Vitamin dopamine -hydroxylase

Tyrosine monooxygenase uses biopterin as a cofactor. Biopterin is made in the body and is not a vitamin. Its structure resembles that of folic acid. Dopa decarboxylase is a vitamin B -requiring enzyme. Dopamine hydroxylase is a copper metalloenzyme. The active form of the enzyme contains copper in the reduced state (cuprous, Cu+). With each catalytic event, the copper is oxidized to the cupric state (Cu ). The enzyme uses ascorbic acid as a cofactor for converting the cupric copper back to cuprous copper. Thus, each catalytic event also results in the conversion of ascorbic acid to semidehydroascorbate. The semidehydroascorbate, perhaps by disproportionation, is converted to ascorbate and dehydroascorbate. The catalytic cycle of dopamine hydroxylase is shown in Figure 9,86. Dopamine hydroxylase, as well as the stored catecholamines, are located in special vesicles... 

Two possible mechanisms for the neurotoxicity of carbon disulfide have been suggested. One mechanism involves the formation of dithiocarbamates. The inhibitory effect of carbon disulfide on the activity of the copper-requiring enzyme dopamine- -hydroxylase was attributed to the formation of dithiocarbamates, which can complex copper (McKenna and DiStefano 1977b). Interference with the formation of this metabolite may be a potential strategy, albeit untested, to reduce neurotoxicity from carbon disulfide poisoning. An alternative mechanism postulated to explain the neurotoxic effect of carbon disulfide is the formation of a dithiocarbamate derivative, a form of vitamin B6, of pyridoxamine, with carbon disulfide (Vasak and Kopecky 1967). Since transaminases and amine oxidases require the pyridoxamine phosphate form of vitamin B6 as a cofactor, it was further postulated that these enzymes would be inhibited in carbon... 

The first step is catalysed by the tetrahydrobiopterin-dependent enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), which is regulated by end-product feedback is the rate controlling step in this pathway. A second hydroxylation reaction, that of dopamine to noradrenaline (norepinephrine) (dopamine [3 oxygenase) requires ascorbate (vitamin C). The final reaction is the conversion of noradrenaline (norepinephrine) to adrenaline (epinephrine). This is a methylation step catalysed by phenylethanolamine-jV-methyl transferase (PNMT) in which S-adenosylmethionine (SAM) acts as the methyl group donor. Contrast this with catechol-O-methyl transferase (COMT) which takes part in catecholamine degradation (Section 4.6). 

Tyrosine is converted to dopa by the rate-limiting enzyme tyrosine hydroxylase, which requires tetrahydrobiopterin, and is inhibited by a-methyltyrosine. Dopa is decarboxylated to dopamine by L-aromatic amino acid decarboxylase, which requires pyridoxal phosphate (vitamin B6) as a coenzyme. Carbidopa, which is used with levodopa in the treatment of parkinsonism, inhibits this enzyme. Dopamine is converted to norepinephrine by dopamine P-hydroxylase, which requires ascorbic acid (vitamin C), and is inhibited by diethyldithiocarbamate. Norepinephrine is converted to epinephrine by phenylethanolamine A -methyltransferase (PNMT), requiring S-adeno-sylmethionine. The activity of PNMT is stimulated by corticosteroids. 

The ability to synthesise ascorbic acid from glucose is absent in a small group of animal species that include man, primates, the guinea pig and the fruit-bat this is due to the absence of the gene that codes for one of the enzymes required for ascorbate synthesis. These species are therefore dependent on an external source of the vitamin in their diet and it is needed as a cofactor for several hydroxylase enzymes, notably the iron-dependent proline and lysine hydroxylases and the copper-dependent dopamine-(3-hydroxylase the function of ascorbate in these enzymes is likely to be its ability to keep the metal in the reduced form which is necessary for hydroxylation. The ability of ascorbate to reduce Fe3+ to Fe2+ is important in promoting the gastrointestinal uptake of iron and for its release from the iron store ferritin. 

Tetrahydrobiopterin is not a vitamin, because it can be synthesized from GTP, as shown in Figure 10.2 (Thony et al., 2000). It is the coenzyme for mixed-function oxidases phenylalanine, tyrosine, and tryptophan hydroxylases alkyl glycerol monoxygenase, which catalyzes the cleavage of alkyl glycerol ethers and nitric oxide synthase in the formation of nitric oxide. In addition to its coenzyme role, tetrahydrobiopterin has a direct effect on neurons, acting to stimulate dopamine release via a cAMP-dependent protein kinase and a calcium channel (Koshimura et al., 2000). 

The next step in the catecholamine biosynthesis is side-chain hydroxylation of DA to NE. The enzyme dopamine (3-hydroxylase (DBH) catalyzes this reaction. This enzyme, like TH, is a mixed-function oxidase utilizing molecular 02, in this case to add the OH onto the (3-carbon of the phenelthylamine side chain. DBH is a Cu2+-containing enzyme that, with ascorbic acid (Vitamin C) as a cofactor, carries out the necessary electron transfers. 

Tyrosine is the precursor for the synthesis of the hormone and neurotransmitter noradrenalin which is formed from dopamine (3,4-dihydroxyphenylethanolamine) by the vitamin C-requiring dopamine j8-mono-oxygenase (also called dopamine-jS-hydroxylase) in the adrenal medulla as shown in Figure 5.14. 

Both the above hydroxylations seem to involve the recycling of tetrahydrobiopterin which may require ascorbic acid. Recently it has been suggested that dopamine-jS-hydroxylase (DBH) works in tandem with semidehydroascorbate reductase (SDR) in order to recycle the vitamin and oxidise NADHj as in Figure 5.15. 

Neurons that secrete norepinephrine synthesize it from dopamine in a hydroxylation reaction catalyzed by dopamine (3-hydroxylase (DBH). This enzyme is present only within the storage vesicles of these cells. Like tyrosine hydroxylase, it is a mixed-function oxidase that requires an electron donor. Ascorbic acid (vitamin C) serves as the electron donor and is oxidized in the reaction. Copper (Cu ) is a bound cofactor required for the electron transfer. 

Ascorbic acid functions as a relatively nonspecific, radical-trapping antioxidant and also reduces the tocopheroxyl radical formed by oxidation of vitamin E. It has a specific metabolic function as the redox coenzyme for dopamine /3-hydroxylase and peptidyl glycine hydroxylase, and it is required to maintain the iron of 2-oxoglutarate-dependent hydroxylases in the reduced state. 

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