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PubMed1990

Preparation of a human DOPA decarboxylase cDNA probe by PCR and its assignment to chromosome 7.

The reverse transcription of mRNA of a human pheochromocytoma using an oligonucleotide complementary to rat DOPA decarboxylase (DDC) sequence as a primer, gave rise to a single strand cDNA. This resultant cDNA permitted by PCR amplification the preparation and cloning in PUC 19 of a human DDC probe of 747 base pairs. The choice of primer was dictated by the presence of tryptophan codons in the DOPA decarboxylase sequence which were conserved in different species throughout evolution. The presence of mismatches on the primers was not an obstacle to a specific amplification and the probe sequence was found identical to the human DDC cDNA sequence. This probe, labelled by nick translation detected on Southern blot of human-rodent hybrids, bands on human DNA after EcoRI, BamHI or HindIII digestion. The results with EcoRI were explicit and drove to the conclusion that DDC is located on chromosome 7. Five bands were obtained on human DNA digested with EcoRI, indicating that either numerous introns could interrupt the coding sequence of DDC gene or duplicated sequences could be present in chromosome 7.

Base Sequence↗
PubMed1988

A cis-acting element and associated binding factor required for CNS expression of the Drosophila melanogaster dopa decarboxylase gene.

A cis-acting sequence from the Drosophila melanogaster dopa decarboxylase (Ddc) gene is selectively required for Ddc expression in the central nervous system. We analyze several parameters influencing the function of the sequence element and describe a factor which interacts with it and mediates CNS expression of Ddc. The element, element I, can function in vivo when included on a synthetic oligonucleotide inserted near its normal location, or closer to the RNA startpoint. It displays partial activity when inverted. Two different 2-bp mutations in element I abolish its ability to stimulate neuronal Ddc expression in the CNS. A factor present in embryonic nuclear extracts specifically protects element I in DNase I footprinting assays. The binding affinity of this factor is reduced by each alteration of element I that inhibits neuronal expression, indicating a role in mediating CNS expression of Ddc. Element I alone has no detectable activity when placed adjacent to a heterologous promoter, although 2.2 kb of 5' Ddc sequences direct correct cell-specific expression of a heterologous promoter.

Animals↗
PubMed1996

Mosquito dopa decarboxylase cDNA characterization and blood-meal-induced ovarian expression.

Dopa decarboxylase (DDC) functions in insect catecholamine biochemistry to produce materials essential for cross-linking reactions that result in tanning and/or melanization, include tanning of the mosquito egg chorion and encapsulation of parasites. We have cloned Ddc from the mosquito, Aedes aegypti, and studied its expression in response to blood-feeding, which initiates events necessary for egg maturation in mosquitoes. The Ae. aegypti Ddc cDNA was isolated via heterologous screening using a clone from Drosophila melanogaster. A resulting 1.87 kilobase (kb) clone was sequenced to reveal an open reading frame of 1464 bp, as well as 5'- and 3'-untranslated segments. The inferred amino acid sequence of this clone shares 81% identity with the published Drosophila Ddc cDNA, including complete identity with twenty-four contiguous amino acids encompassing the pyridoxal-5-phosphate cofactor binding domain. Analysis of an F2 intercross population derived from a parental cross between two Ae. aegypti strains (Hamburg and Moyo-In-Dry) allowed us to map Ddc to a locus on linkage group 2. Expression studies demonstrated the presence of a 2.1 kb message, the majority of which occurs in the ovaries where Ddc-specific mRNA is up-regulated in response to ingestion of a blood meal. The potential for egg-tanning in anautogenous mosquitoes as a model for understanding specific genetic events in the regulation of catecholamine metabolism is addressed.

Aedes↗
PubMed1986

Demonstration of immunohistochemical and immunochemical cross-reactivity of L-histidine and L-dopa decarboxylases using antibodies against the two enzymes.

Both rat L-histidine decarboxylase (HDC) and guinea-pig L-DOPA decarboxylase (DDC) were shown immunohistochemically and immunochemically to react with anti-rat HDC antibody. No cross-reaction was observed in immunoprecipitation experiments, but both anti-rat HDC antibody and anti-rat DDC antibody immunostained neurons in the substantia nigra, raphe nucleus and locus coeruleus of guinea-pig brain. Moreover, on immunoblotting, anti-rat HDC antibody recognized not only rat HDC but also guinea-pig DDC, but not rat DDC. However, anti-rat DDC antibody showed no immunohistochemical or immunochemical cross-reactivity with rat HDC.

Animals↗
PubMed1975

Isolation of isoflavones inhibiting DOPA decarboxylase from fungi and streptomyces.

By screening of culture filtrates of fungi and streptomyces for activity in inhibit dopa decarboxylase the following isoflavone compounds were obtained: psi-tectorigenen (I), genistein (II), orobol (IV), 8-hydroxygenistein (V) and a new compound (III). III was elucidated to be 3', 4', 5, 7-tetrahydroxy-8methoxy isoflavone. Among these isoflavones, IV and III showed the strongest activity in inhibiting dopa decarboxylase. All these isoflavones also inhibited histidine decarboxylase and catechol-O-methyltrasnferase. Activities of these compounds to inhibit tyrosine hydroxylase and dopamine beta-hydroxylase were examined. Orobol which showed no or only slight inhibition of tyrosine hydroxylase and dopamine beta-hydroxylase exhibited a significant hypotensive effect on spontaneously hypertensive rats.

Animals↗
PubMed1984

High levels of intron-containing RNAs are associated with expression of the Drosophila DOPA decarboxylase gene.

We have examined the structure and expression during embryonic development of the Drosophila DOPA decarboxylase gene, Ddc. The Ddc gene is transcribed to make at least five different size classes of RNA. These RNA species first appear late in embryogenesis, coincident with induction of Ddc enzyme activity. The most abundant and smallest RNA appears to be Ddc mRNA. The sequences encoding this RNA are split by two intervening sequences. Each of the larger RNA species contains some or all of the intervening sequences. We have noted two unusual features of Ddc expression during embryogenesis. First, the intervening-sequence-containing RNAs are present as 20% or more of the polyadenylated Ddc RNA molecules, an exceptionally high proportion. Second, these RNAs do not disappear as rapidly as Ddc mRNA after Ddc enzyme activity reaches fully induced levels. These observations indicate slow rates of RNA processing relative to mRNA half-life and suggest that post-transcriptional steps participate in regulating Ddc expression. Although four of the five RNA species were detected at multiple developmental stages during which Ddc is expressed, one was found uniquely during embryogenesis. This RNA differs from Ddc mRNA in length and in time of expression during embryogenesis but is transcribed in the same orientation and from the same genomic sequences as the Ddc primary transcript.

Animals↗
PubMed2000

Reaction of dopa decarboxylase with L-aromatic amino acids under aerobic and anaerobic conditions.

Analysis of the reaction of dopa decarboxylase (DDC) with L-dopa reveals that loss of decarboxylase activity with time is observed at enzyme concentrations approximately equal to the binding constant, K(d), of the enzyme for pyridoxal 5'-phosphate (PLP). Instead, at enzyme concentrations higher than K(d) the course of product formation proceeds linearly until complete consumption of the substrate. Evidence is provided that under both experimental conditions no pyridoxamine 5'-phosphate (PMP) is formed during the reaction and that dissociation of coenzyme occurs at low enzyme concentration, leading to the formation of a PLP-L-dopa Pictet-Spengler cyclic adduct. Taken together, these results indicate that decarboxylation-dependent transamination does not accompany the decarboxylation of L-dopa proposed previously [O'Leary and Baughn (1977) J. Biol. Chem. 252, 7168-7173]. Nevertheless, when the reaction of DDC with L-dopa is studied under anaerobic conditions at an enzyme concentration higher than K(d), we observe that (1) the enzyme is gradually inactivated and inactivation is associated with PMP formation and (2) the initial velocity of decarboxylation is approximately half of that in the presence of O(2). Similar behaviour is observed by comparing the reaction with L-5-hydroxytryptophan occurring in aerobiosis or in anaerobiosis. Therefore the reaction of DDC with L-aromatic amino acids seems to be under O(2) control. In contrast, the reactivity of the enzyme with L-aromatic amino acids does not change in the presence or absence of O(2). These and other results, together with previous results on the effect exerted by O(2) on reaction specificity of DDC towards aromatic amines [Bertoldi, Frigeri, Paci and Borri Voltattorni (1999) J. Biol. Chem. 274, 5514-5521], suggest a productive effect of O(2) on an intermediate complex of the reaction of the enzyme with L-aromatic amino acids or aromatic amines.

5-Hydroxytryptophan↗
PubMed1993

Measuring L-dopa in plasma and urine to monitor therapy of elderly patients with Parkinson disease treated with L-dopa and a dopa decarboxylase inhibitor.

We have established a method for measuring L-dopa in plasma and urine, including the metabolites dopamine and L-dopac, using separation by ion-pair reversed-phase HPLC and quantification with an electrochemical detector. The assay was applied to the therapeutic monitoring of elderly patients with established Parkinson disease being treated with L-dopa plus a dopa decarboxylase inhibitor. Plasma L-dopa was evaluated in relation to dosage and postdose sampling time in 71 outpatients with Parkinson disease. L-Dopa concentrations were greatest in the patients taking the highest dosages prescribed and decreased significantly with increasing time after postdose sampling. Comparison of plasma L-dopa concentrations with a published therapeutic range established by intravenous administration of L-dopa was helpful in assessing the suitability of each patient's drug dosage, assessing patients' compliance, and avoiding overdosage but was not useful in the overall clinical assessment of progression of disease or of the long-term therapeutic response. Urine measurements confirmed the plasma concentrations but showed no further advantage. The recommended time for sample collection is between 1.5 and 3 h after the first morning dose. Plasma is the preferred matrix but if blood sampling is difficult, particularly from elderly/infirm individuals, an untimed urine collection could be used.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Mapping of the dopa decarboxylase gene to the 11A band of the murine genome.

A human DOPA decarboxylase (DDC) cDNA probe of 747 base pairs has been used to map the DDC gene by in situ hybridization on mouse metaphase chromosomes. This result indicates that the gene is located on band 11A, near the erythroblastosis oncogene B (erb b) locus. This provides evidence for a synteny group on mouse chromosome 11 and human chromosome 7.

Animals↗
PubMed1987

Regulation of the Drosophila dopa decarboxylase gene in neuronal and glial cells.

A cis-regulatory element selectively required for the Drosophila melanogaster dopa decarboxylase gene (Ddc) in the central nervous system has been identified previously (Scholnick et al. 1986). Here, we show that at least one additional regulatory element is required for normal neuronal expression of Ddc. We find that Ddc is normally expressed in about 125 discrete neurons and in a diffused network comprising a subset of glial cells. The expression of in vitro-altered Ddc genes was studied by immunohistochemistry following germ line reintegration with P-element vectors. Normal neuron-specific Ddc gene expression requires both the initially identified element (element I) which is 60 bp upstream from the RNA start site, and an additional regulatory element located 800-2200 bp upstream. This latter element is required for neuronal expression but is not necessary for glial expression of Ddc. We provide a model to explain how interactions between multiple regulatory elements may serve to specify cell-specific gene expression.

Animals↗
PubMed1985

Hormonal regulation of dopa decarboxylase during a larval molt.

Cuticular sclerotization in insects requires dopamine derivatives and thus the presence of dopa decarboxylase (DDC), the enzyme which converts dopa to dopamine. During the last half of the larval molt of the tobacco hornworm, Manduca sexta, beginning at 16 hr after head capsule slippage, the epidermal DDC activity increased fourfold. By contrast, allatectomized larvae which were destined to produce a melanized cuticle showed a sevenfold increase. This increase in DDC activity was prevented by infusion of 20-hydroxyecdysone (20HE) into the larva, indicating that the fall of the ecdysteroid titer is necessary for the increase. In vitro 20HE also prevented the increase in a dose-dependent manner when the epidermis was explanted at 16 hr after head capsule slippage but had less effect on epidermis explanted 3 hr later. Both 5 micrograms/ml alpha-amanitin and 100 micrograms/ml cycloheximide also prevented the increase. Application of juvenile hormone I showed that the critical period for determination of the level of the later increase in DDC activity was about 4 hr after head capsule slippage at the peak of the ecdysteroid titer. Apparently then the rise and fall of ecdysteroid regulate different aspects of DDC synthesis, the rise determining its later appearance and the fall timing this appearance.

Animals↗
PubMed1995

Characterization of the dopa decarboxylase gene of Manduca sexta and its suppression by 20-hydroxyecdysone.

Manduca dopa decarboxylase (DDC) cDNA was isolated, sequenced, and found to be most closely related to Drosophila DDC (72% amino acid identity). Culture of Day 2 fourth instar larval epidermis with 20-hydroxyecdysone (20E) showed that 20E was necessary to determine the later expression of the gene, but its removal was required for this expression to occur. Experiments with the protein synthesis inhibitors, cycloheximide and anisomycin, and the mRNA synthesis inhibitor, alpha-amanitin, showed that 20E induced a protein(s) which suppressed transcription of the DDC gene. Gel mobility shift assays using epidermal extracts and various fragments of the first 1.1 kb of the 5' flanking region of the DDC gene showed only one DNA fragment 87 to 167 bp upstream of the 5' initiation site that bound a nuclear protein(s) with the expected developmental specificity. The protein was abundant at the time of high ecdysteroid titer when no DDC mRNA was present, but low both before the rise (no DDC mRNA) and after the decline of ecdysteroid titer (maximal DDC mRNA). Thus, this protein(s) is a candidate for an ecdysteroid-induced transcription factor which acts to suppress DDC transcription. DNase I footprinting assays confirmed by use of a specific oligonucleotide showed that this protein(s) bound to the sequence 5'-GGCTTATGCGCTGCA-3'.

Amino Acid Sequence↗
PubMed1986

Dopaminergic and noradrenergic sympathetic nerves of the dog have different DOPA decarboxylase activities.

We have compared the pattern of neural catecholamine fluorescence with that of immunoreactivity for the catecholamine-synthesizing enzymes tyrosine hydroxylase (TH) and DOPA decarboxylase (DDC) in dog atrium, which is innervated by noradrenergic nerves, and in dog kidney, which is thought to be supplied by dopaminergic nerves as well. In both tissues the distribution of nerves containing catecholamine fluorescence was similar to that of nerves exhibiting TH-like immunoreactivity. By contrast, DDC-like immunoreactivity was present in some (but not all) of the nerves associated with the intrarenal blood vessels, but was not detectable in any atrial nerves. High DDC activity provides further confirmation of the existence of sympathetic dopaminergic neurons supplying the kidney.

Animals↗
PubMed1989

Molecular genetics of dopa decarboxylase and biogenic amines in Drosophila.

The gene Ddc encodes two isoforms of the enzyme dopa decarboxylase in Drosophila. These gene products catalyze the final steps in the synthesis of the biogenic amines serotonin and dopamine. This article summarizes recent progress in understanding the tissue- and cell-specific regulation of Ddc, which occurs at both the transcription and alternate splicing levels. In addition, results that are pertinent to understanding the roles of biogenic amines in the neurophysiology of Drosophila are discussed.

Animals↗
PubMed1989

Effect of vitamin B-6 nutrition on the levels of dopamine, dopamine metabolites, dopa decarboxylase activity, tyrosine, and GABA in the developing rat corpus striatum.

Evidence presented in this manuscript indicates that prenatal and postnatal vitamin B-6 undernutrition produces the loss of dopamine (DA) in the corpus striatum of the developing rat brain. The concentration of striatal DA in rats fed vitamin B-6 inadequate diets was significantly lower than rats fed optimal diets at 28 and 56 days of age. The differences in striatal DA concentrations among vitamin B-6 dietary groups was more evident with age. Measurements of the major metabolites of DA, homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) in rat corpus striatum showed a significant decrease in HVA level in B-6 restricted rats compared to B-6 sufficient groups. Striatal DOPAC levels were not significantly different among any of the groups at any age. The activity of dopa decarboxylase holoenzyme was found to be significantly lower in the corpus striatum of rats fed suboptimal B-6 diets. Whether this finding has a significant effect on DA levels has yet to be determined since dopa decarboxylase is not the rate-limiting enzyme in the synthesis of DA. In an effort to determine the underlying mechanism for the loss of striatal DA, the concentration of its precursor tyrosine (TYR) was measured. Vitamin B-6 undernutrition had no significant effect on the levels of TYR in rat corpus striatum. The concentration of the inhibitory neurotransmitter GABA was also measured. The results indicate that as expected the levels of striatal GABA were significantly lower than controls at 14 and 28 days of age. On the other hand, striatal GABA levels in B-6 restricted rats did not differ from controls at 56 days of age.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1995

Regulation of DOPA decarboxylase activity in brain of living rat.

To test the hypothesis that L-DOPA decarboxylase (DDC) is a regulated enzyme in the synthesis of dopamine (DA), we developed a model of the cerebral uptake and metabolism of [3H]DOPA. The unidirectional blood-brain clearance of [3H]DOPA (K1D) was 0.049 ml g-1 min-1. The relative DDC activity (k3D) was 0.26 min-1 in striatum, 0.04 min-1 in hypothalamus, and 0.02 min-1 in hippocampus. In striatum, 3,4-[3H]dihydroxyphenylacetic acid ([3H]DOPAC) was formed from [3H]DA with a rate constant of 0.013 min-1, [3H]homovanillic acid ([3H]HVA) was formed from [3H]DOPAC at a rate constant of 0.020 min-1, and [3H]HVA was eliminated from brain at a rate constant of 0.037 min-1. Together, these rate constants predicted the ratios of endogenous DOPAC and HVA to DA in rat striatum. Pargyline, an inhibitor of DA catabolism, substantially reduced the contrast between striatum and cortex, in comparison with the contrast seen in autoradiograms of control rats. At 30 min and at 4 h after pargyline, k3D was reduced by 50% in striatum and olfactory tubercle but was unaffected in hypothalamus, indicating that DDC activity is reduced in specific brain regions after monoamine oxidase inhibition. Thus, DDC activity may be a regulated step in the synthesis of DA.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

[Genetic analysis of differences in dopa decarboxylase activity between two Drosophila virilis lines differing in dopamine content].

Activity of dopa decarboxylase (DDC) in two Drosophila virilis lines differing in dopamine (DA) content was investigated. The activity was shown to be significantly higher in flies with lower DA content. A possible reason for this phenomenon is discussed. Genetic analysis of the difference showed that DDC activity in Drosophila virilis is controlled by single autosomal gene (or a cluster of tightly linked genes).

Animals↗