Amino acids phenylalanine metabolism

Ring B and the central three-carbon bridge forming the C ring (see Fig. 5.1) originate from the amino acid phenylalanine, itself a product of the shikimate pathway, a plastid-based process which generates aromatic amino acids from simple carbohydrate building blocks. Phenylalanine, and to a lesser extent tyrosine, are then fed into flavonoid biosynthesis via phenylpropanoid (C6-C3) metabolism (see Fig. 5.1). 

Figure 9-3. Fates of the carbon skeletons upon metabolism of the amino acids. Points of entry at various steps of the tricarboxylic acid (TCA) cycle, glycolysis and gluconeogenesis are shown for the carbons skeletons of the amino acids. Note the multiple fates of the glucogenic amino acids glycine (Gly), serine (Ser), and threonine (Thr) as well as the combined glucogenic and ketogenic amino acids phenylalanine (Phe), tryptophan (Trp), and tyrosine (Tyr). Ala, alanine Cys, cysteine lie, isoleucine Leu, leucine Lys, lysine Asn, asparagine Asp, aspartate Arg, arginine His, histidine Glu, glutamate Gin, glutamine Pro, proline Val, valine Met, methionine.

Tyramine is a natural metabolite of the amino acids phenylalanine and tyrosine. Its structure is very similar to that of epinephrine and norepinephrine which stimulate the nervous system resulting in increased heart rate and blood pressure. All three of these molecules are metabolized by... 

Free amino acids are further catabolized into several volatile flavor compounds. However, the pathways involved are not fully known. A detailed summary of the various studies on the role of the catabolism of amino acids in cheese flavor development was published by Curtin and McSweeney (2004). Two major pathways have been suggested (1) aminotransferase or lyase activity and (2) deamination or decarboxylation. Aminotransferase activity results in the formation of a-ketoacids and glutamic acid. The a-ketoacids are further degraded to flavor compounds such as hydroxy acids, aldehydes, and carboxylic acids. a-Ketoacids from methionine, branched-chain amino acids (leucine, isoleucine, and valine), or aromatic amino acids (phenylalanine, tyrosine, and tryptophan) serve as the precursors to volatile flavor compounds (Yvon and Rijnen, 2001). Volatile sulfur compounds are primarily formed from methionine. Methanethiol, which at low concentrations, contributes to the characteristic flavor of Cheddar cheese, is formed from the catabolism of methionine (Curtin and McSweeney, 2004 Weimer et al., 1999). Furthermore, bacterial lyases also metabolize methionine to a-ketobutyrate, methanethiol, and ammonia (Tanaka et al., 1985). On catabolism by aminotransferase, aromatic amino acids yield volatile flavor compounds such as benzalde-hyde, phenylacetate, phenylethanol, phenyllactate, etc. Deamination reactions also result in a-ketoacids and ammonia, which add to the flavor of... 

Because enzymes are required in all metabolic pathway reactions, a missing or damaged enzyme may result in a metabolic disorder, meaning that the pathway can no longer produce what it should because there is an interruption in the series of required reactions. When this happens, cells may have too much of some substances or too little of others. For example, a disorder called phenylketonuria is caused by the lack of an enzyme called phenylalanine hydroxylase. The enzyme converts the amino acid phenylalanine to another amino acid, tyrosine. When the enzyme is missing, phenylalanine... 

A variety of benzene-derivatives are found in many grape varieties, including vinyl phenols, benzyl alcohol, 2-phenyl ethanol and raspberry ketone. Vinyl phenols are characterised by spice and dove-like, 2-phenyl ethanol by rose and lilac, and raspberry ketone by a raspberry attribute (Francis and Newton 2005). It should be noted that, although a portion of 2-phenyl ethanol can derive from glycoside hydrolysis, a greater proportion of this compound is formed in the metabolism of the amino acid phenylalanine (Ugliano et al. 2006). 

Draw the products formed by acidic hydrolysis of aspartame, the artificial sweetener used in Equal and many diet beverages. One of the products of this hydrolysis reaction is the amino acid phenylalanine. Infants afflicted with phenylketonuria cannot metabolize this amino acid, so it accumulates, causing mental retardation. When the affliction is identified early, a diet limiting the consumption of phenylalanine (and compounds like aspartame that are converted to it) can make a normal life possible. 

The metabolism of aromatic amino acids (phenylalanine and tyrosine) can be studied following the excretion of their characteristic phenolic acid metabolites in urine using chromatographic methods. These apply acids to the investigations of amino acids themselves in diagnostics. 

Because transamination reactions are reversible, it is theoretically possible for all amino acids to be synthesized by transamination. However, experimental evidence indicates that there is no net synthesis of an amino acid if its a-keto acid precursor is not independently synthesized by the organism. For example, alanine, aspartate, and glutamate are nonessential for animals because their a-keto acid precursors (i.e., pyruvate, oxaloacetate, and a-ketoglutarate) are readily available metabolic intermediates. Because the reaction pathways for synthesizing molecules such as phenylpyruvate, a-keto-/Thydroxybutyrate, and imidazolepyruvate do not occur in animal cells, phenylalanine, threonine, and histidine must be provided in the diet. (Reaction pathways that synthesize amino acids from metabolic intermediates, not only by transamination, are referred to as de novo pathways.)... 

The amino acids differ from other classes of biomolecules in that each member of this class is synthesized by a unique pathway. Despite the tremendous diversity of amino acid synthetic pathways, they have one common feature. The carbon skeleton of each amino acid is derived from commonly available metabolic intermediates. Thus in animals, all NAA molecules are derivatives of either glyc-erate-3-phosphate, pyruvate, a-ketoglutarate, or oxaloacetate. Tyrosine, synthesized from the essential amino acid phenylalanine, is an exception to this rule. 

In general, there are protein kinases and, in particular, there are tyrosine kinases tyrosine is a nonessential amino acid present in most proteins and is synthesized metabolically from the essential amino acid phenylalanine. It is also said to be a precursor of thyroid hormones, melanin, and catecholamines. Not only is there more than one tyrosine kinase, but mutations can also occur. 

Two closely related aromatic amino acids are phenylalanine and tyrosine. The metabolism of these two amino acids is of medical interest for two reasons. First, a large number of metabolic diseases is associated with the metabolism of these two amino acids second, a large number of important biological compounds other than protein are formed from these amino acids. Phenylalanine can be converted to tyrosine in a unidirectional, physiologically irreversible reaction. Phenylalanine is an essential amino acid that must be preformed in the diet, whereas tyrosine is not considered an essential amino acid because it can be formed from L-phenylalanine. However, the relationship is analogous to that previously indicated for cysteine and methionine the amount of phenylalanine required in the diet depends on the tyrosine content of the diet, that is, the lower the tyrosine content, the more phenylalanine required. This is referred to as a sparing effect that tyrosine has on the phenylalanine requirement. 

The incidence ol phcnylkeionuiiu is around one in every ten thousand births in the UK. Phenylketonuria arises from impaired conversion of phenylalanine to tyrosine, usually because of a deficiency of phenylalanine hydroxylase. Figure 5 shows how phenylalanine, an essential amino acid, is metabolized. In phenylketonuria. phenylalanine cannot be converted to tyrosine, accumulates in blood and is excreted in the urine. The main urinary metabolite is phenylpyruvic acid (a phenylketone ) which gives the disease its name. The clinical features include ... 

Chorismic acid is a metabolic intermediate that is the branch point in the synthesis of coenzyme Q and the aromatic amino acids, phenylalanine, tyrosine, and tryptophan (Figure 21.12). 

PHENYLKETONURIA A genetic disorder in which a person s body is unable to metabolize the amino acid phenylalanine. 

The presence of excessive THs in the thyrotoxic state induces significant changes in the neuromuscular system. THs cause a predominantly catabolic state, resulting in increased muscle breakdown, wasting and weakness due to an accelerated metabolic rate. There is often an increase in efflux of branched-chain amino acids, phenylalanine and tyrosine from muscle bed, with a net muscle loss. THs also cause an increase in the activity of uncoupled ATPase and sarcoplasmic reticulum vesicles. This increase is much more in the red muscle types than in white ones, which is... 

Plant secondary metabolites are biosynthesized from rather simple building blocks supplied by primary metabolism. Two important metabolic routes in this are the shikimate pathway and the isoprenoid biosynthesis. The shikimate pathway leads to the synthesis of phenolic compounds and the aromatic amino acids phenylalanine, tyrosine and tryptophan. The isoprenoid biosjmthesis is a heavily branched pathway leading to a broad spectrum of compounds (fig. 1). From plants and microorganisms more than 37,000 isoprenoid compounds have been isolated so far [1]. 

Most aromatic compounds in plants are derived from shikimic acid metabolism many of these substances are phenols. Compounds derived from this pathway are extensively modified and considered under other classes of plant secondary metabolites. Although many types of secondary compounds are produced from intermediates of the shikimic acid pathway (e.g., certain naphthoquinones and anthraquinones discussed in Chapter 6), most are derived from four aromatic amino acids phenylalanine, tyrosine, anthranilic acid, and tryptophan. Aromatic compounds that arise from the shikimic acid pathway usually can be distinguished from those of other origins by their substitution patterns and by a knowledge of the compounds with which they co-occur. 

The amino acid phenylalanine is derived from gallic acid, being this compound biosynthesized in the shikimic acid metabolic route. Most of the phenolic compounds from higher plants are also derived from this amino acid, formed in the phenylpropanoid metabolic route, in the cell cytoplasm, being various enzymes involved in this metabolism. Phenylalanine ammonia lyase interacts with phenylalanine forming cinnamic acid, that is, hydrolyzed by citmamate-4-hydroxylase, rendering p-coumaric acid. Different hydroxylations and/or methoxylations, of this... 

It appears that nature rarely uses concerted, pericyclic reactions in biosynthesis or metabolism. However, in at least one instance a Claisen rearrangement is key to a biosynthetic pathway. It i.s, in fact, a crucial pathway, the one that biosynthesizes the amino acids phenylalanine (Phe) and tyrosine (Tyr). The pathway only exists in plants— our bodies cannot synthesize Phe and Tyr, making Phe and Tyr so-called essential amino acids. 

We will use the catabolism of phenylalanine as an example of how an amino acid is metabolized (Figure 25.4). Phenylalanine is one of the essential amino acids, so it must be included in our diet (Section 22.1). The enzyme phenylalanine hydroxylase converts phenylalanine to tyrosine. Thus, tyrosine is not an essential amino acid, unless the diet lacks phenylalanine. 

Inborn errors of metabolism are inherited physiologicai defects which interfere with the normal utilization of nutrients by the body. For example, phenylketonuria (PKU) may cause mental retardation due to the accumulation of phe-nylpyruvic acid, which is derived from the incomplete metabolism of the amino acid phenylalanine. Sometimes, permanent damage from these disorders may be prevented by restricting the dietary content of the nutrients which give rise to the harmful products of metabolism. In other cases. It may be necessary to provide extra amounts of certain nutrients to people who have a genetic defect which leads to poor utilization of these nutrients. 

This term is the registered trademark of the commercially prepared protein formula sold by Mead Johnson Company of Evansville, Indiana. Ninety-five percent of the amino acid phenylalanine is removed from Lofenalac. It provides the basis for dietary management of phenylketonuria (PKU), an inborn error of metabolism. Most proteins contain 4 to 6% phenylalanine and would be detrimental to an infant with PKU. Lofenalac is used to meet the infant s protein and energy needs while the requirement for phenylalanine, an essential amino acid, is just satisfied—no excess—with foods whose phenylalanine content is known. 

One of the metabolic reactions in the biosynthesis of the amino acid phenylalanine occurs by a [3,3] sigmatropic shift in a reaction called a Claisen rearrangement. In this reaction, chorismate, a vinyl ether, rearranges to prephenate. 

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