L-Tyrosine, oxidation

Marquez and Dunford [193] have studied the kinetics of L-tyrosine oxidation by MPO. They measured the rate constants for the reactions of MPO compounds I and II with tyrosine and dityrosine and found out that, comparing with HRP, LPO, and TPO, MPO is the most effective catalyst of tyrosine oxidation at physiological pH (Table 22.1). Furthermore, the rate constant for Reaction (9) with tyrosine turns out to be comparable with that for Reaction (16), confirming the possibility for tyrosine to compete in blood plasma with chloride, which is considered to be the major MPO substrate and a potent oxidizing agent against invading bacteria and viruses. 

One ammo acid often serves as the biological precursor to another L Phenylala nine is classified as an essential ammo acid whereas its p hydroxy derivative L tyro sine IS not This is because animals can convert L phenylalanine to L tyrosine by hydrox ylation of the aromatic ring An arene oxide (Section 24 7) is an intermediate... 

Ascorbic acid is involved in carnitine biosynthesis. Carnitine (y-amino-P-hydroxybutyric acid, trimethylbetaine) (30) is a component of heart muscle, skeletal tissue, Uver and other tissues. It is involved in the transport of fatty acids into mitochondria, where they are oxidized to provide energy for the ceU and animal. It is synthesized in animals from lysine and methionine by two hydroxylases, both containing ferrous iron and L-ascorbic acid. Ascorbic acid donates electrons to the enzymes involved in the metabohsm of L-tyrosine, cholesterol, and histamine (128). 

Melanin biosynthesis in animals is a complex process starting with the L-tyrosine amino acid. In the first step, L-tyrosine is converted first into DOPA and then into dopaquinone, a process catalyzed by tyrosinase. In the biosynthesis of eumelanins, dopaquinone undergoes a cyclization to form dopachrome and subsequently a tau-tomerization into 5,6-dihydroxyindole-2-carboxylic acid (DHICA). DHICA is further oxidized to indole-5,6-quinone2-carboxylic acid, the precnrsor of DHICA eumelanins. Tyrosinase-related proteins TRP-2 and TRP-1, respectively, are responsible for the last two steps, and they are under the control of the tyrosinase promoter. 

Several compounds can be oxidized by peroxidases by a free radical mechanism. Among various substrates of peroxidases, L-tyrosine attracts a great interest as an important phenolic compound containing at 100 200 pmol 1 1 in plasma and cells, which can be involved in lipid and protein oxidation. In 1980, Ralston and Dunford [187] have shown that HRP Compound II oxidizes L-tyrosine and 3,5-diiodo-L-tyrosine with pH-dependent reaction rates. Ohtaki et al. [188] measured the rate constants for the reactions of hog thyroid peroxidase Compounds I and II with L-tyrosine (Table 22.1) and showed that Compound I was reduced directly to ferric enzyme. Thus, in this case the reaction of Compound I with L-tyrosine proceeds by two-electron mechanism. In subsequent work these authors have shown [189] that at physiological pH TPO catalyzed the two-electron oxidation not only L-tyrosine but also D-tyrosine, A -acetyltyrosinamide, and monoiodotyrosine, whereas diiodotyrosine was oxidized by a one-electron mechanism. 

Similar to other phenols, L-tyrosine is oxidized by peroxidases to phenolic free radical [190] ... 

Heinecke et al. [191] studied the oxidation of L-tyrosine by the H202-MP0 system and showed that the main product of this reaction is dityrosine. They have also found that tyrosine successfully competed with chloride as a substrate for MPO that points out at the possibility of in vivo oxidation of tyrosine by MPO even in the presence of big physiological concentration (0.10-0.1 mol l-1) of chloride in human blood. It was also suggested that the tyrosyl radical formed at the catalytic oxidation of tyrosine by peroxidases may interact with... 

The formation of chloramines is an initial step of another mechanism of oxidative modification of LDL. It has been shown that the MPO-hydrogen peroxide-chloride system reacts with L-tyrosine to form p-hydroxyphenylacetaldehyde [163], As activated neutrophils release both MPO and hydrogen peroxide, it was suggested that neutrophils can stimulate the formation of p-hydroxyphenylacetaldehyde by producing chloramines as intermediates during the oxidation of LDL [164],... 

Peroxidases have also been utilized for preparative-scale oxidations of aromatic hydrocarbons. Procedures have been optimized for hydroxylation of l-tyrosine, D-(-)-p-hydroxyphenylglycine, and L-phenylalanine by oxygen, di-hydroxyfumaric acid, and horseradish peroxidase (89). Lactoperoxidase from bovine milk and yeast cytochrome c peroxidase will also catalyze such hydroxylation reactions (89). 

Phenylglycines are important components of the vancomycin/teicoplanin antibiotics, and the conforma-tionally restricted amino acids contribute to the unique architecture and biological function of these clinically important NRPs. 4-Hydroxyphenylglycine is produced from L-tyrosine in a pathway that involves three enzymes. In the key step, a nonheme iron oxidase catalyzes the oxidative decarboxylation of the a-keto acid derivative of L-tyrosine resulting in loss of carbon dioxide and generation of the phenylglycine carbon framework. 

Oxidation of L-tyrosine, for selective introduction of a hydroxyl group at Cj of the tyrosine ring, can be accomplished in a purely synthetic manner by using a mixture of hydrogen peroxide and iron(II) sulfate mixture in water as an oxidant with permanent presence of oxygen [3]. 

True alkaloids derive from amino acid and they share a heterocyclic ring with nitrogen. These alkaloids are highly reactive substances with biological activity even in low doses. All true alkaloids have a bitter taste and appear as a white solid, with the exception of nicotine which has a brown liquid. True alkaloids form water-soluble salts. Moreover, most of them are well-defined crystalline substances which unite with acids to form salts. True alkaloids may occur in plants (1) in the free state, (2) as salts and (3) as N-oxides. These alkaloids occur in a limited number of species and families, and are those compounds in which decarboxylated amino acids are condensed with a non-nitrogenous structural moiety. The primary precursors of true alkaloids are such amino acids as L-ornithine, L-lysine, L-phenylalanine/L-tyrosine, L-tryptophan and L-histidine . Examples of true alkaloids include such biologically active alkaloids as cocaine, quinine, dopamine, morphine and usambarensine (Figure 4). A fuller list of examples appears in Table 1. 

From L-tyrosine, and alternatively also from L-phenylalanine, kreysigine synthesis begins with dopamine (Figure 36). -autumnaline is derived via a Mannich-like reaction. 5 -autumnaline is converted into floramultine by the oxidative coupling. Subsequently, the kreysigine is synthesized through the... 

From L-tyrosine, or alternatively from L-phenylalanine, there is one further alkaloid biosynthesis pathway. This is the galanthamine pathway (Figure 38). Galanthamine synthesizes with tyramine, norbelladine, lycorine, crinine, N-demethylnarwedine and Al-demethylgalanthamine. Schiff base and reduction reaction, oxidative coupling and enzyme NADPH and SAM activity occur in this pathway. Schiff base is a reaction for the ehmination of water in formation with the C—N bonds process. 

Application of the above procedure to the known N-protected phenol 342, derived from L-tyrosine and veratraldehyde, resulted in smooth oxidative cyclisation to the dienone 343 in 66% yield. Since the latter had been previously converted [90] via (+)-epimaritidine (344) into (+)-maritidine (345) [91] in six steps with an overall yield of 1.26%, the preparation of 343 constituted a formal synthesis of the alkaloid. 

Although in principle naturally occurring (—)-galanthamine could have been prepared by an identical sequence of reactions commencing with D-tyrosine, an alternate route to 319, the enantiomer of 314, was developed. Thus, epimeriza-tion of the methyl ester group at C-6 of the A -trifluoroacetamide derived from 315 followed by oxidation of the allylic alcohol with pyridinium chlorochromate furnished 319 in 78% optical purity, albeit in low chemical yield. Since 319 could be converted to (-)-galanthamine (291) by the same sequence of reactions outlined for the transformation of 314 to (+)-galanthamine, its preparation may be considered to represent a formal total synthesis of 291 from L-tyrosine (163). 

Vanadate stimulates protein kinases in the cytosol, as demonstrated in adipose cells and extracts. The activation of a membrane and cytosolic protein tyrosine kinase have been demonstrated in adipocytes, and the membranous enzyme has been postulated to be a way to involve PI-3K actions without activation of insulin receptor substrate-1 (IRS-1) in the insulin signal transduction pathway [140], It is always difficult to determine if protein kinase activation is direct or the result of stimulation of a protein phosphatase. The fact that kinase stimulation was seen in isolated extracts after cell disintegration in this adipocyte cell system supports the idea that vanadium addition to cells could directly stimulate kinases via an as-yet-undetermined mechanism. In other experiments with 3T3-L1 adipocytes bis(acetylacetonato)oxovana-dium (IV) BMOV and bis(l-N-oxide-pyridine-2thiolato)oxovanadium (TV) caused increased tyrosine phosphorylation of both the insulin receptor and IRS-1 in a synergistic way with insulin, as measured by antibodies to phosphotyrosine residues [141]. 

Benzylic oxidation (11, 441). Oxidation of the N-Boc-L-tyrosine 1 with K2S20 with CuS04 as catalyst gives the syn-cyclic carbamate 2, which can be converted to the (J-hydroxy amino acid 4 as shown. 

Also, HPLC methods with electrochemical or fluorescent detection are used (H19, M3). In proteins, dityrosine can be estimated by immunochemical methods employing dityrosine-specific antibodies (K5). Measurements of o,o -dityrosine and o-tyrosine levels in rat urine express dityrosine contents in skeletal muscle proteins, and have been proposed as the noninvasive oxidative stress test in vivo. One should be aware, however, that A-formylkynurenine, also formed in protein oxidation, has similar fluorescence properties as dityrosine (excitation 325 nm, emission at 400-450 nm) (G29). Also, oxidation of mellitin when excited at 325 nm produces an increase in fluorescence at 400—450 nm, despite the fact that mellitin does not contain tyrosine. Oxidation of noncontaining Trp residues ribonuclease A and bovine pancreatic trypsin inhibitor with "OH produces loss of tyrosine residues with no increase in fluorescence at 410 nm (S51). There are also methods measuring the increased hydrophobicity of oxidized proteins. Assays are carried out measuring protein binding of a fluorescent probe, 8-anilino-l-naphthalene-sulfonic acid (ANS). Increase in probe binding reflects increased surface hydrophobicity (C7). 

The procedure, based on the phosphoramidite method, is illustrated in Scheme 7.11. Nn-Fmoc-L-tyrosine was temporarily protected as its ferf-butyldimethylsilyl ester (see section 6.6). Phosphitylation with dimethyl tyN-diethylphosphorami-dite followed by in situ oxidation with /erf-butyl hydroperoxide gave the phos-phodiester 11 3 The labile silyl ester hydrolysed during the sodium metabisulfite workup used to destroy excess /erf-butyl hydroperoxide to give 11.4 in 57% overall yield, By the same procedure, the dkerf-butyl phosphate 11.5, dibenzyl phosphate 11.6 and diallyl phosphate (not shown) were prepared. 

Ty initiates melanin synthesis by the hydroxylation of L-tyrosine to 3,4-dihydroxyphenylalanine (Dopa) and the oxidation of dopa to dopaquinone. In the presence of L-cysteine, dopaquinone rapidly combines with the thiol group to form cysteinyldopas, which undergo nonen-zymatic conversion and polymerization to pheomelanin via benzothiazine intermediates. In the absence of thiol groups, dopaquinone very rapidly undergoes conversion to dopachrome, which is transformed to 5,6-dihydroxyindole-2-carboxylic acid (DHICA) by dopachrome tautomerase. Alternatively, dopachrome is converted nonenzymatically to 5,6-dihydroxyindole (DHI). Oxidation of DHICA and DHI to the corresponding quinones and subsequent polymerization leads to eumelanins. It is still questionable if Ty is involved in this step. 

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