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PubMed1995

3,4-dihydroxyphenylalanine (DOPA) decarboxylase deficiency and resultant high levels of plasma DOPA and dopamine in unfavorable neuroblastoma.

Neuroblastoma (NB) is a tumor which arises from neural crest cells. In the developing neural crest cells, the induction of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase is more delayed than that of tyrosine hydroxylase and dopamine-beta-hydroxylase. If NB cells are arrested in an early stage of neural crest development, the induction of DOPA decarboxylase is insufficient and the accumulation and secretion of DOPA can be caused. The biochemically immature phenotype is thought to represent the undifferentiated characteristics of the cells and might correlate with the grade of malignancy. To investigate whether the hypothesis is clinically applicable or not, we have measured plasma DOPA, dopamine and urinary catecholamine metabolites in NB patients. The levels of plasma DOPA, dopamine, urinary homovanillic acid (HVA) and vanillactic acid (VLA) were significantly higher in patients with unfavorable NBs and the higher plasma DOPA level was significantly associated with the patients' age (> 1 year old), tumor stage (III, IV) and DNA diploidy. Serial determination of plasma DOPA was a good monitor of the disease course. These results are compatible with the hypothesis on DOPA decarboxylase deficiency and DOPA secretion in undifferentiated, unfavorable NBs. In conclusion, the plasma DOPA can be used to predict patients' prognosis as well as to follow up patients with NB.

Biomarkers, Tumor↗
PubMed2003

Cloning and expression of human placental L-Dopa decarboxylase.

L-Dopa decarboxylase (DDC) is a pyridoxal 5-phosphate (PLP)-dependent enzyme that catalyses the decarboxylation of L-Dopa to dopamine. In this study we show the expression of DDC in human placental tissue and present data on the molecular cloning and in vitro expression of the active recombinant enzyme. Our analyses indicated the presence of both alternative DDC mRNA splice variants (neuronal and nonneuronal) in human placenta. Cloning of the coding region of the DDC cDNA into the pTrcHisA expression vector led to the production of the enzymatically active recombinant protein. The obtained recombinant enzyme specific activity values were in good agreement with the results obtained for the purified enzyme from human kidney. The availability of active recombinant human DDC could provide information leading to the better understanding of the enzyme's structure and substrate specificity, as well as its regulation and involvement in pathological conditions.

5' Untranslated Regions↗
PubMed1986

A kinetic analysis of Drosophila melanogaster dopa decarboxylase.

The kinetic mechanism of dopa decarboxylase (3,4-dihydroxy-L-phenylalanine carboxy-lyase, EC 4.1.1.28) was investigated in Drosophila melanogaster. Based on initial velocity and product inhibition studies, an ordered reaction is proposed for dopa decarboxylase. This kinetic mechanism is interpreted in the context of measured enzyme activities and the catecholamine pools in Drosophila. The 1(2)amd gene is immediately adjacent to the gene coding for dopa decarboxylase (Ddc) and determines hypersensitivity to alpha-methyldopa in Drosophila. Dopa decarboxylase does not decarboxylate alpha-methyldopa and hence does not generate a toxic product capable of inhibiting 1(2)amd gene function. We propose that the 1(2)amd gene is involved with an unknown catecholamine pathway involving dopa but not dopamine.

Animals↗
PubMed1983

Effects of dibutyryl cyclic adenosine 3':5'-monophosphate on the growth of cultured human small-cell lung carcinoma and the specific cellular activity of L-dopa decarboxylase.

High activity of L-dopa decarboxylase separates small (oat)-cell from non-small-cell lung cancer in cell culture. The present study investigates relationships between the specific cellular activity of this enzyme and: (a) cell growth kinetics of an established line (O-H-1) of human small cell lung carcinoma, and (b) responses of these cells to treatment with cyclic adenosine 3':5'-monophosphate and sodium butyrate. The O-H-1 cells, as for most other established small-cell lines, grow as suspended cell aggregates. During growth, the specific cellular activity of L-dopa decarboxylase parallels levels for [3H]thymidine labeling index and the ratio of cells in G2-M to those in G1-G0 phases of the cell cycle. Each of these parameters is 2- to 3-fold higher during exponential versus stationary growth. Continuous treatment with dibutyryl cyclic adenosine 3':5'-monophosphate (dcAMP; 0.1 or 1 mM) and 1 mM theophylline produces simultaneous cessation of cell growth and an increase in cellular L-dopa decarboxylase activity. During this period, analyses of DNA histograms reveal an increase in the number of cells in the G2-M phase; the rate of increase in the ratio of G2-M to G1-Go cells paralleled the rate of increase in specific activity of the enzyme. The effects of the dcAMP were promptly reversible; release of the apparent G2-M block preceded regrowth of the cells and was accompanied by a return of L-dopa decarboxylase activity to base-line levels. The changes in enzyme activity were specific for cyclic adenosine 3':5'-monophosphate; another cyclic adenosine 3':5'-monophosphate analogue, 8-bromo adenosine cyclic 3':5'-monophosphate yielded similar increases in L-dopa decarboxylase to those seen with dcAMP, while 0.01 to 1 mM butyrate alone produced the inhibition of cell growth but no changes in specific activity of L-dopa decarboxylase or percentage of cells in the different phases of the cell cycle. We conclude that the specific activity of L-dopa decarboxylase, a key neuroendocrine marker for cultured small-cell lung carcinoma, is highest during proliferative growth and/or when these cells are in the G2M phase of the cell cycle. The differential effects of dcAMP and sodium butyrate offer potential for exploring neuroendocrine differentiation in this important lung cancer and related endocrine neoplasms.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed1987

Some aspects on L-dopa decarboxylase and p-tyrosine decarboxylase in the central nervous and peripheral tissues of the American cockroach Periplaneta americana.

1. Aromatic amino acid decarboxylase activities toward L-DOPA (L-3,4-dihydroxyphenylalanine), 5-HTP (5-hydroxytryptophan) and p-tyrosine in different tissues of the sclerotized and newly ecdysed cockroach were analyzed. 2. The ratios of enzyme activity with regard to L-DOPA and p-tyrosine varied considerably in the tissues and between the two different growth stages. 3. A DOPA decarboxylase and a p-tyrosine decarboxylase were separated by gel filtration and ion exchange chromatography. 4. The optimal pH requirement for both enzymes was 7.5 with the exception of the one decarboxylating 5-HTP. 5. The molecular weights of the cockroach brain DOPA decarboxylase and tyrosine decarboxylase were estimated to be 120,000 and 100,000, respectively. 6. Unlike the mammalian aromatic amino acid decarboxylase, the cockroach DOPA decarboxylase cannot be activated by a small amount of benzene. 7. An increase of over 50-fold of DOPA decarboxylase activity and a 50% reduction of tyrosine decarboxylase activity in the epidermal tissue of the newly ecdysed animals was observed. 8. In the fully sclerotized cockroach, a reversible endogenous inhibitor(s) of DOPA decarboxylase in the integument was observed, suggesting that the DOPA decarboxylase is suppressed in the epidermal tissues when ecdysis does not occur.

Animals↗
PubMed1971

Decrease of the 3,4-dihydroxyphenylalanine (DOPA) decarboxylase activities in human erythrocytes and mouse tissues after administration of DOPA.

Human erythrocytes have been found to contain appreciable amounts of DOPA decarboxylase (EC 4.1.1.26) activity. The enzyme activity in erythrocytes from patients with Parkinson's disease who were treated with DOPA was significantly lower than that of untreated patients and of normal individuals. Administration of the drug to mice led to a marked decrease of DOPA decarboxylase in liver and kidney, but not of the brain enzyme. The findings thus indicate that administration of DOPA leads to a decrease in peripheral DOPA decarboxylase, an effect that is expected to be of benefit in DOPA therapy of patients with Parkinson's disease. Peripheral DOPA decarboxylase concentration also decreases in mice after short periods of fasting; the findings suggest that the peripheral enzyme activities may be affected by various nutritional and perhaps hormonal influences, which may be partially responsible for the observed fluctuations in the motor abilities of Parkinsonian patients receiving constant doses of the drug. Study of DOPA decarboxylase activity in erythrocytes may be useful in following changes in patients receiving DOPA therapy and may also be of general interest and value in investigations of catecholamine metabolism in man.

Age Factors↗
PubMed1985

Immunohistochemical analysis of the cross-reaction of anti-rat histidine decarboxylase antibody with guinea-pig DOPA decarboxylase.

L-Histidine decarboxylase [L-histidine carboxylyase, HDC, EC 4.1.1.22] is an enzyme distinct from L-DOPA decarboxylase [L-aromatic amino acid carboxylyase, DDC, EC 4.1.1.28]: the two decarboxylases from fetal rat liver were completely separated from each other by DEAE-cellulose column chromatography and by affinity chromatography with L-carnosine as a ligand. The antibody raised against this HDC inhibited the HDC's from rat and guinea-pig brains very strongly, but their DDCs very weakly. However, in immunofluorescent histochemical studies, the antibody cross-reacted with DDC-like immunoreactive structures, such as chromaffin cells of the adrenal medulla, the raphe nucleus, the substantia nigra, and the locus coeruleus of the brain of guinea-pigs, but not of rats, suggesting that these two decarboxylases share some antigenic structures.

Adrenal Medulla↗
PubMed1990

Purification and characterization of L-dopa decarboxylase from human kidney.

L-dopa decarboxylase has been purified to homogeneity from post mortem removed human kidneys. Homogeneity was examined by polyacrylamide gel electrophoresis (PAGE) analysis both in the presence and absence of SDS. The enzyme has a molecular weight of 100,000 daltons estimated by gel filtration and 50,000 daltons determined after SDS-PAGE. Human L-dopa decarboxylase therefore is a dimer. Polyclonal antibodies produced against human L-dopa decarboxylase react with the 50,000 daltons enzyme subunit after immuno-blotting and also precipitates enzyme activity. Activity against L-dopa is partially inhibited by 5-hydroxytryptophan (5-HTP). The effect of various cations on L-dopa decarboxylase activity has also been tested.

Adolescent↗
PubMed1994

Increase in plasma 3,4-dihydroxyphenylalanine (DOPA) appearance rate after inhibition of DOPA decarboxylase in humans.

Concentrations of DOPA in plasma are relatively high as compared to norepinephrine. The significance of plasma DOPA has not been elucidated. One would expect that substantial amounts of DOPA are derived from sympathetic nerves. There appears, however, neither to be a depot of DOPA in nerves nor is there a close correlation between plasma DOPA and sympathetic activity. The aim of the present study was to obtain further information about plasma DOPA by studying DOPA kinetics in healthy humans both with and without inhibition of DOPA decarboxylase by benserazide. Plasma DOPA and other catecholamines were measured by reverse-phase HPLC with electrochemical detection and DOPA clearance and appearance rate were studied using infusion of 3H-DOPA. The plasma clearance of DOPA was 1.02 1 min-1. Approximately 20% of this value could be explained by DOPA being decarboxylated in the kidneys and excreted as dopamine. The DOPA appearance rate was 1.13 micrograms min-1 and the extremities accounted for approximately 1/5 of this value. After inhibition of DOPA decarboxylase by benserazide the DOPA appearance rate increased 7-fold, whereas the DOPA clearance only decreased slightly and insignificantly. These findings are probably explained by two factors: (1) There is normally a large production of DOPA in some tissues from which DOPA spillover into plasma only occurs to a minor extent and tracer DOPA only mixes with this compartments to a small degree; (2) These compartments are permeable to benserazide, which blocks the decarboxylation of DOPA, which then leaves the tissues and spillover to plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Use of radiolabeled monofluoromethyl-Dopa to define the subunit structure of human L-Dopa decarboxylase.

Human L-Dopa decarboxylase (L-aromatic amino acid decarboxylase, DDC) has been purified from pheochromocytoma tissue, a benign tumor of the catecholamine-synthesizing cells of the adrenal medulla. The binding characteristics of a new radiolabeled enzyme-activated suicide inhibitor of DDC ( [3H]monofluoromethyl-Dopa, [3H]MFMD) have been established, and the covalent linkage of the inhibitor to the enzyme has been used to identify that human DDC exists as a dimer of a 50-kDa subunit. An antibody to human DDC identically precipitates the enzyme activity from different human, rat, and mouse tissues. Our data demonstrate the value of [3H]MFMD for probing the structure of DDC and facilitating the purification of this enzyme, and further emphasize the high degree of conservation of the DDC molecule over a wide variety of species.

Animals↗
PubMed1990

Purification of dopa decarboxylase from bovine striatum.

Pyridoxal phosphate-dependent DOPA decarboxylase has been purified from bovine striatum to a specific activity of 1.6 U/mg protein. After ammonium sulfate precipitation (30-60%) it was purified by DEAE-Sephacel, Sephacryl S-200, and TSK Phenyl 5 PW chromatography. The purified enzyme showed a single silver straining band with polyacrylamide gel electrophoresis under both denaturing and non-denaturing conditions. The bovine striatal DOPA decarboxylase is a dimer (subunit Mr = 56,000 by SDS-PAGE) with a native Mr of 106,000 as judged by chromatography on Sephacryl S-200 and by sedimentation analysis. Similar to the DOPA decarboxylase purified from non-CNS tissues, the bovine striatal enzyme requires free sulfhydryl groups for activity, is strongly inhibited by heavy metal ions, and can decarboxylate 5-hydroxytryptophan as well. It should be noted, however, that the final enzyme preparation is enriched in DOPA decarboxylase activity. The distribution of the DOPA decarboxylase and 5-HTP decarboxylase activities also varies among several bovine brain regions. In addition, heat treatment of the enzyme preparation inactivated the two decarboxylation activities at different rates.

5-Hydroxytryptophan↗
PubMed1980

Induction of translatable mRNA for dopa decarboxylase in Drosophila: an early response to ecdysterone.

Ecdysteroid titer and dopa decarboxylase (aromatic-L-amino-acid carboxy-lyase, EC 4.1.1.28) activity were determined throughout the life cycle of Drosophila melanogaster. Five peaks in the amount of hormone were observed, which preceeded five dopa decarboxylase peaks by times ranging from 5 to 58 hr. Late in the third instar the hormone and enzyme maxima are nearly coincident. The increase in enzyme activity observed at this time is paralleled by an increase in translatable dopa decarboxylase mRNA. To obtain evidence that ecdysterone induces the appearance of this mRNA we made use of the temperature-sensitive ecd1 mutant. Garen et al. [Garen, A., Kauvar, L. & Lepesant, J.-A. (1977) Proc. Natl, Acad. Sci. USA 74, 5099-5103] have shown that when third instar mutant larvae are kept at 29 degrees C, the ecdysteroid titer remains low. In such larvae we show that the normal increase in dopa decarboxylase activity fails to appear, and no translatable dopa decarboxylase mRNA can be detected. Exogenous feeding of ecdysterone to these larvae results in a rapid synthesis of dopa decarboxylase in the epidermal cells. In addition, a parallel increase in translatable dopa decarboxylase mRNA occurs, which may be a primary response of these target cells to ecdysterone.

Animals↗
PubMed1987

Developmental expression and spatial distribution of dopa decarboxylase in Drosophila.

Regulation of the dopa decarboxylase gene of Drosophila has been studied at the genetic and molecular levels. Here we report a direct assay for the tissue and temporal regulation of Ddc. A dopa decarboxylase (DDC) peptide was obtained by bacterial expression of a portion of the DDC gene in a pUC plasmid. Antisera raised against this biologically purified DDC peptide react specifically with Drosophila DDC in histological preparations and protein blots. The levels of DDC cross-reacting material closely parallel the levels of enzyme activity observed during development, indicating that DDC is degraded during periods of declining activity. We find that DDC is expressed in only two tissues, namely, the epidermis and the nervous system of the larva and adult. Epidermal DDC was found within the epidermal cells and was not detected in the overlying cuticle. DDC-containing neurons were observed in the central as well as in the visceral nervous system. Paired and unpaired midline neurons in the ventral ganglia are arranged in a segmental pattern. A subset of the DDC-positive neurons appears to correlate with the serotonin-positive neurons suggesting that the others are producing only dopamine. We find that the DDC activity associated with the proventriculus and ovary is due to the presence of DDC in the stomatogastric and caudal system neurons specifically associated with those structures.

Animals↗
PubMed2005

A quinonoid is an intermediate of oxidative deamination reaction catalyzed by Dopa decarboxylase.

The reactions of Dopa decarboxylase (DDC) with l- and d-enantiomers of tryptophan methyl ester are described. Although both the enantiomers bind to the active site of the enzyme with similar affinity, their binding modes are different. l-enantiomer binds in an unproductive mode, while d-enantiomer acts as an oxidative deamination substrate. For the first time a quinonoid has been detected as intermediate of this reaction. By using rapid-scanning stopped-flow kinetic technique rate constants for formation and decay of this species have been determined. All these data, besides validating the functional DDC active site model, represent an important step toward the elucidation of the catalytic pathway of oxidative deamination.

Animals↗
PubMed2004

Identification and characterization of a novel form of the human L-dopa decarboxylase mRNA.

L-Dopa decarboxylase (DDC) has been cloned from several species and was shown to undergo alternative splicing within its 5'-untranslated and coding regions. In this report, we describe a novel splice variant of DDC mRNA in human tissue, lacking exons 10-15 of the full-length transcript but including an alternative exon 10. The isolated alternative human DDC cDNA (alt-DDC) was cloned from human placenta, and was found to be of the neuronal type. Northern blot analysis indicated that the alt-DDC transcript is expressed in high levels in human kidney. Our results demonstrate the detection of a new alternative splicing event within the coding region of the human DDC mRNA, further suggesting that the single copy human DDC gene undergoes complex processing leading to the formation of multiple mRNA isoforms.

Alternative Splicing↗
PubMed1994

cis-regulatory sequences responsible for alternative splicing of the Drosophila dopa decarboxylase gene.

The Drosophila dopa decarboxylase gene, Ddc, is expressed in the hypoderm and in specific sets of cells in the central nervous system (CNS). The unique Ddc primary transcript is alternatively spliced in these two tissues. The Ddc CNS mRNA contains all four exons (A through D), whereas the hypodermal mRNA contains only three exons (A, C, and D). To localize cis-regulatory sequences responsible for Ddc alternative splicing, a Ddc minigene and several fusion genes containing various amounts of Ddc sequences fused to fushi tarazu (ftz) exon 1 were constructed and introduced into flies by P-element-mediated germ line transformation. We find that Ddc intron ab and exon B are sufficient to regulate Ddc alternative splicing, since transcripts of a minimal fusion gene containing most of Ddc intron ab and exon B are spliced to exon B in the CNS but not in the hypoderm. These results indicate that Ddc alternative splicing is regulated by either a negative mechanism preventing splicing to exon B in the hypoderm or a positive mechanism activating splicing to exon B in the CNS. Our previous data suggest that Ddc hypodermal splicing is the actively regulated splicing pathway (J. Shen, C. J. Beall, and J. Hirsh, Mol. Cell. Biol. 13:4549-4555, 1993). Here we show that deletion of Ddc intron ab sequences selectively disrupts hypodermal splicing specificity. These results support a model in which Ddc alternative splicing is negatively regulated by a blockage mechanism preventing splicing to exon B in the hypoderm.

Alternative Splicing↗