Tyrosine 3-monooxygenase, function

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. 

How can a simple cofactor, such as heme, give rise to a wide spectrum of protein functionalities While the Fe(III)/Fe(II) couple has a standard redox potential of 0.77 V, when complexed with a protoporphyrin to form free heme, it may decrease to —0.115 V [3-5]. When heme is introduced into a protein matrix, redox potential shows an impressive variation of around 1 V. The electrochemical data for structurally characterized heme proteins involved in electron transfer and redox catalysis has been compiled at the Heme Protein Database (HPD, http //heme.chem. columbia.edu/heme) [6]. The database comprises not only peroxidases but also catalases, oxidases, monooxygenases, and cytochromes. From b-type heme with histidine-tyrosine ligation (E° = 0.55 V) to c-type heme with histidine-methionine... 

The degradation of phenylalanine begins with its hydroxylation to tyrosine, a reaction catalyzed by phenylalanine hydroxylase. This enzyme is called a monooxygenase (or mixed-function oxygenase) because one atom ofO appears in... 

Epinephrine (adrenaline) (Figure 32-7) is synthesized from tyrosine by conversion of tyrosine to 3,4-dihydro-xyphenylalanine (dopa) by tyrosine-3-monooxygenase (tyrosine hydroxylase) in the cytosol. The mixed-function oxidase requires molecular oxygen and tetrahydro-biopterin, which is produced from dihydrobiopterin by NADPH-dependent dihydrofolate reductase. In the reaction, tetrahydrobiopterin is oxidized to dihydrobiopterin, which is reduced to the tetrahydro form by NADH-dependent dihydropteridine reductase. These reactions are similar to the hydroxylations of aromatic amino acids (phenylalanine and tryptophan), in which an obligatory biopterin electron donor system is used (Chapter 17). 

There is a possibility that a couple of nonheme monooxygenases other than methane monooxygenase possess paired iron centers, but most of the iron proteins are suggested to contain a monomeric iron site. These include tyrosine hydroxylase [13-15] phenylalanine hydroxylase [16, 17], and isopenicillin N synthase [18,19]. Unfortunately, the active site structures of this class of enzymes have not been elucidated to date. Neither have the reaction mechanisms of these understood (recently, the crystal structure of isopenicillin N synthase has been reported) [20]. The function of this enzyme is not hydroxylation reaction but catalyzes the cyclization of L-5-(a-aminoadipoyl)-L-cysteinyl-D-valine to afford isopenicillin, while the catalytic reaction of this enzyme is assumed to include the reductive activation of dioxygen which affords water and high valent 0x0 iron species as... 

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