Aromatic L-amino acid decarboxylase AADC

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. 

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.

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]. 

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). 

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...

---