Phenylalanine degradative pathway

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...

Scheme 2 Degradation pathways for aspartame APM = aspartame P-APM = P-aspartame PM = phenylalanine methyl ester DKP = 3-benzyl-6-carboxymethyl-2,5-diketopiperazine a-AP = a-L-aspartyl-Z,-phenylalanine PA = L-phenylalanyl-I-aspartic acid)...

In addition to the degradation pathways shown in Scheme 2, very slow epimerization of all species is also feasible [24], The end products of degradation are aspartate, phenylalanine, and methanol. 

The presence of another contaminant peak in L-tryptophan implicated in EMS was detected upon HPLC with both UV and FL analyses by Toyo oka et al.9 and was characterized as PAA by Goda et al.7 Adachi et al.15 studied the metabolism of PAA in rats and described four metabolites of PAA in the urine (N-(hydroxyphenyl)glycine, N-phenylglycine, 3-(phenylamino)lactic acid, and 3-(hydroxy-phenylamino)-lactic acid). The results suggested that the degradation pathway of PAA was similar to that of phenylalanine. Other studies with PAA are described in Section 11.10. 

Histidine ammonia-lyase is the first enzyme in the degradation pathway of L-histidine and catalyzes the nonoxidative deamination of histidine (12) to form w r-urocanic acid (13) plus ammonia (Equation (3)). Histidine ammonia-lyase is present in several bacteria and in animals. The mechanism for the reaction that is catalyzed by histidine ammonia-lyase is presumed to be similar to that described above for phenylalanine ammonia-lyase (see Scheme 3). 

Racemization has also been observed with many peptides and proteins. Casein exhibits racemization at aspartic acid, phenylalanine, glutamic acid, and alanine residues.799 Racemization of serine and histidine residues has been reported for histrelin (a nonapeptide)800 and a decapeptide,801 agonists of luteinizing hormone-releasing hormone (LH-RH). As shown in Fig. 200, the main degradation pathway of decapeptide (an antagonist of LH-RH) above PH 7 was epimerization.802... 

The amino acids L-phenylalanine and L-tyrosine are broken down via aromatic degradation pathways that are found in mammals and bacteria, to form organic acids that can be utilized for growth. These pathways are the only aromatic degradation pathways found in mammals, and are of some medical significance, since there are several inherited metabolic diseases (phenylketonuria, alkaptonuria, tyrosinemia) that are caused by mutations in enzymes in these pathways. 

Another genetic disease that results from a deficiency of an enzyme in the pathway for phenylalanine degradation is al-captonuria, which is caused by lack of homogentisate dioxygenase. The only ill effect of this enzyme deficiency is black urine. The urine of those afflicted with alcaptonuria turns black because the homogentisate they excrete immediately oxidizes in the air. 

Taking into account the pathway for phenylalanine degradation, answer the following... 

Two of the nonessential amino acids, tyrosine and cysteine, are derived from essential amino acids and may be considered to be breakdown products of them, as they are intermediates in the normal degradation pathway of these amino acids. Provided sufficient quantities of the two essential amino acids, phenylalanine and methionine, are available in the diet, then net synthesis of tyrosine and cysteine occur. 

These two amino acids must be considered as a unit since the degradative pathway for phenylalanine which has been completely defined in mammals... 

There is still little known of the degradative pathways, if they exist at all, of the amino acids histidine and phenylalanine. 

In addition to this main degradation pathway of phenylalanine via tyrosine, there is an alternative reversiblepathway via phenylpyruvic acid, of which only the intermediates are known. In normal as well as in phenylketonuric individuals, phenylalanine and phenylpyruvic and phenyllactic acids are interconvertible. 

Much of the earlier knowledge of the metabolic pathways of phenylalanine and tyrosine was obtained by the study of the defects in the hereditary diseases, alcaptonuria, albinism, phenylpyruvic oligophrenia, and tyrosinosis. Widespread interest in this subject dates from the publication of Garrod s Inborn Errors of Metabolism (2). The metabolic Uoeka at particular steps in the degradative pathways of phenylalanine and tyrosine for the disorders mentioned above are shown in Fig. 15. 

Arias-Barrau E, ER Olivera, JM Lnengo, C Eemandez, B Galan, JL Garcia, E Dfaz, B Minambres (2004) The homogentisate pathway a central catabolic pathway involved in the degradation of L-phenylalanine, L-tyrosine, and 3-hydroxyphenylacetate in Pseudomonas putida J Bacterial 186 5062-5077. 

Notably, nitrile-degrading enzymes (e.g. nitrilase that converts the CN group to carboxylic acid, and nitrile hydratase that produces an amide function) have been described, and they co-exist with aldoxime-degrading enzymes in bacteria (Reference 111 and references cited therein). Smdies in this area led to the proposal that the aldoxime-nitrile pathway, which is implemented in synthesis of drugs and fine chemicals, occurs as a natural enzymic pathway. It is of interest that the enzyme responsible for bacterial conversion of Af-hydroxy-L-phenylalanine to phenacetylaldoxime, an oxidative decarboxylation reaction, lacks heme or flavin groups which are found in plant or human enzymes that catalyze the same reaction. Its dependency on pyridoxal phosphate raised the possibility that similar systems may also be present in plants . 

Dopamine, norepinephrine and epinephrine are products of the metabolism of dietary phenylalanine. This is an interesting sequence of reactions in that we will be discussing not only the three neurotransmitters formed but also considering the DOPA precursor and its use in the treatment of Parkinson s Disease. These molecules are also called catecholamines. Catechol is an ortho dihydroxyphenyl derivative. Degradation of the final product in the pathway, epinephrine, can be accomplished by oxidation (monoamine oxidase - MAO)or methylation (catecholamine 0-methyl transferase - COMT). The diagram on the next page illustrates the scheme of successive oxidations which produce the various catecholamines. 

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... 

VII were identified in plasma and urine [85,99], and it is difficult to distinguish between metabolic changes and chemical degradation. Up to ten C-labelled products of metabolism or hydrolysis of melphalan were detected without identification in the serum, urine, and bile of experimental animals. Metabolic pathways similar to that of phenylalanine were suggested [3]. 

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