AADC

The immediate metabolic precursor to dopamine, l-DOPA (L-dihydroxphenylalanine) is converted to the active neurotransmitter dopamine by the action of the enzyme aromatic amine acid decarboxylase (AADC). l-DOPA (INN name Levodopa) is the main diug used to treat Parkinson s disease. 

MAO converts dopamine to DOPAC (3,4-dihydrox-yphenylacetic acid), which can be further metabolized by COMT to form homovanillic acid (HVA). HVA is the main product of dopamine metabolism and the principal dopamine metabolite in urine. Increased neuronal dopaminergic activity is associated with increases in plasma concentrations of DOPAC and HVA. COMT preferentially methylates dopamine at the 3 -hydroxyl position and utilizes S-adenosyl-L-methio-nine as a methyl group donor. COMT is expressed widely in the periphery and in glial cells. In PD, COMT has been targeted since it can convert l-DOPA to inactive 3-OMD (3-O-methyl-dopa). In the presence of an AADC inhibitor such as carbidopa, 3-OMD is the major metabolite of l-DOPA treatment. 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

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. 

Trace Amines. Figure 1 The main routes of trace amine metabolism. The trace amines (3-phenylethylamine (PEA), p-tyramine (TYR), octopamine (OCT) and tryptamine (TRP), highlighted by white shading, are each generated from their respective precursor amino acids by decarboxylation. They are rapidly metabolized by monoamine oxidase (MAO) to the pharmacologically inactive carboxylic acids. To a limited extent trace amines are also A/-methylated to the corresponding secondary amines which are believed to be pharmacologically active. Abbreviations AADC, aromatic amino acid decarboxylase DBH, dopamine b-hydroxylase NMT, nonspecific A/-methyltransferase PNMT, phenylethanolamine A/-methyltransferase TH, tyrosine hydroxylase. 

V. Comparison of the Drosophila Ddc Gene to the Vertebrate AADC Gene. .. 76... 

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.

Vertebrates also show expression of AADC in both neural and non-neural tissues. AADC has been purified from kidney (Christenson et al., 1972), liver (Ando-Yamamoto et al., 1987), adrenal medulla (Albert et al., 1987), and pheochromocytoma (Coge et al., 1989 Ichinose et al., 1989). In the adrenal medulla dopamine is further processed into epinephrine and norepinephrine, which are released from the chromaffin cells during stress to increase heart rate and blood pressure. There are no detectable monoamines in the liver and kidney, and the function of AADC in these tissues is unknown. AADC activity has also been... 

In the vertebrate CNS monoamines have been associated with a number of physiological functions (reviewed in Kandel et al., 1991). Serotonin has functions associated with mood, pain, sleep, learning, and memory. Dopamine has functions associated with schizophrenia, Parkinson s disease, and cocaine addiction. In vertebrates, dopamine is further metabolized into two additional neurotransmitters, norepinephrine and epinephrine. Norepinephrine increases the excitability of cells in response to sudden sensory input such as fear. Epinephrine has been identified in specific neurons of the brain, but the function of these cells is unknown. In addition, AADC has also been found in a class of neurons that do not have any of the four neurotransmitters discussed above (Jaeger et al., 1983). These neurons may use one of the trace amines, tyramine, tryptamine, or phenylethylamine, as a neurotransmitter. 

V. COMPARISON OF THE DROSOPHILA Ddc GENE TO THE VERTEBRATE AADC GENE... 

In Drosophila the two tissue-specific mRNAs are generated by alternative splicing of a single primary transcript (Fig. 9). In vertebrates the two tissue specific AADC transcripts are generated from two alternative promoters (Fig. 11) (Albert et al., 1992 Ichinose et al., 1992 Thai et al., 1993). In neural tissue transcription initiates from exon Nl, whereas in non-neural tissue transcription initiates from exon LI. This produces two distinct primary transcripts that are then spliced from the first exon (LI or Nl) to exon 2 to generate two tissue-specific mRNAs. Translation initiates within exon 2, such that the same AADC protein product is synthesized from both AADC mRNAs. 

Although there is a different pattern of exons spliced in the two AADC mRNAs, this apparent alternative splicing is a consequence of differences in transcription. In the non-neural mRNAthat initiates at exon LI,... 

Figure 11. Alternate promoters are used for production of the vertebrate neural and non-neural AADC mRNAs. Non-neural AADC transcription initiates at exon L1, whereas neural transcription initiates at exon N1. The non-neural mRNA splices from exon L1 to 2, since the 5 edge of exon N1 is a site of transcriptional initiation instead of a splice acceptor site. Translation initiates from the same AUG in exon 2 in both mRNAs, producing the same protein product in both tissue types. This scheme holds for both human and rat AADC, although the nomenclature of the exons differs. In rat AADC the exon N1 to 2 splice uses a splice acceptor site 5 bp downstream of the splice acceptor used for the exon L1 to 2 splice (Albert et al., 1992).

The other enzyme involved in the synthesis of 5-HT, aromatic L-amino acid decarboxylase (AADC) (EC 4.1.1.28), is a soluble pyridoxal-5 -phosphate-dependent enzyme, which converts 5-HTP to 5-HT (Fig. 13-5). It has been demonstrated that administration of pyridoxine increases the rate of synthesis of 5-HT in monkey brain, as revealed using position emission tomography (this technique is discussed in Ch. 58). This presumably reflects a regulatory effect of pyridoxine on AADC activity and raises the interesting issue of the use of pyridoxine supplementation in situations associated with 5-HT deficiency. 

AADC is present not only in serotonergic neurons but also in catecholaminergic neurons, where it converts 3,4-dihydroxyphenylalanine (DOPA) to dopamine (see Ch. 12). However, different pH optima or concentrations of substrate or cofactor are required for optimum activity of the enzyme in brain homogenates when using either 5-HTP or DOPA as the substrate. cDNAs encoding AADC... 

Because AADC is not saturated with 5-HTP under physiological conditions, (i.e. the concentration of 5-HTP is much less than the enzyme s Km of 10pmol/l), it is possible to raise the content of 5-HT in brain not only by increasing the dietary intake of tryptophan but also by raising the intake of 5-HTP. This procedure, though,... 

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). 

As indicated earlier, a-methyldopa treatment of hypertension sometimes results in the appearance of parkinsonian symptoms. This is presumed to be a consequence of DA depletion by replacement of DA with the relatively inactive false transmitter a-methyldopamine, as well as by inhibition of AADC (Ch. 12). 

AADC aromatic L-amino acid decarboxylase BDZ benzodiazepine... 

AADC. See Aromatic amino acid decarboxyoiase a-Adrenoceptors, 112 density of cardiac, 113 subtypes of, 113... 

Neuroamines are biosynthesized in the central nervous system by decarboxylation of the corresponding amino acids by the amino acid decarboxylases (AADCs), which are present in nerve endings. In consequence, inhibition of the AADCs could be a means to regulate concentration in neuroamines. Research has been based on the hypothesis that a S-fluoromethylene amino acid could be used as a precursor of the inhibitor. If this fluorinated amino acid was a substrate for the AADC, it would then be transformed in situ into a S-fluoromethylene amine, which is an irreversible inhibitor of MAOs (Figure 7.54). ° ... 

Considering the important implications of L-dopa in Parkinson disease, studies have mainly been dedicated to tyrosine derivatives. The starting hypothesis has thus been verified /1-fluoromethylenetyrosines are not substrates of MAOs but are recognized by the AADC, and then decarboxylated into fluoroallyl amines. These latter are indeed inhibitors of MAO A and... 

AADC Amino acid decarboxyiase MAO Monoamine oxidase... 

Whilst the term biogenic amine strictly encompasses all amines of biological origin, for the purpose of this article it will be employed to refer to the catecholamine (dopamine, noradrenaline) and serotonin group of neurotransmitters. These neurotransmitters are generated from the amino acid precursors tyrosine and tryptophan, respectively, via the action of the tetrahydrobiopterin (BH4)-dependent tyrosine and tryptophan hydroxylases. Hydroxylation of the amino acid substrates leads to formation of 3,4-dihydroxy-l-phenylalanine ( -dopa) and 5-hydroxytryptophan, which are then decarboxylated via the pyridoxalphosphate-dependent aromatic amino acid decarboxylase (AADC) to yield dopamine and serotonin [4]. In noradrenergic neurones, dopamine is further metabolised to noradrenaline through the action of dopamine-jS-hydroxylase [1]. 

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