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PubMed1992

The zfh-2 gene product is a potential regulator of neuron-specific dopa decarboxylase gene expression in Drosophila.

We have studied a 40-bp upstream regulatory region of the DOPA decarboxylase gene (Ddc) which is important for cell-specific expression in the Drosophila central nervous system (CNS). This region contains two redundant elements which when simultaneously mutated result in lowered DDC expression in serotonin neurons. We uncovered a protein binding site within one of these elements and have cloned a factor which binds to the site. This factor is the product of the zfh-2 gene, a complex homeodomain/zinc finger protein previously identified by binding to an opsin regulatory element. The in vivo profile of ZFH-2 in the larval CNS shows intriguing overlap with DDC in specific serotonin and dopamine neurons. We show that ZFH-2 is related to a human transcription factor ATBF1. The multiple homeodomain and zinc finger motifs in these two proteins show a similar linear arrangement which implies coordinate action among the motifs. In addition, the homology defines a new homeodomain subtype.

Amino Acid Sequence↗
PubMed1999

On the evolution of Dopa decarboxylase (Ddc) and Drosophila systematics.

We have sequenced most of the coding region of the gene Dopa decarboxylase (Ddc) in 24 fruitfly species. The Ddc gene is quite informative about Drosophila phylogeny. Several outstanding issues in Drosophila phylogeny are resolved by analysis of the Ddc sequences alone or in combination with three other genes, Sod, Adh, and Gpdh. The three species groups, melanogaster, obscura, and willistoni, are each monophyletic and all three combined form a monophyletic group, which corresponds to the subgenus Sophophora. The Sophophora subgenus is the sister group to all other Drosophila subgenera (including some named genera, previously considered outside the Drosophila genus, namely, Scaptomyza and Zaprionus, which are therefore downgraded to the category of subgenus). The Hawaiian Drosophila and Scaptomyza are a monophyletic group, which is the sister clade to the virilis and repleta groups of the subgenus Drosophila. The subgenus Drosophila appears to be paraphyletic, although this is not definitely resolved. The two genera Scaptodrosophila and Chymomyza are older than the genus Drosophila. The data favor the hypothesis that Chymomyza is older than Scaptodrosophila, although this issue is not definitely resolved. Molecular evolution is erratic. The rates of nucleotide substitution in 3rd codon position relative to positions 1 + 2 vary from one species lineage to another and from gene to gene.

Animals↗
PubMed2002

Control of Dopa decarboxylase gene expression by the Broad-Complex during metamorphosis in Drosophila.

The induction of the Dopa decarboxylase gene (Ddc) in the epidermis of Drosophila at pupariation is a receptor-mediated response to the steroid molting hormone, ecdysone. Activity is also dependent on the Broad-Complex (BR-C), an early ecdysone response gene that functions during metamorphosis. BR-C encodes a family of zinc-finger protein isoforms, BR-C(Z1-Z4). Genetic experiments have shown that the Z2 isoform is required for epidermal Ddc to reach maximum expression at pupariation. In this paper, we report that BR-C regulates Ddc expression at two different developmental stages through two different cis-acting regions. At pupariation, BR-C acts synergistically with the ecdysone receptor to up-regulate Ddc. DNase I foot printing has identified four binding sites of the predominant Z2 isoform within a distal regulatory element that is required for maximal Ddc activity. The sites share a conserved core sequence with a set of BR-C sites that had been mapped previously to within the first Ddc intron. Using variously deleted Ddc genomic regions to drive reporter gene expression in transgenic organisms, we show that the intronic binding sites are required for Ddc expression at eclosion. At both pupariation and eclosion, BR-C releases Ddc from an active silencing mechanism, operating through two distinct cis-acting regions of the Ddc genomic domain at these stages. Transgenes, bearing a Ddc fragment from which one of the cis-acting silencers has been deleted, exhibit beta-galactosidase reporter activity in the epidermal cells prior to the appearance of endogenous DDC. Our finding that BR-C is required for Ddc activation at eclosion is the first evidence to suggest that this important regulator of the early metamorphic events, also regulates target gene expression at the end of metamorphosis.

Alternative Splicing↗
PubMed2001

Dopa decarboxylase exhibits low pH half-transaminase and high pH oxidative deaminase activities toward serotonin (5-hydroxytryptamine).

Dopa decarboxylase (DDC) catalyzes not only the decarboxylation of L-aromatic amino acids but also side reactions including half-transamination of D-aromatic amino acids and oxidative deamination of aromatic amines. The latter reaction produces, in equivalent amounts, an aromatic aldehyde or ketone (depending on the nature of the substrate), and ammonia, accompanied by O(2) consumption in a 1 : 2 molar ratio with respect to the products. The kinetic mechanism and the pH dependence of the kinetic parameters have been determined in order to obtain information on the chemical mechanism for this reaction toward 5-hydroxytryptamine (5-HT). The initial velocity studies indicate that 5-HT and O(2) bind to the enzyme sequentially, and that D-Dopa is a competitive inhibitor versus 5-HT and a noncompetitive inhibitor versus O(2). The results are consistent with a mechanism in which 5-HT binds to DDC before O(2). The pH dependency of log V for the oxidative deaminase reaction shows that the enzyme possesses a single ionizing group with a pK value of approximately 7.8 that must be unprotonated for catalysis. In addition to an ionizing residue with a pK value of 7.9 similar to that found in the V profile, the (V/K)(5-HT) profile exhibits a pK value of 9.8, identical to that of free substrate. This pK was therefore tentatively assigned to the alpha-amino group of 5-HT. No titratable ionizing residue was detected in the (V/K)(O2) profile, in the pH range examined. Surprisingly, at pH values lower than 7, where oxidative deamination does not occur to a significant extent, a half-transamination of 5-HT takes place. The rate constant of pyridoxamine 5'-phosphate formation increases below a single pK of approximately 6.7. This value mirrors the spectrophotometric pK(spec) of the shift 420-384 nm of the external aldimine between DDC and 5-HT. Nevertheless, the analysis of the reaction of DDC with 5-HT under anaerobic conditions indicates that only half-transamination occurs with a pH-independent rate constant over the pH range 6-8.5. A model accounting for these data is proposed that provides alternative pathways leading to oxidative deamination or half-transamination.

Animals↗
PubMedDate not supplied

The Wilhelmine E. Key 1992 Invitational lecture. Phenotypic analysis of the Dopa decarboxylase gene cluster mutants in Drosophila melanogaster.

Mutations in a majority of the 18 loci of the Dopa decarboxylase (Ddc) gene cluster effect similar morphological defects of the cuticle and/or catecholamine-related abnormalities. Mutations in 14 loci affect cuticle formation, cuticle sclerotization, or cuticle melanization, with mutations in 11 of these same loci (including Ddc and amd) producing melanotic psueudotumors, symptomatic, perhaps, of abnormal catecholamine metabolism. Mutations in seven of the genes perturb catecholamine pool levels during prepupal and pupal development, all of which also form melanotic pseudotumors, suggesting several of these genes may encode proteins involved in catecholamine metabolism. Thus, the Ddc gene cluster represents in higher eukaryotes an unusual example of a large cluster of functionally related genes involved in a common physiological process.

Animals↗
PubMed1982

Endogenous dopamine synthesis and dopa-decarboxylase activity in rat renal cortex.

The dopamine content of either cortical slices or isolated glomeruli prepared from rat kidneys and of their incubation medium was measured at different times both under basal conditions and in the presence of L-DOPA. Production of dopamine from L-DOPA by purified cytosolic proteins of the whole cortex was also measured. Dopamine synthesized by these 3 renal preparations accumulated linearly with time over 60 min. Dopamine produced by the glomeruli was more rapidly released into the incubation medium than that produced by the cortical slices. The dopamine synthetic rate was very low in the absence of L-DOPA but increased rapidly when L-DOPA was added to the incubation medium. No plateau was reached in the range of concentrations studied (0-100 microM) when cortical slices or cytosolic proteins were studied whereas dopamine production by isolated glomeruli reached an equilibrium above 10 microM L-DOPA. Dopamine synthesis in the presence of 100 microM L-DOPA was linearly related to the amount of renal protein. The synthetic rates were 43, 2.2 and 0.2 nmoles . h-1 . mg -1 for the cytosolic proteins, the cortical slices and the isolated glomeruli respectively. Dopamine synthesis by the cortical slices in the presence of 100 microM L-DOPA was progressively inhibited by increasing concentrations of alpha-methyl-DOPA. Cortical slices prepared from rats treated by benserazide, an inhibitor of L-DOPA decarboxylase, synthesized much less dopamine than those from control rats. These results show that rat renal cortex deprived of neuronal supply can synthesize dopamine in vitro from extracellular L-DOPA.

Animals↗
PubMed1993

Renal effects of atrial natriuretic peptide during dopa-decarboxylase inhibition in patients with essential hypertension.

To assess whether intrarenal dopamine synthesis could contribute to the renal response to ANP in essential hypertension, the effects of alpha-human ANP infusion (50 ng.min-1.kg-1 b.w. for 30 min) on the urinary excretion of dopamine and sodium, urine flow rate and arterial pressure were evaluated in 7 patients with mild-moderate essential hypertension before (control period) and during DOPA-decarboxylase inhibition with carbidopa (carbidopa period). In the control period, urinary dopamine excretion was 400 pg.min-1 in baseline conditions and 340 pg.min-1 during ANP infusion. Carbidopa significantly decreased urinary dopamine excretion both before (210 pg.min-1) and during ANP (99 pg.min-1). In contrast, carbidopa did not affect sodium excretion (control from 184 to 460 mu Eq.min-1; carbidopa period from 140 to 390 mu Eq.min-1) or urine flow rate (control from 5.35 to 11.21 ml.min-1; carbidopa period from 4.29 to 11.54 ml.min-1). Arterial pressure fell significantly during ANP infusion in both periods, and no significant difference was observed between the two study days, i.e. in the absence of and during carbidopa administration. We conclude that DOPA-decarboxylase inhibition does not influence the diuretic and natriuretic response to alpha-human ANP infusion in patients with essential hypertension.

Adult↗
PubMed1988

Expression of neuroendocrine cell markers L-dopa decarboxylase, chromogranin A, and dense core granules in human tumors of endocrine and nonendocrine origin.

We evaluated the usefulness of L-dopa decarboxylase (DDC) as a tumor marker of neuroendocrine (NE) cell differentiation by measuring its expression in 432 human tumors of diverse types and origins. A subset of these tumors and cell lines derived from them also were studied for expression of two other general NE cell markers, chromogranin A (CgA) and dense core granules (DCG). High concentrations of DDC were present in 96 of 117 (82%) tumors recognized to be of NE or neural origin. As expected, endocrine tumors not recognized to be of NE cell origin, as well as leukemias, lymphomas, sarcomas, melanomas, and germ cell tumors, lacked DDC expression. Of interest, modest concentrations of DDC were present in 46 of 220 (21%) nonendocrine carcinomas, especially non-small cell lung and colorectal carcinomas. We studied concordant expression of the three NE cell markers in lung and colorectal tumors and cell lines. In both tumor types there was nearly 100% concordance between CgA and DCG expression. There was an excellent correlation between DDC and CgA expression in lung cancers, both small cell and non-small cell, but DDC positive colorectal carcinomas usually lacked CgA expression. We conclude: (a) DDC is an excellent cellular marker for tumors of the NE cell system; (b) about 20% of carcinomas not of NE cell origin, especially non-small cell lung and colorectal carcinomas, express DDC, suggesting a common endodermal origin of all of the respiratory and gastrointestinal mucosal cells; and (c) CgA and DCG are expressed concordantly, indicating that CgA expression may be used as a substitute for ultrastructural examination of tumors for DCG expression.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed2006

Dopa decarboxylase: a model gene-enzyme system for studying development, behavior, and systematics.

Throughout its long evolutionary history, the Dopa decarboxylase gene (Ddc) has acquired a variety of functions in insects. The enzyme (DDC) catalyzes the production of the neural transmitters dopamine and serotonin. Not surprisingly, evidence of the enzyme's involvement in the behavior of insects is beginning to accumulate. In addition, DDC plays a role in wound healing, parasite defense, pigmentation, and cuticle hardening. A high degree of sequence conservation has allowed comparisons of the Ddc-coding regions from various insects, facilitating a number of recent studies on insect systematics. This review outlines the diverse functions of Ddc and illustrates how studies of this model system address many questions on insect neurobiology, developmental biology, and systematics.

Animals↗
PubMedDate not supplied

Overlapping transcription units in the dopa decarboxylase region of Drosophila.

The many examples of overlap in the genes of various viruses and bacteria illustrate that the parsimonious utilization of the coding capacity of DNA is relatively common amongst prokaryotes. The recent discovery of a pupal cuticle gene within an intron of the completely unrelated Gart locus in Drosophila shows that overlapping transcription units also exist in higher organisms. However, the prevalence of such phenomena in unknown. We report here a quite different situation of overlap between the 3' termini of a pair of convergent transcription units in another region of the Drosophila genome. This 88-base-pair (bp) genomic region encodes the 3' terminus of the messenger RNA for the enzyme dopa decarboxylase (Ddc) and, in opposite orientation, the 3' terminus of the adjacent gene whose function is unknown. An analysis of the temporal and spatial distribution of the two transcripts within the organism shows that high levels of both transcripts are never concordant. However, within the testes, where the 3' transcript is maximally expressed, low levels of Ddc transcript were detected. This result raises the possibility that a hybrid molecule involving the two transcripts forms in vivo or that transcription interference occurs, with concomitant regulatory implications.

Animals↗
PubMed1993

Dissociation, unfolding and refolding trials of pig kidney 3,4-dihydroxyphenylalanine (dopa) decarboxylase.

The effect of guanidinium chloride (GuCl) on enzyme activity, hydrodynamic volume, circular dichroism, and fluorescence of 3,4-dihydroxyphenylalanine (Dopa) decarboxylase from pig kidney (pkDDC) was studied under equilibrium conditions. Unfolding proceeds in at least three stages. The first transition, occurring between 0 and 1 M GuCl, gives rise to a dimeric inactive species which has lost pyridoxal 5'-phosphate (PLP), and has a high tendency to aggregate, but retains almost all of the native spectroscopic characteristics. The second equilibrium transition, between 1 and 2.2 M GuCl, involves dimer dissociation, with some loss of tertiary and secondary structure. Additionally, gross conformational changes at or near the PLP microenvironment were detected by fluorescence of NaBH4-reduced enzyme. The third step, presumably representing complete unfolding of pkDDC, appears to be complete at 4.5 M GuCl, as indicated by the lack of further substantial changes in any of the signals being studied. Attempts at refolding resulted in the findings that: (1) partial reactivation is observed only starting from enzyme denatured at concentrations below 1.5 M GuCl, and (2) starting from completely denatured protein, the refolding process is apparently reversible down to concentrations of approx. 2 M GuCl. Taken together, this would seem to indicate that the monomer-dimer transition is impaired under the experimental conditions tested. A plausible model is presented for the unfolding/refolding of pkDDC.

Animals↗
PubMed1992

Reduced cellular immune competence of a temperature-sensitive dopa decarboxylase mutant strain of Drosophila melanogaster against the parasite Leptopilina boulardi.

1. The melanotic encapsulation response made by larvae of a temperature-sensitive dopa decarboxylase (DDC) mutant strain of Drosophila against the parasitic wasp Leptopilina was severely compromised in hosts with reduced levels of DDC. 2. Dopa and 5,6-dihydroxyindole (DHI) were two hemolymph components identified in hosts exhibiting a melanotic encapsulation response. 3. This is the first study to implicate DDC in insect cellular immune responses, and to provide chemical evidence that the pigment formed during such responses is eumelanin derived from tyrosine.

Animals↗
PubMed1986

Evidence for regulatory variants of the dopa decarboxylase and alpha-methyldopa hypersensitive loci in Drosophila.

We have analyzed two variants of Drosophila melanogaster (RS and RE) which lead to the dual phenotype of elevated DDC activity and increased resistance to dietary alpha-methyldopa relative to Oregon-R controls. Both phenotypes show tight genetic linkage to the dopa decarboxylase, Ddc, and l(2)amd genes (i.e., less than 0.05 cM distant). We find that low (Oregon-R), medium (RS) and high (RE and Canton-S) levels of DDC activity seen at both pupariation and eclosion in these strains are completely accounted for by differences in accumulation of DDC protein as measured by immunoprecipitation. Genetic reconstruction experiments in which Ddc+ and amd+ gene doses are varied show that increasing DDC activity does not lead to a measurable increase in resistance to dietary alpha-methyldopa. This suggests that the increased resistance to dietary alpha-methyldopa is not the result of increased DDC activity but, rather, results from increased l(2)amd+ activity. Both cytogenetic and molecular analyses indicate that these overproduction variants are not the result of small duplications of the Ddc and amd genes, nor are they associated with small (greater than or equal to 100 bp) insertions or deletions. Measurements of DDC activity in wild-type strains of Drosophila reveal a unimodal distribution of activity levels with the Canton-S and RE strains at the high end of the scale, the Oregon-R control at the low end and RS near the modal value. We conclude that accumulated changes in a genetic element (or elements) in close proximity to the Ddc+ and amd+ genes lead to the coordinated changes in the expression of the Ddc and amd genes in these strains.

Animals↗
PubMed1991

Neuronal metabolism and DOPA decarboxylase immunoreactivity in terminal noradrenergic sympathetic axons of rat.

This study was undertaken to determine whether immuno-histochemical staining for DOPA decarboxylase (DDC) is present in axons of rat noradrenergic sympathetic neurons. A sparse plexus of varicose axons exhibiting DDC-like immunoreactivity (DDC-IR) was associated with blood vessels and acini in the submandibular gland, but this was much less extensive than the population that exhibited tyrosine hydroxylase-like immunoreactivity (TH-IR). The varicose terminal TH-IR axons in atrium, spleen, and vas deferens were devoid of DDC-IR both in grown rats and during the post-natal period of axon growth, although weak DDC-IR was seen in large pre-terminal nerve bundles. Similar patterns of staining were seen with paraffin-embedded and with frozen, formaldehyde-fixed material. No enhancement of DDC-IR was seen in any tissue after chronic alteration of catecholamine turnover with reserpine or alpha-methyl-para-tyrosine, and the numbers of submandibular DDC-IR axons were not increased by disruption of axonal transport with colchicine or by decentralization of the superior cervical ganglion. We conclude that terminal noradrenergic axons contain insufficient DDC-IR for microscopic visualization, regardless of their metabolic state, reinforcing previous evidence that DDC-IR can be used as a histochemical marker for dopaminergic axons. By this criterion, the rat submandibular gland may receive a sparse dopaminergic innervation.

Animals↗