Aromatic amino acid decarboxylase dopamine synthesis

The synthesis and metabolism of trace amines and monoamine neurotransmitters largely overlap [1]. The trace amines PEA, TYR and TRP are synthesized in neurons by decarboxylation of precursor amino acids through the enzyme aromatic amino acid decarboxylase (AADC). OCT is derived from TYR. by involvement of the enzyme dopamine (3-hydroxylase (Fig. 1 DBH). The catabolism of trace amines occurs in both glia and neurons and is predominantly mediated by monoamine oxidases (MAO-A and -B). While TYR., TRP and OCT show approximately equal affinities toward MAO-A and MAO-B, PEA serves as preferred substrate for MAO-B. The metabolites phenylacetic acid (PEA), hydroxyphenylacetic acid (TYR.), hydroxymandelic acid (OCT), and indole-3-acetic (TRP) are believed to be pharmacologically inactive. 

By contrast, the cytoplasmic decarboxylation of dopa to dopamine by the enzyme dopa decarboxylase is about 100 times more rapid (Am 4x 10 " M) than its synthesis and indeed it is difficult to detect endogenous dopa in the CNS. This enzyme, which requires pyridoxal phosphate (vitamin B6) as co-factor, can decarboxylate other amino acids (e.g. tryptophan and tyrosine) and in view of its low substrate specificity is known as a general L-aromatic amino-acid decarboxylase. 

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). 

Fig. 1. A. Chemical structure of key molecules involved in the key steps in intracerebral synthesis and metabolism of dopamine. The successive steps are regulated by the enzymes tyrosine hydroxylase (TH), aromatic amino acid decarboxylase (AADC), monoamine oxidase (MAO) and dopamine-p-hydroxylase (DBH). B. Structure of key toxins and other drugs acting on dopamine neurones, including 6-hydroxydopamine (6-OHDA), a-methyl tyrosine, and amphetamine. For further details see Iversen and Iversen (1981) or Cooper et al. (1996).

Figure 13.4. Synthesis of the catecholamines. Tyrosine hydroxylase, EC 1.14.16.2 (see also Fignre 10.10) aromatic amino acid decarboxylase, EC 4.1.1.26 and dopamine -hydroxylase, EC 1.14.17.1.

Tyrosine is actively transported into nerve endings and is converted to dihydroxyphenylalanine DOPA) via tyrosine hydroxylase 1). This step is rate limiting in the synthesis of NE. DOPA is converted to dopamine (DA) via L-aromatic amino acid decarboxylase (DOPA decarboxylase). DA in turn is metabolized to NE via DA beta hydroxylase and is taken up and stored in granules (6). Inactivation ofNE via monoamine oxidase (MAO) (2) may regulate prejunctional levels of transmitter in the mobile pool (3) but not the NE stored in granules. 

It is known that the activity of the rate-limiting enzyme in the biological synthesis of dopamine, tyrosine hydroxylase, can be modulated through a Dj-receptor mediated pathway. To determine whether quinpirole reduces exocytotic quantal size by inhibiting this enzyme or by blocking the vesicular uptake of cytosolic dopamine via inhibition of the vesicular monoamine transporter, VMATl, the tyrosine hydroxylase product l-DOPA has been measured in the presence of an aromatic amino acid decarboxylase inhibitor that blocks the conversion of l-DOPA to dopamine [56]. Interestingly, it has been determined that quinpirole decreases tyrosine hydroxylase activity to approximately 59% of control values, a value close to the percentage of the reduced quantal size reported... 

The majority of catecholamine and serotonin biosynthesis occurs within the nerve terminals by synthetic enzymes transported from the neuronal cell bodies. In all catecholamine neurons, the rate-limiting step in synthesis is conversion of tyrosine to dihydroxyphenylalanine by tyrosine hydroxylase. Dihydroxyphenylalanine is then converted to DA, norepinephrine, and epinephrine through a sequential process involving L-aromatic amino acid decarboxylase (conversion of dihydroxyphenylalanine to DA), dopamine-P-hydroxylase (conversion of DA to norepinephrine), and phenylethanol-amine-N-methyltransferase (conversion of norepinephrine to epinephrine). Cell-specific expression of these enzymes determines the main neurotransmitter for an individual catecholamine neuron. The synthesis pathway for serotonin involves a two-step process in which tryptophan hydroxylase first converts tryptophan to 5-hydroxytryptophan, which is then converted to... 

Figure 13.7 Synthesis and structure of the trace amines phenylethylamine, /)-tyramine and tryptamine. These are all formed by decarboxylation rather than hydroxylation of the precursors of the established monoamine neurotransmitters, dopamine and 5-HT. (1) Decarboxylation by aromatic L-amino acid decarboxylase (2) phenylaline hydroxylase (3) tyrosine hydroxylase (4) tryptophan hydroxylase...

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. 

The synthesis of dopamine originates from the precursor the amino acid L-tyrosine, which must be transported across the blood-brain barrier into the dopaminergic neuron. The rate limiting step in the synthesis is the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) by the enzyme tyrosine hydroxylase (TH). L-DOPA is subsequently converted to dopamine by aromatic L-amino acid decarboxylase. The latter enzyme turns over so rapidly that L-DOPA levels in the brain are negligible under normal conditions.1... 

Synthesis and metabolism of catecholamines. Arrows indicate molecular conversions catalyzed by specific enzymes. Bold arrows indicate major (preferred) pathways. Enzymes (I) tyrosine hydroxylase (2) aromatic L-amino acid decarboxylase (3) dopamine-jSymonooxygenase (4) PNMT (5) cateckel-o-methyltransferase (6) monoamine oxidase. 

L-dopa is a chemical intermediate produced in the synthesis of dopamine (see Figure below). It is formed from the actions of tyrosine hydroxylase on tyrosine, and is subsequently converted into dopamine by aromatic-L-amino acid decarboxylase (LAAD, or dopa decarboxylase). This molecule is taken up into the dopaminergic nerve terminal and converted to dopamine, which is then released into the synaptic cleft. Unlike dopamine, dopa is in nonionized form at physiologic pH and thus will cross into the central nervous system (CNS). 

SYNTHESIS, STORAGE, AND RELEASE OF CATECHOLAMINES Synthesis—The steps in the synthesis of DA, NE (known outside the U.S. as noradrenaline), and Epi (known as adrenahne) are shown in Eigure 6-A. Tyrosine is sequentially 3-hydroxylated and decarboxylated to form DA. DA is 3-hydroxylated to yield NE (the transmitter in postganglionic nerves of the sympathetic branch of the ANS), which is N-methylated in chromaffin tissue to give Epi. The enzymes involved are not completely specific consequently, other endogenous substances and some drugs are also substrates. 5-hydroxytryptamine (5-HT, serotonin) can be produced from 5-hydroxy-L-tryptophan by aromatic L-amino acid decarboxylase (AAD or dopa decarboxylase). AAD also converts dopa into DA, and methyldopa to a-methyl-DA, which is converted to a-methyl-NE by dopamine /3-hydroxylase (Dj3H Table 6-4). 

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