Pterins monooxygenase

Fig. 12. Hypothetical high-valent hydroxylating species for different monooxygenases. For the pterin monooxygenases, the N represents histidine residues coordinated to the catalyrtically active Fe in tyrosine, phenylalanine, and tryptophan hydroxylases (.140, 141). The two squares for cyttochrome F450 represent the porphyrin ring, and the + represents a rr-radical delocalized over this ring.

The least understood aspect of NO synthases is the requirement for tetrahydrobiopterin, BH4, the same coenzyme required by the other pterin-dependent monooxygenases (Eq. 18-44). The presence of this coenzyme in the reduced BH4 form is essential for step a of Eq. 18-65 but not for step b. This suggests that in step a an organic peroxide might be generated by BH4 and used to form an oxo-iron hydroxylating reagent. 

One of the best characterized physiological functions of (6R)-tetrahydrobio-pterin (BH4, 43) is the action as a cofactor for aromatic amino acid hydroxylases (Scheme 28). There are three types of aromatic amino acid hydroxylases phenylalanine hydroxylase [PAH phenylalanine monooxygenase (EC 1.14.16.1)], tyrosine hydroxylase [TH tyrosine monooxygenase (EC 1.14.16.2)] and tryptophan hydroxylase [TPH tryptophan monooxygenase (EC 1.14.16.4)]. PAH converts L-phenylalanine (125) to L-tyrosine (126), a reaction important for the catabolism of excess phenylalanine taken from the diet. TH and TPH catalyze the first step in the biosyntheses of catecholamines and serotonin, respectively. Catecholamines, i.e., dopamine, noradrenaline and adrenaline, and serotonin, are important neurotransmitters and hormones. TH hydroxylates L-tyrosine (126) to form l-DOPA (3,4-dihydroxyphenylalanine, 127), and TPH catalyzes the hydroxylation of L-tryptophan (128) to 5-hydroxytryptophan (129). The hydroxylated products, 127 and 129, are decarboxylated by the action of aromatic amino acid decarboxylase to dopamine (130) and serotonin (131), respectively. 

The important metaboUsm of the neurotransmitters norepinephrine, epinephrine, dopa, and serotonin involves pterin-dependent monooxygenases. The direct biocatalytic hydroxylation of the aromatic amino acids phenylalanine, tyrosine, and tryptophane requires tetrahydrobiopterin and Fe as the cofactors [60]. The cleavage of unsaturated glyceryl ethers by glyceryl ether monooxygenase also requires tetrahydrobioterin as the cofactor [61]. 

In addition to these three, there are also monooxygenase enzymes containing single nonheme iron or copper ions, or nonheme iron plus an organic cofactor such as a reduced pterin at their active sites.Just as with the dioxygenase enzymes, we do not know how similar the mechanisms of the different metal-containing monooxygenase enzymes are to one another. The enzyme for which we have the most information is cytochrome P-450, and we will therefore focus our discussion on that system. Speculations about the mechanisms for the other systems are discussed at the end of this section. 

Tetrahydrobiopterin (BPH4) is the natural cofactor required for the mammalian aromatic amino acid monooxygenases phenylalanine, tyrosine and tryptophan hydroxylase [4,89]. During the course of the reaction catalyzed by these enzymes, a molecule of oxygen is cleaved in order to hydroxylate the respective amino acid substrate. The remaining atom of oxygen is reduced to water at the expense of the cofactor, which is oxidized to the quinonoid form. Despite the many studies on the pterin-dependent hydroxylases, their precise mechanism of action is not well understood. This discussion will focus on mammalian phenylalanine hydroxylase (PAH), which has been favored for investigation due to its relative stability and ease of... 

The pterin-dependent amino acid hydroxylases (AAH) are a group of mononuclear, nonheme monooxygenases that catalyze the oxidation of aromatic amino acids necessary for the biosynthesis of a variety of neurotransmitters. " The three primary enzymes that have been... 

Walsh C. Flavin- and pterin-dependent monooxygenases. In Enzymatic Reaction Mechanisms. San Francisco W. H. Freeman, 1979 Chapter 12. 

Tetrahydrobiopterin and tetrahydrofolic acid are coenzymes of monooxygenases (C 2.6) and of enzymes of the Ci-metabolism, respectively (D 3.2). Folic acid is a vitamin for humans, being reduced in the human body to tetrahydrofolic acid (E 2.1). Pterins, e.g., xanthopterin and leucopterin, sepiapterin and isosepiapterin are wing pigments of insects, for instance, of butterflies and flies. Similar compounds are skin pigments of fishes, amphibians, and reptiles and in this respect are of ecological significance. 

Important nonheme iron monooxygenases other than sMMO are pterin-dependent enzymes and isopenicillin N synthase. Three enzymes are known as the pterin-dependent monooxygenases phenylalanine hydroxylase (PAH), tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH). These enzymes perform metabolically important transformations, e,g, for the biosynthesis of neurotransmitters, and catalyze the reactions shown in Fig. 8. 

Figure 8. Reaction catalyzed by pterine-dependent non-heme iron monooxygenases [93].

Pterin appears to cycle between the tetrahydro (BPH4) and dihydro forms, providing the two electrons necessary for reduction of dioxygen as shown in Scheme 6. One oxygen atom is incorporated into substrate and another into water as shown in the general equation of monooxygenase-catalyzed reaction [see eq. (1)]. Interesting information from the side of chemistry has been obtained recently in the studies of PAH and TH, but not TPH. 

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