Dopa-decarboxylase DDC

Fig. 2. Biosynthetic pathway for epinephrine, norepinephrine, and dopamine. The enzymes cataly2ing the reaction are (1) tyrosine hydroxylase (TH), tetrahydrobiopterin and O2 are also involved (2) dopa decarboxylase (DDC) with pyridoxal phosphate (3) dopamine-P-oxidase (DBH) with ascorbate, O2 in the adrenal medulla, brain, and peripheral nerves and (4) phenethanolamine A/-methyltransferase (PNMT) with. Cadenosylmethionine in the adrenal...

The main clinical use of COMT inhibitors is as adjunct (or additional adjunct) in the therapy of Parkinson s disease. The standard therapy of Parkinson s disease is oral L-dopa (as a drug levodopa) given with a dopa decarboxylase (DDC) inhibitor (e.g. carbidopa and benserazide), which does not reach the brain. When the peripheral DDC is inhibited, the concentration of 3-O-methyldopa (3-OMD), a product of COMT, in plasma is many times that of L-dopa. Since the half-life of 3-OMD is about 15 h, compared to about 1 h for L-dopa, the concentration of 3-OMD remains particularly high during chronic therapy, especially if new slow release L-dopa preparations are used. A triple therapy (L-dopa plus DDC inhibitor plus COMT-inhibitor) will... 

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). 

FIGURE 5—31. Dopamine (DA) is produced in dopaminergic neurons from the precursor tyrosine (tyr), which is transported into the neuron by an active transport pump, called the tyrosine transporter, and then converted into DA by two of the same three enzymes that also synthesize norepinephrine (Fig. 5-17). The DA-synthesizing enzymes are tyrosine hydroxylase (TOH), which produces DOPA, and DOPA decarboxylase (DDC), which produces DA. 

Figure 1. Biosynthetic pathways for biogenic amines. In Drosophila and vertebrates decarboxylation of DOPA and 5-hydroxy-tryptophan is catalyzed by the same enzyme, DDC. In vertebrates this enzyme is called amino acid decarboxylase (AADC). Only vertebrates further metabolize dopamine to norepinephrine and epinephrine. TH, tryosine hydroxylase DDC, DOPA decarboxylase DBH, dopamine b-hydroxylase PNMT, phenylethanolamine N-methyltransferase. Tryp-OH tryptophan hydroxylase.

The main metabolic routes of dopamine and noradrenaline in the brain. COMT, Catechol O-methyltransferase MAO, monoamino oxidase DDC, dopa decarboxylase DBH, dopamine (3-hydroxylase 3-OMD, 3-methoxytyrosine Dopac, dihydroxyphenyl acetic acid. 

Fig. 3. Schematic representation of the neurochemical events associated with neurotransmitter synthesis, release, re-uptake and metabolism in axons of diencephalic DA neurons terminating in classical synapses (Top Panel), and TIDA neurosecretory neurons terminating in close proximity to the hypophysial portal system (Botton Panel). Arrows with dashed lines represent end-product inhibition of TH activiy by DA (Top + Bottom Panels) or DA presynaptic autoreceptor-mediated inhibition of DA synthesis and release (Top Panel). Abbreviations COMT, Catechol-O-methyltransferase D, dopamine DDC, DOPA decarboxylase DOPA, 3,4-dihydrophenylalanine DOPAC, 3,4-dihydroxyphenylacetic acid HVA, homovanillic acid MAO, monoamine oxidase 3MT, 3-methoxytyramine TH, tyrosine hydroxylase.

DDC catalyzes the conversion of L-3,4-dihydroxyphenylalanine (l-DOPA) into dopamine (Figure 10), a neurotransmitter found in the nervous system and peripheral tissues of both vertebrates and invertebrates and also in plants where it is implicated in the biosynthesis of benzylisoquinoline alkaloids. " DDC also catalyzes the decarboxylation of tryptophan, phenylalanine, and tyrosine and of 5-hydroxy-L-tryptophan to give 5-hydroxytryptamine (serotonin), and, therefore, is also referred to as aromatic amino acid decarboxylase. Inhibitors of DDC, for example, carbiDOPA and benserazide, are currently used in the treatment of Parkinson s disease to increase the amount of l-DOPA in the brain. 

---