Phenylalanine monooxygenase

A second competitive pathway for the disposal of PA requires the initial conversion of PA into tyrosine. This reaction is catalyzed by the enzyme PAH (phenylalanine-4-monooxygenase EC 1.14.16.1). The resulting tyrosine molecule can then be catabolized into fumarate and ace-toacetate. Both products are nontoxic and can be further catabolized in the citric acid cycle. In Mrs. Urick and the majority of individuals suffering from HPA and PKU, there is a defect in the PAH enzyme system (NIH Consensus State-... 

Phenylalanine. Phenylalanine is converted to tyrosine by phenylalanine-4-monooxygenase in a reaction illustrated in Figure 15.6. Tyrosine is degraded to... 

The reaction catalyzed by phenylalanine-4-monooxygenase is irreversible. The electrons required for the hydroxylation of phenylalanine are carried to O, from NADPH by tetrahydrobiopterin. 

As a specific example, let us consider the human disease phenylketonuria, which is caused by the lack of an essential enzyme, phenylalanine 4-monooxygenase. I shall return to this in the next chapter, and for the moment it is sufficient to say that people who lack the enzyme completely have the disease, but people who have only half of the normal amount of enzyme have no related health problems at aU half the normal amount of enzyme appears to be just as good as the full amount. How can this be If they have half the normal amount of enzyme (as they do, in this and other similar cases), then the reaction the enzyme catalyzes should proceed half as fast, and ought this not have at least some effect If not, does this not mean that normal individuals have at least twice as much of the enzyme as they need, and that the human species could evolve to become more efficient by decreasing the amount they make, thereby releasing precious resources for other purposes ... 

CjHiiNsOj, Mr 237.22. The (l J ,2 S) form (L-erythro form) form ale yellow cryst., mp. 250-280 C (decomp.), [a]o-66 (0.1 m HCI), pK, 2.23, pK 2 7.89. In alkaline solution B. shows blue fluorescence. It is widely distributed in microorganisms, insects (e.g. in royaI jelly of queen bees), algae, amphibians, and mammals and is also found in urine. In metabolism tet-rahydro-B. acts as a cofactor for phenylalanine 4-monooxygenase (EC 1.14.16.1). B. is a growth factor for insects. The (l /, 2 /f) form (D-threo form) known as dictyopterin melts at >300 C and has pK , 2.20, pKa2 7.92. It occurs in the slime mold Dictyostelium discoideum. The biosynthesis starts from guanosine triphosphate. 

The activity of phenylalanine-4-monooxygenase (EC 1.14 16.1) has been monitored in vivo in man by monitoring the conversion of phenylalanine-ds to tyrosine-d4 (Zaylak et al., 1977)... 

More complicated are enzymes which dehydrogenate the cosubstrate by a separate protein which itself interacts with the oxygenating enzyme. An example of this type is phenylalanine 4-monooxygenase (Fig. 17, see also D 22). 

Fig. 17. Monooxygenase with simple electron transport chain (phenylalanine 4-monooxygenase, D 22)...

Chorismate mutase 2 prephenate aminotransferase 3 prephenate dehydratase 4 prephenate dehydrogenase 5 arogenate dehydrogenase 6 phenylalanine aminotransferase 7 tyrosine aminotransferase 8 tyrosine 3-monooxygenase 9 phenylalanine 4-monooxygenase (C 2.6.5)... 

With the failure to demonstrate that norbelladine or its relatives plays a role in the biosynthesis of the mesembrine alkaloids, a reevaluation led to a modified approach in which attempts to identify the sequence of occurrence of the post-tyrosine and post-phenylalanine intermediates were made. There is now a substantial body of information available to suggest that phenylalanine and tyrosine have separate metabolic roles in plants belonging to the order Dictolyoden. Not only do they lack the enzyme phenylalanine hydroxylase (phenylalanine 4-monooxygenase) which is necessary for the conversion of phenylalanine to tyrosine, but the metabolic pathways of these two amino acids are generally quite different in secondary metabolism (70). Phenylalanine is involved in initial conversion to cinnamic acid and subsequent transformation to structural units of the so-called phenyl-propanoid pathway, which include Ar—C3, Ar—C2, and Ar—Cj structural entities. On the other hand, the role of tyrosine in the biosynthesis of secondary metabolities is most frequently seen as the precursor of Ar—Cj—N and Cg—C2—N units, and somewhat less frequently, as Ar—C2 and Q—C2 units. 

The biosynthesis of tyrosine (174) in some mammals involves an oxidation that is formally an aromatic substitution of phenylalanine (172). Phenylalanine is obtained from food in a normal diet in the presence of tetrahydrobiopterin (173), oxygen, and the enzyme phenylalanine-4-monooxygenase, tyrosine is formed along with dihydrobiopterin (175). In the body, dihydrobiopterin is converted by NADPH (176) back to 173 and NADP+ (177). Note that the conversion of 176 to 177 is for all practical purposes a Birch reduction (see Section 21.6.1). 

These oxidation reactions require oxygen (O2) and tetrahydrobiopterin as a cofactor. Thus, as shown in Scheme 13.39, 7,8-dihydroneopterin 3 -triphosphate (generated from guanosine triphosphate [GTP] as seen in Scheme 12.118) is converted to 6-pyruvoyl-5,6,7,8-tetrahydropterin by an elimination reaction and two keto-enol isomerizations. The process is catalyzed by the enzyme 6-pyruvoyltetra-hydropterin synthase (EC 4.2.3.12). Then, via an intermediate, written as an equilibrium between a-hydroxyketones (named dihydrosepiapterin) linked by a common enol, reduction to tetrahydrobiopterin is effected (in two separate steps) by 2 equivalents of NADPH used by the enzyme sepiapterin reductase (EC 1.1.1.153). Tetrahydrobiopterin is the cofactor involved in the National Institutes of Health (NIH) shift (cf. Chapter 6) pathway used by the iron-containing enzyme phenylalanine 4-monooxygenase (EC 1.14.16.1) to convert phenylalanine (Phe, F) to tyrosine (Tyr, Y) and is converted to (6i )-6-(L-erythro-l,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4a-hydroxypterin in the process. 

Scheme 1339. A representation of the conversion of phenylalanine (Phe, F) to tyrosine (Tyr, Y) using tetrahydrobiopterin as the cofactor (involved in the NIH shift [cf. Chapter 6] pathway) used by the iron-containing enzyme phenylalanine 4-monooxygenase (EC 1.14.16.1). EC numbers and some graphic materials provided in this scheme have been taken from appropriate links in a URL starting with http //www.chem.qmnl.ac.uk/iubmb/enzyme/.

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