Dihydroxyphenylalanine decarboxylase

FACCHINI, P.J., PENZES-YOST, C., SAMANANI, N KOWALCHUK, B., Expression patterns conferred by tyrosine/dihydroxyphenylalanine decarboxylase promoters from opium poppy are conserved in transgenic tobacco. Plant Physiol., 1998,118,69-81. 

PARK, S.-U., JOHNSON, A.G., PENZES-YOST, C FACCHINI, P.J., Analysis of promoters from tyrosine/dihydroxyphenylalanine decarboxylase and berberine bridge enzyme genes involved in benzylisoquinoline alkaloid biosynthesis in opium poppy. Plant Mol. Biol., 1999,40,121-131. 

Rosengren, E., Are dihydroxyphenylalanine decarboxylase and 5-hydroxytryptophan decarboxylase individual enzymes , Acta, physiol, scand. 49, 364 (1960). 

SouRKES, T. L., Inhibition of dihydroxyphenylalanine decarboxylase by derivatives of phenylalanine. Arch. Biochem. 51, 444 (1954). 

Dopamine synthesis in dopaminergic terminals (Fig. 46-3) requires tyrosine hydroxylase (TH) which, in the presence of iron and tetrahydropteridine, oxidizes tyrosine to 3,4-dihydroxyphenylalanine (levodopa.l-DOPA). Levodopa is decarboxylated to dopamine by aromatic amino acid decarboxylase (AADC), an enzyme which requires pyri-doxyl phosphate as a coenzyme (see also in Ch. 12). 

Dopamine is the decarboxylation product of DOPA, dihydroxyphenylalanine, and is formed in a reaction catalysed by DOPA decarboxylase. This enzyme is sometimes referred to as aromatic amino acid decarboxylase, since it is relatively non-specific in its action and can catalyse decarboxylation of other aromatic amino acids, e.g. tryptophan and histidine. DOPA is itself derived by aromatic hydroxylation of tyrosine, using tetrahydrobiopterin (a pteridine derivative see Section 11.9.2) as cofactor. 

Synthesis of norepinephrine begins with the amino acid tyrosine, which enters the neuron by active transport, perhaps facilitated by a permease. In the neuronal cytosol, tyrosine is converted by the enzyme tyrosine hydroxylase to dihydroxyphenylalanine (dopa), which is converted to dopamine by the enzyme aromatic L-amino acid decarboxylase, sometimes termed dopa-decarboxylase. The dopamine is actively transported into storage vesicles, where it is converted to norepinephrine (the transmitter) by dopamine (3-hydroxylase, an enzyme within the storage vesicle. 

Specific decarboxylases for most of the common amino acids have been isolated. In mammals, a decarboxylase involved in the biosynthesis of neuroactive amines is particularly important. This enzyme decarboxylates 3,4-dihydroxyphenylalanine and 5-hydroxytryp-tophan (both products of tetrahydrobiopterin-dependent hydroxylations—Section 1.10.5.1) to give 3,4-dihydroxyphenethylamine and serotonin (equation 10), respectively (70MI11002). 

Noradrenergic neurons. The noradrenergic neuron uses NE for its neurotransmitter. Monoamine neurotransmitters are synthesized by means of enzymes, which assemble neurotransmitters in the cell body or nerve terminal. For the noradrenergic neuron, this process starts with tyrosine, the amino acid precursor of NE, which is transported into the nervous system from the blood by means of an active transport pump (Fig. 5 — 17). Once inside the neuron, the tyrosine is acted on by three enzymes in sequence, the first of which is tyrosine hydroxylase (TOH), the rate-limiting and most important enzyme in the regulation of NE synthesis. Tyrosine hydroxylase converts the amino acid tyrosine into dihydroxyphenylalanine (DOPA). The second enzyme DOPA decarboxylase (DDC), then acts, converting DOPA into dopamine (DA), which itself is a neurotransmitter in some neurons. However, for NE neurons, DA is just a precursor of NE. In fact, the third and final NE synthetic enzyme, dopamine beta-hydroxylase (DBH), converts DA into NE. The NE is then stored in synaptic packages called vesicles until released by a nerve impulse (Fig. 5—17). 

Dopa decarboxylase The enzyme that converts dihydroxyphenylalanine (dopa) into dopamine. 

FIGURE 23.7 Dopamine (DA) is synthesized within neuronal terminals from the precursor tyrosine by the sequential actions of the enzymes tyrosine hydroxylase, producing the intermediary L-dihydroxyphenylalanine (Dopa), and aromatic L-amino acid decarboxylase. In the terminal, dopamine is transported into storage vesicles by a transporter protein (T) associated with the vesicular membrane. Release, triggered by depolarization and entry of Ca2+, allows dopamine to act on postsynaptic dopamine receptors (DAR). Several distinct types of dopamine receptors are present in the brain, and the differential actions of dopamine on postsynaptic targets bearing different types of dopamine receptors have important implications for the function of neural circuits. The actions of dopamine are terminated by the sequential actions of the enzymes catechol-O-methyl-transferase (COMT) and monoamine oxidase (MAO), or by reuptake of dopamine into the terminal. 

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. 

L-Dopa. Dopamine itself cannot penetrate the blood-brain barrier however, its natural precursor, L-dihydroxyphenylalanine (levo-dopa), is effective in replenishing striatal dopamine levels, because it is transported across the blood-brain barrier via an amino acid carrier and is subsequently decarboxy-lated by dopa decarboxylase, present in striatal tissue. Decarboxylation also takes place in peripheral organs where dopamine is not needed and is likely to cause undesirable effects (vomiting hypotension p.116). Extracerebral production of dopamine can be prevented by inhibitors of dopa decarboxylase (carbidopa, benserazide) that do not penetrate the blood-brain barrier, leaving intracerebral decarboxylation unaffected. 

Histamine, serotonin and the catecholamines (dopamine, epinephrine and norepinephrine) are synthesized from the aromatic amino acids histidine, tryptophan and phenylalanine, respectively. The biosynthesis of catecholamines in adrenal medulla cells and catecholamine-secreting neurons can be simply summarized as follows [the enzyme catalysing the reaction and the key additional reagents are in square brackets] phenylalanine — tyrosine [via liver phenylalanine hydroxylase + tetrahydrobiopterin] —> i.-dopa (l.-dihydroxyphenylalanine) [via tyrosine hydroxylase + tetrahydrobiopterin] —> dopamine (dihydroxyphenylethylamine) [via dopa decarboxylase + pyridoxal phosphate] — norepinephrine (2-hydroxydopamine) [via dopamine [J-hydroxylasc + ascorbate] —> epinephrine (jV-methyl norepinephrine) [via phenylethanolamine jV-methyltransferase + S-adenosylmethionine]. 

The concept of inhibition via p elimination of fluoride ion has now been extended to the irreversible inhibition of a-amino acid decarboxylases. Ornithine decarboxylase (ODC), which catalyzes the decarboxylation of ornithine to putrescine is irreversibly inhibited by a-difluoromethylornithine (IX Fig. 9) (28). In this case, the carbanion formation which precedes P elimination is generated by loss of CO2, and not by proton abstraction (Fig. 9). Similarly, aromatic amino acid decarboxylase is irreversibly inhibited by C-difluoromethyl-3,4-dihydroxyphenylalanine (29) while histidine decarboxylase, ornithine decarboxylase and aromatic amino acid decarboxylase have been inhibited by the corresponding <=d-monof luoromethylanri.no acids, respectively (29). 

Carboni E, Tanda G, Di Chiara G (1992) Extracellular striatal concentrations of endogenous 3,4-dihydroxyphenylalanine in the absence of a decarboxylase inhibitor—A dynamic index of dopamine synthesis in vivo. / Neurochem 59 2230-2236. 

Robert F, Lambassenas L, Ortemann C, Pujol JF, Renaud B (1993) Microdialysis monitoring of 3,4-dihydroxyphenylalanine accumulation after decarboxylase inhibition—A means of estimate in vivo changes in tyrosine hydroxylase activity of the rat locus ceruleus. J Neurochem 60 721-729. 

Decarboxylation of L-3,4-dihydroxyphenylalanine to dopamine, and of 5-hydroxytryptophan to serotonin, is catalyzed by aromatic L-amino acid decarboxylase. A single enzyme may be responsible for both activities. This assay permits simultaneous determination of both activities. 

The catecholamines - dopamine, norepinephrine, and epinephrine are successively derived from tyrosine. S m-thesis occurs in the nerve terminals and in the adrenal gland. Tyrosine hydroxylase catalyzes the first step (Figure 10.2a) and is the major site of regulation (inhibition by dopamine and noradrenaline, activation by cAMP). This step gives rise to 3,4-dihydroxyphenylalanine (L-DOPA), which in turn is a substrate for L-aromatic acid decarboxylase. De-... 

Dopamlne (dlhydroxyphenylethylamine) DOPA (3,4-dihydroxyphenylalanine) Aromatic amino acid decarboxylase 4.1. 1.28... 

Transamination and Oxidative Deamination Catalyzed by Di-hydroxyphenylalanine (DOPA) Decarboxylase DOPA decarboxylase catalyzes the decarboxylation of dihydroxyphenylalanine to yield dopamine (and hence the other catecholamine neurotransmitters see Figure 13.4) and... 

Opacka-Juffi ey J, Brooks DJ (1995) Dihydroxyphenylalanine and its decarboxylase New ideas on die neuroregulatory roles. Mov Disord 10 241-249. 

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