enantiopure d-Arylalanines Exploiting an Engineered d-Amino Acid Dehydrogenase
Parmeggiani, Fabio,Ahmed, Syed T.,Thompson, Matthew P.,Weise, Nicholas J.,Galman, James L.,Gahloth, Deepankar,Dunstan, Mark S.,Leys, David,Turner, Nicholas J.
, p. 3298 - 3306 (2016/10/20)
A practical and efficient biocatalytic synthesis of aromatic d-amino acids has been developed, based on the reductive amination of the corresponding α-keto acids via a recombinant whole cell system composed of an engineered dehydrogenase and cofactor recycling apparatus. The reaction was shown to give excellent enantioselectivity (≥98%) and good yields at the preparative scale across a broad range of substrates. Additionally, the structure of the variant enzyme was solved to allow rationalisation of the observed reaction rates. The engineered whole cell catalyst was also used to mediate the production of d-phenylalanine derivatives from racemic mixtures and cheaper l-amino acids by combining it with an enantiocomplementary deaminase. (Figure presented.).
The bacterial ammonia lyase EncP: A tunable biocatalyst for the synthesis of unnatural amino acids
Weise, Nicholas J.,Parmeggiani, Fabio,Ahmed, Syed T.,Turner, Nicholas J.
supporting information, p. 12977 - 12983 (2015/10/28)
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.
Immunomodulatory peptides
-
, (2014/12/12)
The invention relates to peptides derivatized with a hydrophilic polymer which, in some embodiments, bind to human FcRn and inhibit binding of the Fc portion of an IgG to an FcRn, thereby modulating serum IgG levels. The disclosed compositions and methods may be used in some embodiments, for example, in treating autoimmune diseases and inflammatory disorders. The invention also relates, in further embodiments, to methods of using and methods of making the peptides of the invention.
Mechanistic approach of the difference in non-enzymatic hydrolysis rate between the L and D enantiomers of no-carrier added 2-[18F] fluoromethyl-phenylalanine
Kersemans, Ken,Mertens, John,De Proft, Frank,Geerlings, Paul
scheme or table, p. 80 - 85 (2011/10/30)
No-carrier added (n.c.a.) 2-[18F]fluoromethyl-l-phenylalanine was found to be very sensitive to hydrolysis in aqueous solutions. This problem was solved partially by the addition of calcium ions (0.04M), increasing the shelf-life to at least 6h. In this paper the defluorination reaction was studied in detail to elucidate its mechanism. Therefore, L and D enantiomers of 2-[18F]FMP and 4-[18F]FMP were synthesized, as well as 2-[18F]fluoromethyl-phenethylamine and 4-[18F] fluoromethyl-phenethylamine, both decarboxylated 'mimetic' molecules of the amino acid analogues. Radiosynthesis, using a customized Scintomics automatic synthesis hotboxthree module, resulted in a high overall yield and a radiochemical purity of >99%. The defluorination rates of all compounds were studied by HPLC. The L enantiomer of n.c.a 2-[18F]FMP defluorinated seven times faster than the D enantiomer and 2-[18F]fluoromethyl- phenethylamine. Both enantiomers of 4-[18F]FMP and 4-[ 18F]fluoromethyl-phenethylamine were stable. From these data, the reaction mechanism, involving two distinct intramolecular interactions, was derived. First, the interaction between the amine and the benzylic fluorine weakens the carbon-fluorine bond. Secondly, the formation of a second hydrogen bridge between the carboxyl group and one of the benzylic hydrogen atoms renders the fluorine atom even more susceptible to hydrolysis. The latter interaction induces an additional chiral center. The probability of its formation differs considerably between L and D enantiomers of n.c.a. 2-[18F]FMP, which explains the difference in hydrolysis rate. Copyright
