Disease relevance of Ddc

• By screening of an expression library derived from rat insulinoma cells, we have identified the 51-kDa protein as aromatic-L-amino-acid decarboxylase (EC 4.1.1.28) [1].
• The role of AADC in vivo will be assessed in future experiments involving animal models of Parkinson's disease [2].
• Suppression of L-dopa-induced circling in rats with nigral lesions by blockade of central dopa-decarboxylase: implications for mechanism of action of L-dopa in parkinsonism [3].
• In addition to the potential clinical benefit of improving decarboxylation efficiency in Parkinson's disease, our approach may be relevant for the treatment of AADC deficiency, a rare, autosomal recessive disorder causing a severe movement disorder and progressive cognitive impairment [4].
• L-DOPA (L-dihydroxyphenylalanine), which is metabolized to dopamine by dopa decarboxylase, is the primary therapy for PD, but may also contribute to disease progression [5].

Psychiatry related information on Ddc

• Inhibition of brain dopa-decarboxylase by RO 4-4602 infused ICV blocks alcohol drinking induced in rats by cyanamide [6].
• We attempted to clarify whether or not under inhibition of central dopa decarboxylase non-effective i.p. doses of L-dopa potentiate D2 receptor-mediated locomotor activities without conversion to dopamine in normal and i.v.t. 6-hydroxydopamine-treated rats [7].
• Pre-test epinephrine injections reverse DDC-induced retrograde amnesia [8].

High impact information on Ddc

• Suppression of noradrenaline synthesis in sympathetic nerves by carbidopa, an inhibitor of peripheral dopa decarboxylase [9].
• Neurons containing the enzyme aromatic-L-amino-acid decarboxylase (AADC) but lacking either tyrosine hydroxylase or serotonin were found in the spinal cord of neonatal and adult rats by light and electron microscopic immunocytochemistry [10].
• Thus, spinal AADC neurons have the enzymatic capacity to catalyze directly the conversion of the amino acids tyrosine, tryptophan, or phenylalanine to their respective amines tyramine, tryptamine, or phenylethylamine [10].
• Some neurons of the rat central nervous system contain aromatic-L-amino-acid decarboxylase but not monoamines [10].
• Additional specimens were incubated with 3H-5-HTP and carbidopa, an inhibitor of DOPA-decarboxylase, used to block the decarboxylation of 3H-5-HTP to 3H-5-HT, or with 3H-5-HT, used to determine where exogenous 3H-5-HT localizes in the pyloric mucosa [11].

Chemical compound and disease context of Ddc

• Role of aromatic L-amino acid decarboxylase for dopamine replacement by genetically modified fibroblasts in a rat model of Parkinson's disease [12].
• AADC mRNA from cultured astrocytes and C6 glioma cells was present as a single band, 2.2 kbp in size, that comigrated with the RNA from rat kidney [13].
• The results suggest that the stimulation of AADC mRNA by amantadine may be one of its effects on dopamine metabolism that may have relevance for potentiation of L-Dopa therapy in Parkinsonism [14].
• Aromatic L-amino acid decarboxylase, dopamine beta-hydroxylase, monoamine oxidase, malondialdehyde, and acid phosphatase in rat brain capillaries and kidney glomeruli in experimental hypertension [15].
• By microinjections into unilateral RVLM, L-DOPA (30-300 ng) produced dose-dependent hypertension and tachycardia similarly in rats untreated, treated with i.p. 3-hydroxybenzylhydrazine, a central DOPA decarboxylase inhibitor, or with i.v.t. 6-hydroxydopamine [16].

Biological context of Ddc

• Aromatic L-amino acid decarboxylase catalyzes the decarboxylation of L-5-hydroxytryptophan to serotonin and that of L-3,4-dihydroxyphenylalanine to dopamine [1].
• These data suggest that transcription initiating at distinct promoters, followed by alternative splicing, is responsible for the expression of the neuronal and nonneuronal forms of the AADC message [17].
• Circadian gene expression of AADC was observed with a peak at subjective day and a trough at subjective night [18].
• The circadian rhythm of AADC enzyme activity in the SCN reflects the expression of the gene [18].
• We have analyzed the expression of the nonneuronal promoter of the rat AADC gene in the kidney epithelial cell line LLC-PK1 and in cells which do not express the nonneuronal form of AADC by transient transfection [19].

Anatomical context of Ddc

• Circadian rhythm of aromatic L-amino acid decarboxylase in the rat suprachiasmatic nucleus: gene expression and decarboxylating activity in clock oscillating cells [18].
• RESULTS: AADC gene expression was observed in neurones of the dorsomedial subdivision of the SCN and its dorsal continuant in the anterior hypothalamic area [18].
• The rat peritoneal mast cell, on the other hand, had high histamine (17 pg/cell) and serotonin (0.6 pg/cell) contents but lesser amounts of soluble histidine decarboxylase and little DOPA-decarboxylase activity [20].
• To restore the capacity to produce and store dopamine in parkinsonian rats, primary skin fibroblast cells (PF) were genetically modified with aromatic L-amino acid decarboxylase (AADC) and VMAT-2 genes [21].
• Tissue-specific expression of the nonneuronal promoter of the aromatic L-amino acid decarboxylase gene is regulated by hepatocyte nuclear factor 1 [19].

Associations of Ddc with chemical compounds

• Aromatic L-amino acid decarboxylase (AADC, EC 4.1.1.28) catalyzes the decarboxylation of L-dopa to dopamine in catecholamine cells and 5-hydroxytryptophan to serotonin in serotonin-producing neurons [17].
• The parkinsonian neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) mediates release of l-3,4-dihydroxyphenylalanine (l-DOPA) and inhibition of l-DOPA decarboxylase in the rat striatum: a microdialysis study [22].
• AADC was co-expressed with vasopressin and the clock gene Per1 in the neurones of the SCN [18].
• BACKGROUND: Aromatic L-amino acid decarboxylase (AADC) is the enzyme responsible for the decarboxylation step in both the catecholamine and indoleamine synthetic pathways [18].
• Replacements of His192, Asp252, Asp271, Ser296, Lys303, Tyr332, and Arg355 with alanine residues decreased the AADC activity (kcat/K(m)) by more than 10(4)-fold [23].

Regulatory relationships of Ddc

• Specific irreversible monoamine oxidase B inhibitors stimulate gene expression of aromatic L-amino acid decarboxylase in PC12 cells [24].
• Tyrosine hydroxylase activity in the stalk-median eminence was determined from the in vitro or in vivo rate of 3,4-dihydroxyphenylalanine (DOPA) accumulation after inhibiting DOPA decarboxylase with brocresine or m-hydroxybenzylhydrazine, respectively [25].
• Injection of the central aromatic L-amino-acid decarboxylase inhibitor NSD-1015 30min before and 15min after the injection of L-DOPA suppressed the rotational behavior and the striatal induction of Fos [26].
• Effect of the dopa decarboxylase inhibitor MK-486 on L-dopa-induced inhibition of prolactin secretion: evidence for CNS participation in the L-dopa effects [27].

Other interactions of Ddc

• Postmortem changes in the activities of tyrosine hydroxylase, dopa decarboxylase, and dopamine-beta-hydroxylase were examined in various areas of rat brain [28].
• A delay of 2-3 days between the detection of the tyrosine hydroxylase and the aromatic L-amino-acid decarboxylase and dopamine beta-hydroxylase activities was observed [29].
• The addition of mesencephalic membrane fragments and striatal culture-conditioned media along with the cytokine mixture induced the expression of morphologically mature TH-ir cells that were also immunoreactive for dopa-decarboxylase, the DA transporter, and DA itself [30].
• In lactating and salt-loaded rats, magnocellular neurons were devoid of the catecholamine biosynthesis markers aromatic L-amino acid decarboxylase, L-3,4 dihydroxyphenylalanine, dopamine and GTP-cyclohydrolase I [31].
• Enzyme assays demonstrated that aromatic L-amino acid decarboxylase activity was unchanged in the gliotic striatum, but both MAO-A and MAO-B activities increased by 23% and 21%, respectively [32].

Analytical, diagnostic and therapeutic context of Ddc

• However, MPP(+) induced a transient, concentration-dependent rise of extracellular l-3,4-dihydroxyphenylalanine (l-DOPA), identified on the basis of dialysate analysis using several HPLC methods and its conversion to DA by purified l-DOPA decarboxylase (DDC) [22].
• Functionally important residues of aromatic L-amino acid decarboxylase probed by sequence alignment and site-directed mutagenesis [23].
• Molecular cloning and sequencing of a cDNA of rat dopa decarboxylase: partial amino acid homologies with other enzymes synthesizing catecholamines [33].
• Monoclonal antibodies (MAbs) directed against the major inducible isozymes of P-450 were used to probe Western blots of microsomal protein following DDC analogue treatment [34].
• Only rats with neutralizing antibody titers of 1:1208 +/- 332 had significantly decreased AADC transgene expression compared to the unimmunized control group [35].

References