154-06-3Relevant articles and documents
Biocatalysts from cyanobacterial hapalindole pathway afford antivirulent isonitriles against MRSA
Bunn, Brittney M,Xu, Mizhi,Webb, Chase M,Viswanathan, Rajesh
, (2021/04/26)
Abstract: The emergence of resistance to frontline antibiotics has called for novel strategies to combat serious pathogenic infections. Methicillin-resistant Staphylococcus aureus [MRSA] is one such pathogen. As opposed to traditional antibiotics, bacteriostatic anti-virulent agents disarm MRSA, without exerting pressure, that cause resistance. Herein, we employed a thermophilic Thermotoga maritima tryptophan synthase (TmTrpB1) enzyme followed by an isonitrile synthase and Fe(II)-α-ketoglutarate-dependent oxygenase, in sequence as biocatalysts to produce antivirulent indole vinyl isonitriles. We report on conversion of simple derivatives of indoles to their C3-vinyl isonitriles, as the enzymes employed here demonstrated broader substrate tolerance. In toto, eight distinct L-Tryptophan derived α-amino acids (7) were converted to their bioactive vinyl isonitriles (3) by action of an isonitrile synthase (WelI1) and an Fe(II)-α-ketoglutarate-dependent oxygenase (WelI3) yielding structural variants possessing antivirulence against MRSA. These indole vinyl isonitriles at 10 μg/mL are effective as antivirulent compounds against MRSA, as evidenced through analysis of rabbit blood hemolysis assay. Based on a homology modelling exercise, of enzyme-substrate complexes, we deduced potential three dimensional alignments of active sites and glean mechanistic insights into the substrate tolerance of the Fe(II)-α-ketoglutarate-dependent oxygenase. Graphic abstract: [Figure not available: see fulltext.]
Dynamic Kinetic Resolution for Asymmetric Synthesis of L-Noncanonical Amino Acids from D-Ser Using Tryptophan Synthase and Alanine Racemase
Yu, Jinhai,Li, Jing,Gao, Xia,Zeng, Shuiyun,Zhang, Hongjuan,Liu, Junzhong,Jiao, Qingcai
, p. 6618 - 6625 (2019/11/03)
L-Ser is often used to synthesize some significant l-noncanonical α-amino acids(l-ncAAs), which are the prevalent intermediates and precursors for functional synthetic compounds. In this study, threonine aldolase from Escherichia coli k-12 MG1655 has been used to synthesize l-Ser. In contrast to the maximum catalytic capacity (20 g/L) for l-threonine aldolase(LTA), d-Ser was synthesized with high yield (240 g/L) from cheap Gly and paraformaldehyde using d-threonine aldolase (DTA) from Arthrobacter sp ATCC. In order to fully utilize d-Ser and expand the resource of l-Ser, a dynamic kinetic resolution system was constructed to convert d/dl-Ser to l-Ser through combining alanine racemase (Alr) from Bacillus subtilis with l-tryptophan synthase (TrpS) from Escherichia coli k-12 MG1655, and l-ncAAs including l-Trp and l-Cys derivatives were synthesized with excellent enantioselectivity and in high yields. The results indicated l-ncAAs could be efficiently synthesized from d-Ser using this original and green dynamic kinetic resolution system, and the reliable l-Ser resource has been established from simple and achiral substrates.
A Panel of TrpB Biocatalysts Derived from Tryptophan Synthase through the Transfer of Mutations that Mimic Allosteric Activation
Murciano-Calles, Javier,Romney, David K.,Brinkmann-Chen, Sabine,Buller, Andrew R.,Arnold, Frances H.
supporting information, p. 11577 - 11581 (2016/10/24)
Naturally occurring enzyme homologues often display highly divergent activity with non-natural substrates. Exploiting this diversity with enzymes engineered for new or altered function, however, is laborious because the engineering must be replicated for each homologue. A small set of mutations of the tryptophan synthase β-subunit (TrpB) from Pyrococcus furiosus, which mimics the activation afforded by binding of the α-subunit, was demonstrated to have a similar activating effect in different TrpB homologues with as little as 57 % sequence identity. Kinetic and spectroscopic analyses indicate that the mutations function through the same mechanism: mimicry of α-subunit binding. From these enzymes, we identified a new TrpB catalyst that displays a remarkably broad activity profile in the synthesis of 5-substituted tryptophans. This demonstrates that allosteric activation can be recapitulated throughout a protein family to explore natural sequence diversity for desirable biocatalytic transformations.
Synthesis of tripeptides containing d-Trp substituted at the indole ring, assessment of opioid receptor binding and in vivo central antinociception
De Marco, Rossella,Bedini, Andrea,Spampinato, Santi,Gentilucci, Luca
supporting information, p. 6861 - 6866 (2014/10/15)
The noncationizable tripeptide Ac-d-Trp-Phe-GlyNH2 was recently proposed as a novel minimal recognition motif for μ-opioid receptor. The introduction of different substituents (methyl, halogens, nitro, etc.) at the indole of d-Trp significantly influenced receptor affinities and resulted in serum stability and in a measurable effect on central antinociception in mice after ip administration.
Regioselective enzymatic halogenation of substituted tryptophan derivatives using the FAD-dependent halogenase RebH
Frese, Marcel,Guzowska, Paulina H.,Voss, Hauke,Sewald, Norbert
, p. 1270 - 1276 (2014/05/20)
Regioselective methods to establish carbon-halide bonds are still rare, although halogenation is considered as a commonly used methodology for the functionalization of organic compounds. The incorporation of halogen substituents by organic synthesis usually requires hazardous conditions, shows poor regioselectivity and results in the formation of unwanted byproducts. In addition, halogenation by electrophilic aromatic substitution (SEAr) obeys distinct rules depending on electron-withdrawing or -donating groups already present in the aromatic ring. We employed the tryptophan-7-halogenase RebH for regioselective enzymatic halogenation to overcome these limitations. In combination with a tryptophan synthase, an array of C5- and C6-substituted tryptophan derivatives was synthesized and halogenated by RebH. The halogenase is able override these directing effects and halogenates at the electronically unfavored C7-meta-position, even in presence of ortho/para-directing groups. No business as usual: The tryptophan halogenase RebH from Lechevalieria aerocolonigenes is able to halogenate at the electronically unfavored C7-meta-position of C5-substituted tryptophan derivatives, even in presence of deactivating ortho/para-directing groups.
Chiral ligand-exchange resolution of underivatized amino acids on a dynamically modified stationary phase for RP-HPTLC
Remelli, Maurizio,Faccini, Stefania,Conato, Chiara
, p. 313 - 318 (2014/06/09)
The synthesis of Spi(τ-dec), derived from the selective alkylation of L-spinacine (4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid) at the τ-nitrogen of its heteroaromatic ring, with a linear hydrocarbon chain of 10 carbon atoms, is described here for the first time. Spi(τ-dec) was successfully employed in the past to prepare home-made chiral columns for chiral ligand-exchange high-performance liquid chromatography. In the present article a new method is described, using Spi(τ-dec) as a chiral selector in high-performance thin-layer chromatography (HPTLC): commercial hydrophobic plates were first coated with Spi(τ-dec) and then treated with copper sulfate. The performance of this new chiral stationary phase was tested against racemic mixtures of aromatic amino acids, after appropriate optimization of both the conditions of preparation of the plates and the mobile phase composition. The enantioselectivity values obtained for the studied compounds were higher than those reported in the literature for similar systems. The method employed here for the preparation of chiral HPTLC plates proved practical, efficient, and inexpensive. Chirality 26:313-318, 2014. 2014 Wiley Periodicals, Inc.
COMPOSITIONS AND METHODS FOR CYCLOFRUCTANS AS SEPARATION AGENTS
-
Page/Page column 45-49; 61, (2010/12/31)
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.
Efficient asymmetric synthesis of biologically important tryptophan analogues via a palladium-mediated heteroannulation reaction
Ma,Liu,Li,Flippen-Anderson,Yu,Cook
, p. 4525 - 4542 (2007/10/03)
A novel and concise synthesis of optically active tryptophan derivatives was developed via a palladium-catalyzed heteroannulation reaction of substituted o-iodoanilines with an internal alkyne. The required internal alkyne 14a or 25 was prepared in greater than 96% de via alkylation of the Schoellkopf chiral auxiliary 19 employing diphenyl phosphate as the leaving group. The Schoellkopf chiral auxiliary was chosen here for the preparation of L-tryptophans would be available from D-valine while the D-isomers required for natural product total synthesis would originate from the inexpensive L-valine (300-g scale). Applications of the palladium-catalyzed heteroannulation reaction were extended to the first asymmetric synthesis of L-isotryptophan 38 and L-benz[f]tryptophan 39. More importantly, the optically pure 6-methoxy-D-tryptophan 62 was prepared by this protocol on a large scale (>300 g). This should permit entry into many ring-A oxygenated indole alkaloids when coupled with the asymmetric Pictet-Spengler reaction. In addition, an improved total synthesis of tryprostatin A (9a) was accomplished in 43% overall yield employing this palladium-mediated process.
Substituent Effects on the Spectral, Acid-Base, and Redox Properties of Indolyl Radicals: A Pulse Radiolysis Study
Jovanovic, Slobodan V.,Steenken, Steen
, p. 6674 - 6679 (2007/10/02)
Spectral and acid-base properties and reduction potentials of various substituted indolyl radicals were studied by pulse radiolysis in aqueous solutions at 20 deg C.Except for the 5-methoxyindolyl and 5-carboxyindolyl radicals, the spectra of the substituted indolyl radicals resemble the previously published 320- and 520-nm spectra of the neutral and 330- and 580-nm spectra of the cation indolyl and tryptophan radicals.The substitution of indolyl radical cation by electron-attracting groups (positive ?+) results in a blue shift of the 580-nm band by ca. 30 nm,, whereas the spectra of methylindolyl (?+ = -0.31) are similar to those of unsubstituted indolyl radicals.The 430- and 455-nm bands appearing in the spectra of the 5-carboxyindolyl and 5-methoxyindolyl radical cations, respectively, indicate even stronger interaction of the unpaired electron with the 5-substituent.The radical cations of various indole-3-acetic acids decarboxylate at pH values below their pKa to produce allyl radicals.The 5-bromoindolyl radical undergoes solvolysis to 5-hydroxyindolyl radical in acidic and alkaline media.The dissociation constants and reduction potentials of the substituted indolyl radicals correlate with the Brown substituent constants: pKr = 4.14 - 2.13Σ?+, correlation coefficient 0.987, and E0/0.059 = 22.29 + 3.5Σ?+, correlation coefficient 0.980.The ρ values from these correlations (-2.13 and 3.5) are similar to that of the Hammett correlation of the dissociation constants of the protonated indole nitrogen in various substituted indoles, ρ = -2.49, but smaller than the ρ value of the dependence on the substituent of the reduction potentials of phenoxyl radicals, ρ = 5.4.
Process for preparing optically active tryptophans
-
, (2008/06/13)
Biochemical optical resolution of DL-tryptophans in which DL-tryptophan amides are interacted with the culture products, or their treated products, of a microorganism capable of producing amidase is described. L-Tryptophan amides in racemic DL-tryptophan amides are asymmetrically hydrolyzed to form optically active L-tryptophans at a high yield and almost all D-tryptophan amides remain without being subjected to hydrolysis. The resultant D-tryptophan amides are readily hydrolyzed, after separating L-tryptophans, to form optically active D-tryptophans at a high yield.
