266360-63-8Relevant articles and documents
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.
Optimization and mechanistic studies of psammaplin A type antibacterial agents active against methicillin-resistant Staphylococcus aureus (MRSA)
Nicolaou,Hughes,Hughes, Robert,Pfefferkorn,Pfefferkorn, Jeffrey A.,Barluenga,Barluenga, Sofia
, p. 4296 - 4310 (2007/10/03)
As described in the preceding article, utilizing a novel combinatorial disulfide exchange strategy, a library of psammaplin A (1) analogues was constructed and screened for antibacterial activity leading to the identification of a collection of diverse lead compounds. These combinatorial leads were subsequently refined, through parallel synthesis, to afford a series of highly potent antibacterial agents (e.g. 17, 57, 58, 69, and 70), some possessing greater than 50-fold higher activities than the natural product. Evaluation of the selectivity and serum binding properties of some of the most promising compounds and preliminary studies directed at deciphering the mechanism of action of this novel class of antibacterial agents are also included.
Phenylalanine ammonia-lyase: The use of its broad substrate specificity for mechanistic investigations and biocatalysis - Synthesis of L-arylalanines
Gloge, Andreas,Zon, Jerzy,Koevari, Agnes,Poppe, Laszlo,Retey, Janos
, p. 3386 - 3390 (2007/10/03)
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.
