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PubMed2000

Aedes aegypti dopa decarboxylase: gene structure and regulation.

Dopa decarboxylase converts L-dopa to dopamine, a precursor molecule for diverse biological activities in insects including neurotransmission and a variety of tanning reactions required for development, reproduction and defence against parasites. Herein, we report the cloning and sequencing of the Aedes aegypti Ddc gene, including 2.1 kb of the upstream promoter region. The transcribed region of the gene spans more than 16 kb and contains five exons. In situ hybridization localizes the blood-meal-induced ovarian transcription of this gene to the follicular epithelial cells surrounding individual oocytes. Ovary tissue transcription of Ddc is increased in response to injection of 20-hydroxyecdysone to levels equal to those observed for blood-fed controls, however coinjection with the translational inhibitor cycloheximide negates the effect, indicating an indirect regulatory role for this hormone. Clusters of putative ecdysone-responsive elements and zinc-finger binding domains for the products of Broad-Complex gene family are identified in the 5'-promoter region. These elements are discussed in the context of common insect Ddc regulatory mechanisms.

Aedes↗
PubMed1993

Human striatal L-dopa decarboxylase activity estimated in vivo using 6-[18F]fluoro-dopa and positron emission tomography: error analysis and application to normal subjects.

DOPA decarboxylase is the enzyme directly responsible for the synthesis of the neurotransmitters dopamine and serotonin, and indirectly of noradrenaline, in brain. We used the decarboxylation coefficient (k3D) of 6-[18F]fluoro-DOPA (FDOPA) to denote the relative activity of L-DOPA decarboxylase in vivo in the human brain. To determine the relative enzyme activity with positron emission tomography (PET), we evaluated the model that separates the metabolism into compartments of nondiffusible and diffusible (i.e., transient) tracer metabolites. Error analysis indicated that the least-squares optimization alone was not sufficient to yield accurate estimates of k3D in the presence of the inherent error of PET. To improve the accuracy of the k3D estimates by optimizing the number of parameters, we introduced biological constraints which included a tracer partition volume (Ve) common to frontal cortex and striatum, and a fixed ratio (q) between the blood-brain barrier transport coefficients of O-methyl-[18F]fluoro-DOPA and FDOPA, the two sources of radioactivity in plasma. We found that a two-step analysis yielded sufficiently accurate estimates of k3D. The two steps include the initial estimation of the partition volume in frontal cortex and the subsequent use of this value to determine k3D in striatum and other structures. We studied twelve healthy controls (age 45 +/- 15 years). The average k3D value was 0.081 +/- 0.024 min-1 (coefficient of variation (COV) 30%) for caudate nucleus, 0.074 +/- 0.013 min-1 (COV 18%) for putamen, and 0.010 +/- 0.005 min-1 (COV 50%) for cerebral cortex.

Adult↗
PubMed1980

Larvicidal activity of inhibitors of DOPA decarboxylase on the Australian sheep blowfly, Lucilia cuprina.

Inhibitors of DOPA decarboxylase, the key enzyme in the formation of the sclerotizing agent (N-acetyl dopamine) of the blowfly cuticle, have been tested for larvicidal activity against L. cuprina. A significant level of DOPA decarboxylase activity has been shown to be present throughout larval life in this species. Four potent in vitro inhibitors of L. cuprina larval DOPA decarboxylase (carbidopa, benserazide, methyl tyrosine and methyl DOPA) have been shown to be effective larvicides when fed to first- or second-instar larvae. However, no correlation is seen between the apparent Ki and LD50 values for these compounds. Treated larvae are observed to die at the next moult but death can be averted by the addition of N-acetyl dopamine to the food. Thus the toxic effects of the DOPA decarboxylase inhibitors appear to result from an inhibition of the formation of the sclerotizing agent in the cuticles of treated larvae.

Animals↗
PubMed1993

Assignment of the rat genes coding for dopa decarboxylase (DDC) and glutamic acid decarboxylases (GAD1 and GAD2).

By use of rat cDNA probes and a panel of cell hybrids segregating rat chromosomes, the genes encoding three pyridoxal 5'-phosphate (PLP)-dependent decarboxylases--namely, DOPA-decarboxylase (Ddc), glutamic acid decarboxylase 1 and 2 (Gad1 and Gad2)--were assigned to rat Chromosomes (Chrs) 14, 3, and 17, respectively. If one takes into account chromosome localizations in the human and the mouse, the present results (i) show that a synteny group is retained on rat Chr 14, human Chr 7, and mouse Chr 11 (Ddc); (ii) strengthen the homology relation known between rat Chr 3 and human and mouse Chrs 2 (Gad1); (iii) suggest that rat Chr 17 has no extensive homology to any human chromosome; and (iv) suggest the order (Prl, Fdp)--Tpl2--Gad2 on the rat Chr 17.

Animals↗
PubMed1990

Immuno-cross-reactivity of histidine and dopa decarboxylases.

Immuno-cross-reactivity between histidine decarboxylase (HDC) and dopa decarboxylase (DDC) was investigated. By comparing the cDNA sequences of rat HDC with rat and guinea-pig DDCs, we found a region that may possibly be related to the cross-reactivity of anti-rat HDC antibody with guinea-pig DDC. The peptide encoded by this region was synthesized and anti-peptide antibody was prepared. We also purified HDC and DDC homogeniously from fetal rat liver and guinea-pig liver, respectively. On immunoblotting, anti-peptide antibody recognized both rat HDC and guinea-pig DDC. Anti-HDC polyclonal antibody which also recognizes both enzymes detected only rat HDC when it was absorbed by the peptide. This result indicates that this region is responsible for the immuno-cross-reactivity of anti-rat HDC antibody with guinea-pig DDC.

Amino Acid Sequence↗
PubMed1971

Failure of vitamin B6 to reverse the L-dopa effect in patients on a dopa decarboxylase inhibitor.

Seven patients with Parkinsonism previously on l-dopa were placed on a regimen of l-dopa and alpha methyl dopa hydrazine (a dopa decarboxylase inhibitor). Two of these patients had previously shown marked clinical deterioration of the l-dopa improvement when given pyridoxine. None of the seven patients receiving alpha methyl dopa hydrazine demonstrated any change in their condition when given pyridoxine. The failure of vitamin B(6) to reverse the clinical effect of l-dopa in patients receiving both l-dopa and a peripheral dopa decarboxylase inhibitor suggests that reversal of the l-dopa effect induced by vitamin B(6) is due to increasing the activity of the enzyme dopa decarboxylase outside the central nervous system.

Adult↗
PubMed2001

Acute neuroleptic stimulates DOPA decarboxylase in porcine brain in vivo.

The activity of DOPA decarboxylase measured in homogenates from rat striatum, or calculated from the rate of tracer decarboxylation measured ex vivo, is stimulated following acute treatment with antagonists of dopamine D2-like receptors. We used compartmental kinetics to test the hypothesis that utilization of the DOPA decarboxylase substrate [(18)F]fluorodopa is potentiated in living striatum following acute treatment with a typical neuroleptic. The kinetics of the tracer uptake were determined in eight anesthetized female pigs (40 kg) and in three animals receiving an infusion of haloperidol (75 microg kg(-1) h(-1)) for 1 h prior to tracer administration and throughout the 2-h positron emission recording. The relative activity of DOPA decarboxylase in striatum was increased threefold by the treatment. This potentiation of DOPA decarboxylation after pharmacological blockade of dopamine D2-like receptors may be used to optimize the utilization of exogenous DOPA in the treatment of Parkinson's disease.

Animals↗
PubMed1986

Effect of leupeptin, a protease inhibitor, on dopa decarboxylase and protease activities in homogenates of submandibular salivary glands from young rats.

Dopa-decarboxylase activity was high at 2-3 weeks of age, low at 5-6 weeks, and very low in adult rats; protease activity increased with age. Trypsin-like proteases, which decrease dopa-decarboxylase activity, were detected in the gland and were inhibited by a protease inhibitor, leupeptin. High concentrations (20 mg/ml) of leupeptin increased dopa-decarboxylase activity in the glands of adult rats to the level found at 5-6 weeks of age. The low activity of dopa decarboxylase in adult gland may be due in part to endogenous proteases.

Aging↗
PubMed1986

CNS and hypoderm regulatory elements of the Drosophila melanogaster dopa decarboxylase gene.

Expression of the dopa decarboxylase gene (Ddc) is regulated in a tissue- and developmental stage-specific manner throughout the life cycle of the fruit fly, Drosophila melanogaster. Essential Ddc regulatory elements lie within 208 base pairs upstream from the RNA start point. Functional elements within this 5' flanking region were mapped by deletion analysis, which assayed expression in vivo after germline integration via P element vectors. One of the elements is essential for expression in both the larval and adult central nervous system, and at least two other elements are necessary for quantitatively normal expression in the hypoderm. Within each of the intervals that have regulatory effects are found sequence elements conserved between the Ddc genes of two distantly related species of flies. On the basis of this correlation, regulatory functions for these sequence elements can be postulated.

Animals↗
PubMed2000

Bacterial-injection-induced syntheses of N-beta-alanyldopamine and Dopa decarboxylase in the hemolymph of coleopteran insect, Tenebrio molitor larvae.

Injection of Escherichia coli into larvae of the coleopteran Tenebrio molitor resulted in the appearance of a dopamine-like substance on the electrochemical detector. To characterize this dopamine-like substance, we purified it to homogeneity from the immunized hemolymph and determined its molecular structure to be N-beta-alanyldopamine using the liquid chromatographic/tandem mass spectrometric method. Chemically synthesized N-beta-alanyldopamine showed the same retention time on HPLC as the purified N-beta-alanyldopamine from immunized larvae. To elucidate the molecular mechanism of N-beta-alanyldopamine synthesis in vivo, we examined the enzyme activity of Dopa decarboxylase against E. coli-injected hemolymph of T. molitor larvae. The enzyme activity of Dopa decarboxylase increased dramatically approximately 8 h after injection; Dopa decarboxylase activity of injected larvae being 10-times higher than naive larvae after 24 h. To evaluate the extent of quantitative changes of Dopa decarboxylase in response to bacterial challenge, Tenebrio Dopa decarboxylase was purified to homogeneity from the whole larvae and a cDNA clone for Tenebrio Dopa decarboxylase was isolated. RNA blot hybridization revealed that expression of the Dopa decarboxylase gene was activated transiently 3-8 h after E. coli challenge. Immunoprecipitation experiments showed that Tenebrio Dopa decarboxylase was detected from 8 to 24 h in E. coli-injected larval extract. Thus, bacterial injection into T. molitor larvae might induce transcriptional activation of a Dopa decarboxylase gene, and then synthesis of N-beta-alanyldopamine. The synthesized N-beta-alanyldopamine might be used as a substrate by phenoloxidase during melanin synthesis in the humoral defense response or the melanotic encapsulation reaction of the cellular defense response.

Amino Acid Sequence↗
PubMed1991

Dopa decarboxylase activity of the living human brain.

Monoaminergic neurons use dopa decarboxylase (DDC; aromatic-L-amino-acid carboxy-lyase, EC 4.1.1.28) to form dopamine from L-3,4-dihydroxyphenylalanine (L-dopa). We measured regional dopa decarboxylase activity in brains of six healthy volunteers with 6-[18F]fluoro-L-dopa and positron emission tomography. We calculated the enzyme activity, relative to its Km, with a kinetic model that yielded the relative rate of conversion of 6-[18F]fluoro-L-dopa to [18F]fluorodopamine. Regional values of relative dopa decarboxylase activity ranged from nil in occipital cortex to 1.9 h-1 in caudate nucleus and putamen, in agreement with values obtained in vitro.

Brain↗
PubMed1984

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.

Dopamine (DA) elevations in rat striatum produced by combined administration of L-dopa and carbidopa were abolished when L-dopa was injected with NSD-1015, an inhibitor of central dopa-decarboxylase. In all rats with unilateral 6-OH-DA nigral lesions, L-dopa-induced contraversive circling occurred after carbidopa, but was totally abolished (in 60%) or markedly suppressed after pretreatment with NSD-1015. Administration of the DA metabolites DOPAC and HVA systemically and of 3-methoxytyramine intrastriatally evoked no circling in animals with 6-OH-DA lesions. In rats with unilateral nigrotomies, the direction of L-dopa-induced circling was reversed and became ipsiversive after DA receptors were reduced by the addition of kainic acid lesions in ipsilateral striata. Findings provide evidence that circling in rats--and by analogy, efficacy in parkinsonians--requires the decarboxylation of exogenous L-dopa and interaction of the formed DA with DA receptors in striatum.

Animals↗
PubMed1978

Substrate specificity and other properties of DOPA decarboxylase from guinea pig kidneys.

DOPA decarboxylase (aromatic-l-amino-acid carboxy-lyase, EC 4.1.1.28) from guinea pig kidneys has been purified to a specific activity of 9370 or 330-fold. Efficient purification was possible by employing apolar interaction chromatography. The purified enzyme gives a single component on polyacrylamide gel electrophoresis and the absorption spectrum of the enzyme reveals two forms of binding of pyridoxal 5-phosphate. The pure enzyme decarboxylates l-DOPA, 5-hydroxytryptophan, o-tyrosine and m-tyrosine but it is inactive towards phenylalanine, tyrosine, tryptophan, histidine and 3-methoxy-phenylalanine. The enzyme behaves as an undissociated enzyme but only towards 5-hydroxytryptophan. It behaves as an enzyme from which the coenzyme is partially dissociated when it attacks l-DOPA, o-tyrosine and m-tyrosine.

5-Hydroxytryptophan↗
PubMed1984

Dye-sensitized photo-oxidation of pig kidney Dopa decarboxylase.

The effects of irradiation of pig kidney Dopa decarboxylase by visible light absorbed by the intrinsic chromophore, pyridoxal-P, and by the externally added dyes, pyridoxal-P or proflavin, have been studied. In all cases inactivation was observed, even though to different extens, which seemed to be essentially correlated to tryptophanyl residues photodestruction. Kinetics of inactivation and oxidation of these amino acid residues revealed the presence of two distinct groups of tryptophan residues with different photooxidation rate constants. A different role for these classes of residues in the structure and function of Dopa decarboxylase has been suggested.

Amino Acids↗