Transamination tyrosine

With the clear demonstration of the wide scope of transamination in animal tissues,i this cycle seems a highly likely one, and evidence in support of this has been published (Table IX). More recently it has been clearly demonstrated that in the oxidative deamination of tyrosine, transamination is an obligatory intermediate step. Preliminary evidence supports the role of transamination as an intermediate reaction in... 

Much of the early understanding of the position of p-hydroxy-phenyl pyruvate oxidation in phenylalanine metabolism arose from the study of metabolic lesions involving tyrosine and phenylalanine (reviewed by Dalgliesh (182)). The period of present interest commences with the demonstration of tyrosine transamination in the presence of ketoglutarate, forming p-hydroxyphenylpyruvate (429, 465), and discovery of soluble enzyme systems which catalyze subsequent oxidation of this substance. 

Pyridoxamine phosphate serves as a coenzyme of transaminases, e.g., lysyl oxidase (collagen biosynthesis), serine hydroxymethyl transferase (Cl-metabolism), S-aminolevulinate synthase (porphyrin biosynthesis), glycogen phosphoiylase (mobilization of glycogen), aspartate aminotransferase (transamination), alanine aminotransferase (transamination), kynureninase (biosynthesis of niacin), glutamate decarboxylase (biosynthesis of GABA), tyrosine decarboxylase (biosynthesis of tyramine), serine dehydratase ((3-elimination), cystathionine 3-synthase (metabolism of methionine), and cystathionine y-lyase (y-elimination). 

Following transamination, the carbon skeleton of tyrosine is degraded to ftimarate and acetoacetate. Metabohc diseases of tyrosine catabohsm include tyrosinosis, Richner-Hanhart syndrome, neonatal ty-rosinemia, and alkaptonuria. 

Fig. 25.8 (a) Normal metabolism, in which phenylalanine is converted by phenylalanine 4-mono-oxygenase to tyrosine, (b) Phenylketonuria, in which there is a transamination reaction between phenylalanine and a-ketoglutaric acid. Phenylalanine 4-mono-oxygenase is absent in about 1 in every 10000 human beings because of a recessive mutant gene. 

The deamination of primary amines such as phenylethylamine by Escherichia coli (Cooper et al. 1992) and Klebsiella oxytoca (Flacisalihoglu et al. 1997) is carried out by an oxidase. This contains copper and topaquinone (TPQ), which is produced from tyrosine by dioxygenation. TPQ is reduced to an aminoquinol that in the form of a Cu(l) radical reacts with O2 to form H2O2, Cu(ll), and the imine. The mechanism has been elucidated (Wihnot et al. 1999), and involves formation of a Schiff base followed by hydrolysis in reactions that are formally analogous to those involved in pyridoxal-mediated transamination. 

Vitamin Ba (pyridoxine, pyridoxal, pyridoxamine) like nicotinic acid is a pyridine derivative. Its phosphorylated form is the coenzyme in enzymes that decarboxylate amino acids, e.g., tyrosine, arginine, glycine, glutamic acid, and dihydroxyphenylalanine. Vitamin B participates as coenzyme in various transaminations. It also functions in the conversion of tryptophan to nicotinic acid and amide. It is generally concerned with protein metabolism, e.g., the vitamin B8 requirement is increased in rats during increased protein intake. Vitamin B6 is also involved in the formation of unsaturated fatty acids. 

In the branched-chain amino acids (Val, Leu, He) and also tyrosine and ornithine, degradation starts with a transamination. For alanine and aspartate, this is actually the only degradation step. The mechanism of transamination is discussed in detail on p. 178. 

The precursors of true alkaloids and protoalkaloids are aminoacids (both their precursors and postcursors), while transamination reactions precede pseudoalkaloids (Tables 1 and 10). It is not difficult to see that from all aminoacids only a small part is known as alkaloid precursors (Table 19). Both true and proto alkaloids are synthesized mainly from the aromatic amino acids, phenylalanine, tyrosine (isoquinoline alkaloids) and tryptophan (indole alkaloids). Lysine is the... 

In plants and bacteria, phenylalanine and tyrosine are synthesized from chorismate in pathways much less complex than the tryptophan pathway. The common intermediate is prephenate (Fig. 22-19). The final step in both cases is transamination with glutamate. 

In E. coli and many other bacteria a second bifunctional enzyme, chorismate mutase-prephenate dehydrogenase causes the isomerization of chorismate and the oxidative decarboxylation of prephenate to p-hydroxyphenylpyruvate (steps h and /c, Fig. 25-l).39 The latter can be converted by transamination to tyrosine.40-42... 

Figure 25-5 shows the principal catabolic pathways, as well as a few biosynthetic reactions, of phenylalanine and tyrosine in animals. Transamination to phenylpyruvate (reaction a) occurs readily, and the product may be oxidatively decarboxylated to phen-ylacetate. The latter may be excreted after conjugation with glycine (as in Knoop s experiments in which phenylacetate was excreted by dogs after conjugation with glycine, Box 10-A). Although it does exist, this degradative pathway for phenylalanine must be of limited importance in humans, for an excess of phenylalanine is toxic unless it can be oxidized to tyrosine (reaction b, Fig. 25-5). Formation of phenylpyruvate may have some function in animals. The enzyme phenylpyruvate tautomerase, which catalyzes interconversion of enol and oxo isomers of its substrate, is also an important immunoregulatory cytokine known as macrophage migration inhibitory factor.863...

The major route of degradation of tyrosine in animals begins with transamination (Fig. 25-5, reaction c) to p-hydroxyphenylpyruvate. The enzyme tyrosine aminotransferase94 is induced in the liver in response to the action of glucorticoid hormones (Chapter 22). The synthesis of the enzyme is also controlled at the translational level, release of the newly formed protein from liver ribosomes being stimulated by cyclic AMP. The enzyme is subject to posttranscriptional... 

Previously, AAT had been transformed into an L-tyrosine aminotransferase (TAT) by site-specific mutation of up to six amino acid residues lining the active site of wild-type AAT. The hextuple AAT-mutant achieved kinetic data towards the transamination of aromatic substrates such as i-phenylalanine within an order of magnitude of wild-type TAT (Onuffer, 1995). 

Phenylalanine is first converted to tyrosine by the monooxygenase phenylalanine hydroxylase a reaction involving the coenzyme tetrahydrobiopterin. The tyrosine is then converted first by transamination and then by a dioxygenase reaction to homogentisate, which in turn is further metabolized to fumarate and acetoacetate. 

One of the earliest published attempts to create antibodies with catalytic activity had as its goal the generation of a transaminase. Raso and Stollar prepared V-(5-phosphopyridoxyl)-3 -amino-L-tyrosine 154 as a mimic of the Schiff s base intermediate that is formed during the pyridoxal-dependent transamination of tyrosine and showed that it was a site-directed inhibitor of the enzymes tyrosine transaminase and tyrosine decarboxylase.132 Partially purified polyclonal antibodies, elicited against y-globulin conjugates of the hapten, recognized both the... 

An inability to degrade amino acids causes many genetic diseases in humans. These diseases include phenylketonuria (PKU), which results from an inability to convert phenylalanine to tyrosine. The phenylalanine is instead transaminated to phenylpyruvic acid, which is excreted in the urine, although not fast enough to prevent harm. PKU was formerly a major cause of severe mental retardation. Now, however, public health laboratories screen the urine of every newborn child in the United States for the presence of phenylpyru-vate, and place children with the genetic disease on a synthetic low-phenylalanine diet to prevent neurological damage. 

They lack the enzyme phenylalanine oxidase, which converts phenylalanine to tyrosine. Thus phenylalanine accumulates in the body and it is degraded to phenylpyruvate by transamination ... 

Four of the amino acids, alanine, aspartate, glutamate, and serine, are formed by the transamination of their corresponding oxoacids. The other nonessential amino acids are then derived from these four amino acids. The syntheses of serine and tyrosine are described below because of either their importance in aspects of metabolism or their clinical significance the synthesis of serine is essential for folic acid metabolism, while deficiencies in the enzymes synthesizing tyrosine can lead to phenylketonuria. 

We have arrived at prephenic acid, which as its name suggests is the last compound before aromatic compounds are formed, and we may call this the end of the shikimic acid pathway. The final stages of the formation of phenylalanine and tyrosine start with aromatization. Prephenic acid is unstable and loses water and CO2 to form phenylpyruvic acid. This a-keto-acid can be converted into the amino acid by the usual transamination with pyridoxal. 

We end this section on enzyme inhibition with a case study about 4-hydroxyphenyl-pyruvate dioxygenase (HPPD) and disorders in tyrosine catabolism. After transamination of tyrosine, 4-hydroxyphenylpyruvate (148) is formed which is then decarboxylated, isomerized and oxygenated by HPPD to yield homogentisate (149) or by hydroxyman-delate synthase (HMS) to yield p-hydroxymandelate (150). 149 serves as the precursor for plastoquinones and tocopherols in plants . Thus, inhibitors of HPPD have been designed... 

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