Aromatic amino acid decarboxylase AADC

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. 

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). 

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]. 

Fig. 6.2.2a-bc High-performance liquid chromatography (HPLC) with electrochemical (EC) detection of neurotransmitter metabolites, a standard mixture b cerebrospinal fluid (CSF) sample - control c CSF sample - aromatic amino acid decarboxylase (AADC) deficiency. Peak identification 1 = 5HIAA (7.7 min), 2 = 3-MD (9.6 min), 3 = HVA (11.7 min)... 

Another transmitter replacement approach involves improving the effectiveness of oral L-DOPA by supplying the DA depleted neostriatum with an overabundance of the enzyme-aromatic amino-acid decarboxylase (AADC). In principle, this would convert oral L-DOPA to DA more efficiently in the striatum. In cell culture, as well as rat and monkey models of PD, rAAV-delivered AADC has been shown to increase striatal DA production in response to systemic L-DOPA administration (Kang et al., 1993 Leff et al., 1999 Shen et al., 2000 Sanchez-Pernaute et al., 2001 Muramatsu et al., 2002). 

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).

Benserazide (BZ), 2-amino-3-hydroxy-A, -[(2,3,4-trihydroxyphenyl) methyl] propane hydrazide is an irreversible inhibitor of peripheral L-aromatic amino acid decarboxylase (AADC). The decarboxylase inhibitor drugs, e.g., carbidopa and benserazide, inhibit dopamine production outside the brain and permit direct deliveiy of dopamine (LD metabolite) to the brain. This synergistic therapy also minimizes the side effects such as nausea and vomiting induced by levodopa.1 2 Benserazide at the recommended therapeutic dose does not cross the blood-brain barrier to any significant degree. Synergistic effect of levodopa and benserazide reduces the required dose of levodopa for the optimal and earlier therapeutic response.3... 

Some neuroendocrine tumors overexpress the enzyme aromatic amino acid decarboxylase (AADC). This can be used to visualize the tumor and at the same time gain information about the type of tumor. In these tumors l-[P- C]DOPA is converted to [ C]dopamine, which is trapped in the tumor whereas L-[carboxylic- C]DOPA gives unlabeled dopamine and [ C]carbon dioxide. In O Fig. 41.34, the tumor is clearly visualized after administration of l-[P- C]DOPA indicating that AADC is overexpressed. Labeled carbon dioxide is washed out firom the tumor, which is demonstrated in the right image. 

The enzyme L-aromatic amino acid decarboxylase (AADC, EC 4.1.1.28) lacks substrate specificity and has been considered to be involved in the formation of the catecholamines and serotonin. There are many differences in the optimal conditions for enzyme activity, including kinetics, affinity for PLP, activation and inhibition by specific chemicals, and regional differences in the distribution of DOPA and 5-HTP decarboxylation activities. Nonparallel changes in brain monoamines in the vitamin Bg-deficient rat have been reported (7-9). Brain content of dopamine and norepinephrine were not decreased during deficiency, whereas serotonin was significantly decreased. 

Fig. 1.1. Biosynthesis and regeneration of tetrahydrobiopterin including possible metabolic defects and catabolism of phenylalanine. l.l=phenylalanine-4-hydroxylase (PAH) 1.2/1.6 = GTP cyclohydrolase I (GTPCH), 1.3 = 6-pyruvoyl-tetra-hydropterin synthase (PTPS), 1.4 = dihydropteridine reductase (DHPR), 1.5 = pterin-4a-carbinolamine dehydratase (PCD), 1.7 = sepiapterin reductase SR, carbonyl reductase (CR), aldose reductase (AR), dihydrofolate reductase (DHFR), aromatic amino acid decarboxylase (AADC), tyrosine hydroxylase (TH), tryptophan hydroxylase (TPH), nitric oxide synthase (NOS). Pathological metabolites used as specific markers in the differential diagnosis are marked in squares. n.e.=non-enzymatic...

The biosynthesis of other volatile phenyl-propanoid-related compoimds such as phenyla-cetaldehyde and 2-phenylethanol, does not occur via trans-cinnamic acid and competes with PAL for Phe utilization [90, 96, 97]. Phenylacetaldehyde biosynthesis from Phe requires the removal of both the carboxyl and amino groups. A classical sequential two-step removal is believed to occur in tomato where Phe was shown to be first converted to phe-nylethylamine by aromatic amino acid decarboxylase (AADC) and further required the action of a hypothesized amine oxidase, dehydrogenase, or transaminase for phenylacetaldehyde formation [97]. On the other hand, in petunia, one bifunctional enzyme, phenylacetaldehyde synthase (PAAS) catalyzes the unprecedented efficient coupling of Phe decarboxylation to oxidation resulting in... 

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. 

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. 

Table 6.2.2 Typical CSF profiles of HVA, 5HIAA and 3-methyldopa (3-MD) for the inborn errors of metabolism associated with a disruption of biogenic amine metabolism. A downward-pointing arrow indicates that a particular metabolite is below the established reference range. An upward pointing arrow is indicative that a metabolite is above the established reference range. WR indicates that the concentration of the metabolite is likely to be within the reference range. AADC Aromatic amino acid decarboxylase, PNPO pyridox(am)ine-5 -phosphate oxidase...

In the presence of the cofactor pyridoxyl phosphate, Dopa decarboxylase catalyzes the decarboxylation of L-dopa to dopamine. This enzyme has been shown to be the same protein as 5-hydroxytryptophan decarboxylase, and both are referred to by the name aromatic L-amino acid decarboxylase (AADC). 

The synthesis of serotonin from tryptophan is carried out in two steps controlled by two enzymes tryptophan hydroxylase (TPH) and aromatic L-amino acid decarboxylase (AADC). The second enzyme, A ADC, is also known as DOPA carboxylase or 5-hydroxytryptophan carboxylase when it acts specifically in 5-HT synthesis. In the first step, the TPH adds a hydroxyl chemical group (OH) to tryptophan to make 5-hydroxytryptophan, Fig (1). In the second step, AADC removes the carboxyl group (-COOH) from 5-hydroxy tryptophan to make serotonin. Fig (2). 

PEA is S5mthesized from phenylalanine by the enzyme aromatic L-amino acid decarboxylase (AADC). Accordingly, high phenylalanine levels in the... 

Described defects in biogenic amine metabolism include deficiencies of tyrosine hydroxylase (TH) (EC 1.14.16.2) [1, 2], aromatic L-amino acid decarboxylase (AADC) (EC 4.1.1.28) [3], dopamine jff-hydroxylase (DjffH) (EC 1.14.17.1) [4, 5] and monoamine oxidase (MAO) (EC 1.4.3.4). MAO deficiency has been described as an isolated defect of MAO-A [6] and as a deficiency of either MAO-A or MAO-B, or both, in association with Norrie disease [7]. Inheritance in all of these disorders is thought to be autosomal recessive. 

Aromatic L-amino acid decarboxylase (AADC) deficiency Brain, liver, kidney, peripheral neurons 7pl2,l-pl2,3 107930... 

Plant aromatic L-amino acid decarboxylases (AADCs) catalyze the initial reactions in the formation of terpenoid indole alkaloids (TIAs) such as quinine and strychnine, and benzyliso-quiuoline alkaloids (BIAs) such as morphine and codeine (Fig. 3). L-tryptophan decarboxylase (TDC) initiates TIA synthesis with the formation of tryptamine. TDC is encoded by two genes in Cola accuminata TDCl is expressed as part of a developmentally regulated chemical defense system, whereas TDC2 is induced after elicitation with yeast extract or methyl jas-monate (MI). 

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

Figure 9-1. Biosynthesis of catecholamines. Denotes enzyme in transformation AADC = aromatic L-amino acid decarboxylase COMT = catechol-o-methyl transferase DBH = dopamine-B-hydroxylase MAO = monoamine oxidase PNMT = phenylethanolamine-N-methyl transferase TH = tyrosine hydroxylase.

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