Dopamine /3-monooxygenase function

MPTP is also metabolized by other routes involving cytochromes P-450, FAD-dependent monooxygenases, and aldehyde oxidase. However, these seem to be detoxication pathways, as they divert MPTP away from uptake and metabolism in the brain. However, MPTP may inhibit its own metabolism by cytochromes P-450 and thereby reduce one means of detoxication. This example illustrates the importance of structure and physicochemical properties in toxicology. MPTP is sufficiently lipophilic to cross the blood-brain barrier and gain access to the astrocytes. The structure of the metabolite is important for uptake via the dopamine system, hence localizing the compound to a particular type of neuron. Again, uptake into mitochondria is presumably a function of structure, as a specific energy-dependent carrier is involved. 

Tyrosinase is both an oxidase and a hydroxylase. Some other copper enzymes have only a hydroxylase function. One of the best understood of these is the peptidylglycine a-hydroxylating monoxygenase, which catalyzes the first step of the reaction of Eq. 10-11. The enzyme is a colorless two-copper protein but the copper atoms are 1.1 nm apart and do not form a binuclear center.570 Ascorbate is an essential cosubstrate, with two molecules being oxidized to the semidehydro-ascorbate radical as both coppers are reduced to Cu(I). A ternary complex of reduced enzyme, peptide, and 02 is formed and reacts to give the hydroxylated product.570 A related two-copper enzyme is dopamine (J-monooxygenase, which utilizes 02 and ascorbate to hydroxylate dopamine to noradrenaline (Chapter 25).571/572 These and other types of hydroxylases are compared in Chapter 18. 

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. 

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