L-tyrosine Derivatives Research Articles

Lignin-based monophenolic model compounds in L-tyrosine derivative synthesis via tyrosine phenol lyase

Tyrosine phenol lyase (TPL) synthesises L-tyrosine derivatives from monophenols, pyruvate and ammonia. Production of such high-value aromatic chemicals from biomass-derived raw materials is of great interest. In this study, six monophenols (guaiacol, phenol, o-cresol, m-cresol, catechol and syringol) were chosen based on the structure of lignin and were studied as substrates in the enzymatic reaction. Single monophenol reactions (SMR) and binary monophenol reactions (BMR) with guaiacol were carried out. TPL-M379V was found to be selective towards guaiacol (84.5 % conv.). The highest single activity was measured towards phenol (93.9 % conv.). However, the enzyme preferred guaiacol over phenol in the BMRs. Syringol was found to be inert in the reaction, whereas catechol had an inhibitory effect on the enzymatic reaction, in addition to causing degradation of all the substrates in the medium. Doubling the guaiacol concentration in the SMR did not significantly increase the production of 3-O-methyldopa (conv. 45.9 %). However, in the binary reaction systems the total monophenol conversions were higher with guaiacol and phenol (total 62.4 %) or o-cresol (total 57.1 %). This indicates possible substrate/product specific inhibition. The study provides new data on activity, selectivity and inhibitory effects of monophenols in the synthetic reaction catalysed by TPL-M379V, especially in mixed-substrate reactions.

The Mechanism of Action of L-Tyrosine Derivatives against Chikungunya Virus Infection In Vitro Depends on Structural Changes.

Although the disease caused by chikungunya virus (CHIKV) is of great interest to public health organizations around the world, there are still no authorized antivirals for its treatment. Previously, dihalogenated anti-CHIKV compounds derived from L-tyrosine (dH-Y) were identified as being effective against in vitro infection by this virus, so the objective of this study was to determine the mechanisms of its antiviral action. Six dH-Y compounds (C1 to C6) dihalogenated with bromine or chlorine and modified in their amino groups were evaluated by different in vitro antiviral strategies and in silico tools. When the cells were exposed before infection, all compounds decreased the expression of viral proteins; only C4, C5 and C6 inhibited the genome; and C1, C2 and C3 inhibited infectious viral particles (IVPs). Furthermore, C1 and C3 reduce adhesion, while C2 and C3 reduce internalization, which could be related to the in silico interaction with the fusion peptide of the E1 viral protein. Only C3, C4, C5 and C6 inhibited IVPs when the cells were exposed after infection, and their effect occurred in late stages after viral translation and replication, such as assembly, and not during budding. In summary, the structural changes of these compounds determine their mechanism of action. Additionally, C3 was the only compound that inhibited CHIKV infection at different stages of the replicative cycle, making it a compound of interest for conversion as a potential drug.

Non-thermal plasma modulated l-tyrosine self-assemblies: a potential avenue for fabrication of supramolecular self-assembled biomaterials.

Aromatic amino acids (AAs) have garnered particular interest due to their pivotal roles in numerous biological processes and disorders. Variations in AA self-assembly not only affect protein structures and functions, but their non-covalent interactions such as hydrogen bonding, van der Waals forces, and π-π stacking, yield versatile assemblies vital in bio-inspired material fabrication. Tyrosine (Tyr), a non-essential aromatic amino acid, holds multifaceted significance in the body as a protein building block, neurotransmitter precursor, thyroid hormone contributor, and melanin synthesis regulator. The proficiency of Cold Atmospheric Plasma (CAP) in generating a spectrum of reactive oxygen and nitrogen species has spurred innovative research avenues in the studies of biomolecular components, including its potential for targeted cancer cell ablation and biomolecule modification. In this work, we have assessed the chemical as well as the structural changes in Tyrosine-derived self-assembled structures arising from the CAP-induced reactive species. For a comprehensive understanding of the mechanism, different treatment times, feed gases, and the role of solvent acidification are compared using various spectroscopic and microscopic techniques. LC-ESI-QQQ mass spectra unveiled the emergence of oxygenated and nitro derivatives of l-tyrosine following its interaction with CAP-derived ROS/RNS. SEM and TEM images demonstrated an enhanced surface size of self-assembled structures and the formation of novel nanomaterial-shaped assemblies following CAP treatment. Overall, this study aims to explore CAP's interaction with a single-amino acid, hypothesizing the creation of novel supramolecular structures and scrutinizing CAP-instigated transformations in l-tyrosine self-assembled structures, potentially advancing biomimetic-attributed nanomaterial fabrication which might present a novel frontier in the field of designing functional biomaterials.

Radical scavenging abilities of L-tyrosine and L-DOPA Schiff bases and their fluorescence binding studies and molecular docking interactions with bovine serum albumin

Phenolic compounds are known for their abilities to scavenge and eliminate reactive oxygen species (ROS) which may lead to oxidative stress. Bearing in mind that Schiff bases are biologically active compounds, a series of Schiff bases derived from the monophenolic l-tyrosine and diphenolic l-DOPA were synthesized and characterized by spectral and elemental analysis. The structure of the l-DOPA naphthyl Schiff base was confirmed and characterized by X-ray. 1,1-Diphenyl-2-picrylhydrazyl (DPPH) and 2,2′-azino-bis-3-ethylbenzthiazoline-6-sulphonic acid (ABTS) radical assays were used in assessing the effectiveness of these compounds as radical scavengers. l-DOPA derivatives were better radical scavengers with lower IC50 compared to l-tyrosine derivatives. To understand the distribution of these compounds in the blood plasma, their interactions with bovine serum albumin (BSA) were monitored using fluorescent emission spectroscopy where they were found to quench the BSA intrinsic fluorescence by combined static and dynamic mechanism. The fluorescence and FT-IR data showed that conformational changes occurred in BSA after interaction with the Schiff bases. The binding constant of tyrosine and DOPA Schiff bases were in the order of 104 to 108 M−1 suggesting a moderate to good binding ability with BSA. Higher binding affinity and better radical scavenging ability was observed for compounds bearing the naphthyl moiety.The radical scavenging ability of the l-DOPA naphthyl Schiff base was found to increase with decrease in IC50 values from 17 to 15 µM when bound to BSA. Fluorescence measurement and molecular docking studies demonstrated that hydrophobic interactions and hydrogen bonds dominated the interaction between BSA and tyrosine or l-DOPA derivatives. These results gave valuable information for pharmacological mechanism for l-tyrosine and l-DOPA Schiff bases in vivo conditions which can have a vital role in the development of drugs.

Toward an Electronic Tongue Based on Surfactant-Stabilized Chemosensory Microparticles with a Dual Detection Mode.

We propose a novel type of electronic tongue based on four types of monodispersed chemosensory microparticles (MPs) with a lipophilic core stabilized by a nonionic poloxamer surfactant. The lipophilic core composition was designed to achieve cross-sensitivity toward various ions and to enable spectrophotometric and/or spectrofluorimetric detection. Thus, generic anion-selective MPs, generic cation-selective MPs, as well as two types of metalloporphyrin-based MPs were fabricated and their morphology was characterized. Next, their differential sensing ability toward the discrimination of five l-tyrosine derivatives (dopamine, 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxy-l-phenylalanine, normetanephrine, 4-hydroxy-3-methoxymandelic acid) was assessed. Comparison with the respective ion-selective electrode (ISE) responses was also provided to verify if the results from the potentiometric e-tongue correspond to outputs of the developed MP optode array. The recognition of dietary supplements containing l-tyrosine (l-Tyr) derivatives with the use of the MP-based e-tongue proved the potential of the developed sensing assay in pharmaceutical analysis.

O-15 - At-211-labeled L-tyrosine derivatives via neopentyl scaffold for targeted α-therapy

O-15 - At-211-labeled L-tyrosine derivatives via neopentyl scaffold for targeted α-therapy

Synthesis of Halogenated Diphenylpiperazines from l-Tyrosine Derivatives by Biotransformation

Abstract Piperazine-containing compounds tend to exhibit good biological activities. In this study, four novel halogenated diphenylpiperazines were biosynthesized in one step by feeding halogenated l-tyrosine derivatives to Escherichia coli cells expressing heterologous non-ribosomal peptide synthetase HqlA and short-chain reductase HqlB. The work showed potential for synthesis of halogenated diphenylpiperazines using engineered microorganism.

Enhancement of the Antioxidant and Antimicrobial Activities of Porphyran through Chemical Modification with Tyrosine Derivatives.

The chemical modification of porphyran hydrocolloid is attempted, with the objective of enhancing its antioxidant and antimicrobial activities. Sulfated galactan porphyran is obtained from commercial samples of the red algae Porphyra dioica using Soxhlet extraction with water at 100 °C and precipitation with isopropyl alcohol. The extracted porphyran is then treated with modified L-tyrosines in aqueous medium in the presence of NaOH, at ca. 70 °C. The modified tyrosines L1 and L2 are prepared through a Mannich reaction with either thymol or 2,4-di-tert-butylphenol, respectively. While the reaction with 2,4-di-tert-butylphenol yields the expected tyrosine derivative, a mixture of products is obtained with thymol. The resulting polysaccharides are structurally characterized and the respective antioxidant and antimicrobial activities are determined. Porphyran treated with the N-(2-hydroxy-3,5-di-tert-butyl-benzyl)-L-tyrosine derivative, POR-L2, presents a noticeable superior radical scavenging and antioxidant activity compared to native porphyran, POR. Furthermore, it exhibited some antimicrobial activity against S. aureus. The surface morphology of films prepared by casting with native and modified porphyrans is studied by SEM/EDS. Both POR and POR-L2 present potential applicability in the production of films and washable coatings for food packaging with improved protecting characteristics.

Recent advances in biocatalytic derivatization of l-tyrosine

L-Tyrosine is an aromatic, polar, non-essential amino acid that contains a highly reactive α-amino, α-carboxyl, and phenolic hydroxyl group. Derivatization of these functional groups can produce chemicals, such as L-3,4-dihydroxyphenylalanine, tyramine, 4-hydroxyphenylpyruvic acid, and benzylisoquinoline alkaloids, which are widely employed in the pharmaceutical, food, and cosmetics industries. In this review, we summarize typical L-tyrosine derivatizations catalyzed by enzymatic biocatalysts, as well as the strategies and challenges associated with their production processes. Finally, we discuss future perspectives pertaining to the enzymatic production of L-tyrosine derivatives.Key points• Summary of recent advances in enzyme-catalyzed L-tyrosine derivatization.• Highlights of relevant strategies involved in L-tyrosine derivatives biosynthesis.• Future perspectives on industrial applications of L-tyrosine derivatization.

Nickel(II) complexes based on L-amino-acid-derived ligands: synthesis, characterization and study of the role of the supramolecular structure in carbon dioxide capture.

The formation of the symmetrical μ3-carbonate-bridged self-assembled trinuclear NiII complex Na2{[Ni(LO)2(H2O)]3(μ3-CO3)} (LO is the carboxylate anion of a L-tyrosine derivative), involves atmospheric CO2 uptake. The asymmetric unit of the complex comprises an octahedral coordination for the NiII with two L-tyrosine-based ligands, a water molecule and one O atom of the carbonate bridge. The Ni3-μ3-CO3 core in this compound is the first reported of this kind according to the Cambridge Structural Database (CSD). The supramolecular structure is mainly sustained by hydrogen bonds developed by the phenolic functionality of the L-tyrosine moiety of one ligand and the carboxylate group of a neighbouring ligand. The crystal packing is then characterized by three interpenetrated supramolecular helices associated with a diastereoisomer of the type R-supP, which is essential for the assembly process. Magnetic susceptibility and magnetization data support weak ferromagnetic exchange interactions within the novel Ni3-μ3-CO3 core. The NiII complex obtained under the same synthetic conditions but using the analogous ligand derived from the amino acid L-phenylalanine instead of L-tyrosine gives rise to to a mononuclear octahedral system. The results obtained for the different complexes demonstrate the role of the supramolecular structure regarding the CO2 uptake property for these NiII-amino-acid-based systems.

Methylated derivatives of l-tyrosine in reaction catalyzed by l-amino acid oxidase: isotope and inhibitory effects.

l-Amino acid oxidase (LAAO) is widely distributed in nature and shows important biological activity. It induces cell apoptosis and has antibacterial properties. This study was designed to investigate the effect of methyl substituent on its activity as methylated derivatives of l-tyrosine, labelled with short-lived B+ emitters, have been used in oncological diagnostics. To study isotope effects in the oxidative deamination of O-methyl-l-tyrosine, the deuterated isotopomer, i.e. O-methyl-[2-2H]-l-tyrosine, was synthesized by isotope exchange, catalyzed enzymatically by tryptophanase. Isotope effects were determined using the spectrophotometric non-competitive method. The values of isotope effects indicate that the α-C-H bond cleavage occurs in the rate determining step of the investigated reaction and α-hydrogen plays a role in the substrate binding process at the enzyme active site. The inhibitory effect on LAAO activity was studied with α-methyl-l-tyrosine and N-methyl-l-tyrosine. The mode of inhibition was determined based on Lineweavear-Burk plots intersections. α-Methyl-l-tyrosine has been found a mixed type inhibitor of the investigated enzyme, whereas N-methyl-l-tyrosine is a non-competitive inhibitor of LAAO.

Synthesis and trypanocide activity of chloro-l-tyrosine and bromo-l-tyrosine derivatives

Twenty-two halogenated l-tyrosine derivatives were synthesized to examine new substances for the treatment of Chagas disease. The synthesis of these derivatives with different degree of substitution in the amino group with methyl iodide, giving primary, tertiary, and quaternary amino acids. All compounds were tested in vitro against intracellular amastigotes of Trypanosoma cruzi, and the cytotoxicity were evaluated over monocytic cell line U-937. Compound 25 was the most active against T. cruzi with a EC50 of 75.52 µM compared with benznidazole with a EC50 of 58.79 µM. Compounds 3, 4, 7, and 15 were the derivatives with the best selectivity index (SI) with values of 7.5, 8.3,12.1, and 8.6, respectively. Finally, compound 7 was the safer and the more promising derivative against T. cruzi.

Isotope effects in the tyrosinase catalysed hydroxylation of l-tyrosine methyl derivatives

ABSTRACTTo investigate isotope effects in the hydroxylation of [3′,5′-2H2]-α-methyl- and [3′,5′-2H2]-N-methyl-l-tyrosine, they were synthesised using acid catalysed isotope exchange at high temperature. The kinetic and solvent deuterium isotope effects on Vmax and Vmax/Km parameters of tyrosinase in its action on methylated derivatives of l-tyrosine were determined using the non-competitive spectrophotometric method. Lineweaver–Burk plots were used to consider the inhibition type of O-methyl-l-tyrosine, revealing that it is an uncompetitive inhibitor of tyrosinase.

Anti-Parasite and Cytotoxic Activities of Chloro and Bromo L-Tyrosine Derivatives

A series of twenty-one L-tyrosine derivatives with modifications in the halogenation pattern of the aromatic ring and different degree of methylations on the amine and phenolic hydroxyl groups were synthesized. The structures of all the intermediates and target compounds were confirmed unambiguous by spectroscopy analysis. Additionally, all compounds were evaluated against Plasmodium falciparum and Leishmania panamensis parasites between 20-702 µg mL-1. The cytotoxic evaluation was done to determine the selectivity index for each compound. Six compounds had the lower EC50 (effective concentration 50) against L. panamensis. One of these compounds was the most active with an EC50 at 24.13 µg mL-1 (76.07 µM). All derivatives showed no significant activity against P. falciparum and no compound has in vitro antifungal activity at 500 µg mL-1.

Isotope effects in mechanistic studies of l-tyrosine halogen derivatives hydroxylation catalyzed by tyrosinase

The kinetic (KIE) and solvent (SIE) isotope effect methods were used to investigate the mechanism of enzymatic hydroxylation of halogenated derivatives of l-tyrosine to l-DOPA catalyzed by the enzyme tyrosinase (EC 1.14.18.1). The values of deuterium KIE and SIE were obtained using the non-competitive method with spectrophotometric measurements. The Lineweaver–Burk plots were used for determination of the inhibition mode of 3′-iodo-l-tyrosine. Based upon kinetic effects values the mechanism of action of enzyme tyrosinase was proposed.

Family portraits: the enzymes behind benzylisoquinoline alkaloid diversity

Benzylisoquinoline alkaloids (BIAs) are a group of specialized metabolites found predominantly in the plant order Ranunculales. Approximately 2500 naturally occurring BIAs have been identified, many of which possess a variety of potent biological and pharmacological properties. The initial BIA skeleton is formed via condensation by a unique enzyme, norcoclaurine synthase, of the l-tyrosine derivatives dopamine and 4-hydroxyphenylacetaldehyde, yielding (S)-norcoclaurine as a central intermediate. The vast diversity of BIA structures is subsequently derived from (1) transformation of the basic BIA backbone by oxidative enzymes, particularly cytochromes P450 and FAD-linked oxidases, and (2) further structural and functional group modification by tailoring enzymes, which also include various reductases, dioxygenases, acetyltransferases, and carboxylesterases. Most of the biosynthetic enzymes responsible for the biosynthesis of major BIAs (i.e. morphine, noscapine, papaverine, and sanguinarine) in opium poppy (Papaver somniferum), and other compounds (e.g. berberine) in related plants, have been isolated and partially characterized. Diversity in BIA metabolism is driven by the modular and repetitive recruitment, and subsequent neo-functionalization, of a limited number of ancestral enzymes. In this review, BIA biosynthetic enzymes are discussed in the context of their respective families, facilitating exploration of common phylogeny and biochemical mechanisms.

Highly photocytotoxic silicon(IV) phthalocyanines axially modified with l-tyrosine derivatives: Effects of mode of axial substituent connection and of formulation on photodynamic activity

Three novel silicon(IV) phthalocyanines (SiPcs) axially substituted with l-tyrosine moieties possessing different modes of connection have been synthesized and characterized. The ester-linked SiPc 3 shows a slight red-shift of Q band, higher fluorescence emission and photosensitizing efficiency relative to the ether-linked SiPcs 1 and 2. However, SiPcs 1 and 2 exhibit more potent photocytotoxicity than SiPc 3, due to higher cellular uptake. When formulated with Cremophor EL™, all SiPcs show very high photocytotoxicity toward HepG2 cells, particularly for SiPc 2 which has a low IC50 value (1.3 nM). In the case of the phosphate buffered saline formulation, the photodynamic activities follow the trend 1 > 2 >>3, which is different with that formulated with Cremophor EL™ (2 > 1 > 3). Thus, varying the mode of attachment of l-tyrosine moieties on the axial positions of SiPcs affects their photophysical and photochemical properties, and biological behavior.

One-Pot, Two-Module Three-Step Cascade To Transform Phenol Derivatives to Enantiomerically Pure (R)- or (S)-p-Hydroxyphenyl Lactic Acids

Readily available phenol derivatives were substituted in para-position via a C–C bond formation to give enantiomerically pure (R)- or (S)-3-(para-hydroxyphenyl) lactic acids. The transformation was achieved by designing a biocatalytic cascade consisting of three linear steps, namely, (i) the C–C coupling of the phenol and pyruvate in the presence of ammonia to afford the corresponding l-tyrosine derivative, followed by (ii) oxidative deamination and (iii) enantioselective reduction. Compatibility analysis showed that the reaction rate of the first step is slowed in the presence of the product of the third step; consequently, the three-step cascade was subdivided in two modules (module 1 = step 1; module 2 = steps 2 and 3), which were run in one pot sequentially. Because of the exquisite selectivity achieved in the C–C coupling step, para-isomers were obtained exclusively. By choosing the appropriate alcohol dehydrogenase, the (R)- as well as the (S)-isomer were isolated in enantiopure form. Preparative tr...

Chemically modified cysteine in CHO fed-batch processes and impact on the specific productivity

Background Mammalian fed-batch processes for monoclonal antibody (mAb) production rely on strategic feeding of several nutrients such as glucose, vitamins and amino acids to extend culture time and improve protein production [1]. In actual processes, L-cysteine and L-tyrosine are fed separately at alkaline pH due their low stability and low solubility at neutral pH, resulting in pH peaks and precipitations [2]. To simplify next generation processes, both amino acids have been chemically modified to enhance their respective stability and solubility profiles. Previous work has demonstrated that phosphotyrosine disodium salt (PTyr2Na) is a stable L-tyrosine derivative and can be used in neutral pH feeds without having a detectable impact on the culture performance or the mAb quality attributes [3]. Here, we present results obtained using a L-cysteine derivative in a neutral pH, single-feed system.

Biocatalytic One-Pot Synthesis of l-Tyrosine Derivatives from Monosubstituted Benzenes, Pyruvate, and Ammonia

l-Tyrosine derivatives were obtained in >97% ee via a biocatalytic one-pot two-step cascade using substituted benzenes, pyruvate, and NH3 as starting materials. In the first step, monosubstituted arenes were regioselectively hydroxylated in the o-position by monooxygenase P450 BM3 (using O2 as oxidant with NADPH-recycling) to yield the corresponding phenols, which subsequently underwent C–C coupling and simultaneous asymmetric amination with pyruvate and NH3 using tyrosine phenol lyase to furnish l-DOPA surrogates in up to 5.2 g L–1. Instead of analytically pure arenes, crude aromatic gasoline blends containing toluene were used to yield 3-methyl-l-tyrosine in excellent yield (2 g L–1) and >97% ee.