Phenylalanine metabolic pathway

Some people lack the enzymes necessary to convert L-phenylalanine to L-tyrosine. Any L-phenylalanine that they obtain from their diet is diverted along a different metabolic pathway, giving phenylpyruvic acid ... 

Another way to enhance the production of an amino acid is to make use of DNA-recombinant technology, often in combination with foe mutations already described. In this way foe negative features of foe micro-organisms are avoided. To help explain this, we will consider a well known fermentation of L-phenylalanine using Escherichia coli. We have already seen foe metabolic pathway leading to foe production of L-phenylalanine in Figure 8.4. 

The amino acid L-tryptophan is the precursor for the synthesis of 5-HT. The synthesis and primary metabolic pathways of 5-HT are shown in Figure 13-5. The initial step in the synthesis of serotonin is the facilitated transport of the amino acid L-tryptophan from blood into brain. The primary source of tryptophan is dietary protein. Other neutral amino acids, such as phenylalanine, leucine and methionine, are transported by the same carrier into the brain. Therefore, the entry of tryptophan into brain is not only related to its concentration in blood but is also a function of its concentration in relation to the concentrations of other neutral amino acids. Consequently, lowering the dietary intake of tryptophan while raising the intake of the amino acids with which it competes for transport into brain lowers the content of 5-HT in brain and changes certain behaviors associated with 5-HT function. This strategy for lowering the brain content of 5-HT has been used clinically to evaluate the importance of brain 5-HT in the mechanism of action of psychotherapeutic drugs. 

Rarely, phenylketonuria results from a defect in the metabolism of biopterin, a cofactor for the phenylalanine hydroxylase pathway 673... 

Rarely, phenylketonuria results from a defect in the metabolism of biopterin, a cofactor for the phenylalanine hydroxylase pathway. The electron donor for phenylalanine hydroxylase is tetrahydrobiopterin (BH4), which transfers electrons to molecular oxygen to form tyrosine and dihydrobiopterin (QH2 Fig. 40-2 reaction 2). BH4 is regenerated from QH2 in an NADH-dependent reaction that is catalyzed by dihydropteridine reductase (DHPR), which is widely distributed. In the brain, this... 

Backman K, O Connor MJ, Maruya A, Rudd E, McKay D, Balakrishnan R, Radjai M, DiPasquantonio V, Shoda D, Hatch R, Venkatsubramanian K. (1990) Genetic engineering of metabolic pathways applied to the production of phenylalanine. Ann NY Acad Sci 589 16-24. 

The true biochemical significance of this deamination, and the function of the secondary metabolic pathway originating from L-phenylalanine (6-... 

In individuals with PKU, a secondary, normally little-used pathway of phenylalanine metabolism comes into play. In this pathway phenylalanine undergoes transamination with pyruvate to yield phenylpyruvate (Fig. 18-25). Phenylalanine and phenylpyruvate accumulate in the blood and tissues and are excreted in the urine—hence the name phenylketonuria. Much of the phenylpyruvate, rather than being excreted as such, is either decarboxylated to phenylacetate or reduced to phenyllactate. Phenylacetate imparts a characteristic odor to the urine, which nurses have traditionally used to detect PKU in infants. The accumulation of phenylalanine or its metabolites in early life impairs normal development of the brain, causing severe mental retardation. This may be caused by excess phenylalanine competing with other amino acids for transport across the blood-brain barrier, resulting in a deficit of required metabolites. 

Pathways of phenylalanine metabolism in normal individuals and in patients with phenylketonuria... 

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]. 

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... 

Inborn errors of metabolism are inherited metabolic disorders caused by the absence of an enzyme in a metabolic pathway. Alkaptonuria is caused by the lack of homogentisate oxidase and is harmless, whereas phenylketonuria, which is due to a lack of phenylalanine hydroxylase, can cause severe mental retardation. 

The metabolic pathways of phenylalanine and tyrosine are identical, because the essential phenylalanine must be converted to tyrosine to become metabolized. Figure 20.22 illustrates this pathway, which is termed the liver pathway to distinguish it from those leading to catecholamine biosynthesis. It is localized in the cytosol, with the exception of tyrosine transaminase, which is also present in the mitochondria. 

Figure 19-1. Pathways for the metabolic disposal of phenylalanine. There are two competitive pathways for the disposal of phenylalanine. One pathway involves a transaminase enzyme phenylpyruvate, while the first step in the second pathway requires phenylalanine to be initially converted to tyrosine. Continued metabolism of the phenylpyruvate produced by the first pathway leads to products that cannot be further metabolized, while tyrosine can be converted into citric acid cycle intermediates. Glu, glutamate aKG CoASH, coenzyme A BH4, tetrahydrobiopterin TPP, thiamine pyrophosphate.

Fig. 2 Metabolic pathways in C. glutamicum for biosynthesis of the aromatic amino acids tryptophan, tyrosine, and phenylalanine (a) and amino acids belonging to the aspartate family including lysine, methionine, threonine, and isoleucine (b). Metabolic regulation by feedback inhibition is indicated by dotted lines...

It is now well established that the primary metabolic target of glyphosate is an enzyme of the shikimic acid metabolic pathway, enolpyruvyl shikimate-3-phosphate synthase (2.f ). Via this action, glyphosate blocks the synthesis of the end products of this pathway, notably phenylalanine and tryptophan, but also various subsequent products (Figure 1) ( ,i). It has seemed logical to conclude that the herbicidal effect of glyphosate is a direct result of its effect on the shikimic acid pathway. 

Fig. 12. Metabolic pathways leading to the biosynthesis of phenylalanine, anthranilic acid, and cyclopenin in Penicillium cyclopium (67). Symbols in parenthesis indicate observed feedback inhibition (-) or activation (-I-) of enzyme activities by L-amino acids. Number in circles (pkat/cm of mycelial area) represent either in vitro activities of the enzymes indicated or the rate of alkaloid formation in vivo. All data were measured after 7 days of growth in surface cultures. E 4-P, Erythrose 4-phosphate PEP, phosphoenolpyruvate DAHP, 3-deoxo-D-arabiuoheptuIosonic acid-7-phosphate InGP, inositol glycerophosphate SAM, 5-adeno ylmethionine.

The low incorporation of phenylalanine precludes its involvement as an intermediate in the normal biosynthetic pathway to tyrosine and indicates that tyrosine and phenylalanine have different metabolic pathways in H. canadensis. 

Aspartame is hydrolyzed entirely in the gastrointestinal tract to its constituent amino acids, aspartate and phenylalanine, and methanol. These are absorbed by the body and utilized via the same metabolic pathways as when these same constituents are derived from common foods they are found in common foods in much larger quantities than from aspartame in foods or beverages. 

Phenylketonuria (PKU) is an inborn error of metabolism by which the body is unable to convert surplus phenylalanine (PA) to tyrosine for use in the biosynthesis of, for example, thyroxine, adrenaline and noradrenaline. This results from a deficiency in the liver enzyme phenylalanine 4-mono-oxygenase (phenylalanine hydroxylase). A secondary metabolic pathway comes into play in which there is a transamination reaction between PA and a-keto-glutaric acid to produce phenylpyruvic acid (PPVA), a ketone and glutamic acid. Overall, PKU may be defined as a genetic defect in PA metabolism such that there are elevated levels of both PA and PPVA in blood and excessive excretion of PPVA (Fig. 25.7). 

---