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PubMed1991

Affinity labeling of pig kidney 3,4-dihydroxyphenylalanine (Dopa) decarboxylase with N-(bromoacetyl)pyridoxamine 5'-phosphate. Modification of an active-site cysteine.

Pig kidney 3,4-dihydroxyphenylalanine (Dopa) decarboxylase is inactivated by N-(bromoacetyl)pyridoxamine 5'-phosphate (BAPMP) in a reaction which follows first-order kinetics at pH 7.5 and 25 degrees C. The concentration dependence of inactivation reveals saturation kinetics with an apparent Ki of 0.16 mM and kinact of 0.086 min-1 at saturating inhibitor concentration. Enzyme can be protected from inactivation by pyridoxal 5'-phosphate. Inactivation of enzyme by [14C]BAPMP proceeds with the incorporation of a stoichiometric amount of labeled inhibitor. Proteolytic digestions of the radioactively labeled enzyme followed by high-performance liquid chromatography allow the isolation of the modified peptide corresponding to the sequence Ala-Ala-Ser-Pro-Ala-Cys-Thr-Glu-Leu in which cysteine (Cys111) is the modified residue. The conservation of this residue and also of an extended region around it in all Dopa decarboxylases so far sequenced is underlined. The overall conclusion of these findings is that Cys111 may be at, or near, the pyridoxal-5'-phosphate binding site of pig kidney Dopa decarboxylase and plays a critical role in the catalytic function of the enzyme. Furthermore, fluorescence studies of BAPMP-modified apoenzyme provide useful information on the microenvironment of the affinity label at its binding site.

Affinity Labels↗
PubMed1988

The Fourier transforms of the laser-induced absorption decay from glycogen phosphorylase and DOPA decarboxylase.

Fourier analysis of the laser-induced absorption decay curves of 3,4-dihydroxyphenylalanine (DOPA) decarboxylase and glycogen phosphorylase demonstrates a powerful technique in the analysis of complicated decay behavior. Phosphorylase which uses the pyridoxal 5'-phosphate cofactor in an unknown manner exhibits over weak absorption an intense decay while decarboxylase demonstrates only weak absorption. Fourier analysis of the decay curves clearly shows that phosphorylase has an intense absorption decay in the midst of three weaker ones and that decarboxylase only has three weak decays. This conclusion justifies the isolation and use of the intense decay of phosphorylase as an observable in the study of protein dynamics at the active site about the cofactor. The decay has demonstrated a movement of positive charge to substrate in the mechanism of phosphorylation of glycogen units.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed1985

Developmental control of transduced dopa decarboxylase genes in D. melanogaster.

Seventeen new euchromatic integration sites of the dopa-decarboxylase gene (Ddc) have been generated using p-mediated transduction. The developmental expression of the integrated genes was examined by monitoring the embryonic induction of dopa decarboxylase enzyme activity (DDC) and by monitoring the developmental pattern of DDC activity from late third instar to eclosion. The majority of inserts are regulated correctly within about 30% of controls. Several cases of multiple insertion events were recovered and these show correspondingly elevated levels of activity and are regulated normally. The pattern of expression of one insert (15C) falls outside the normal range. Multiple copies of transduced Ddc genes are used to test for effects of elevated gene dose on levels of expression. One insert on the X chromosome shows little or no dosage compensation. Possible reasons for the differences between the regulation of transduced genes in Drosophila and the regulation of transformed genes in mammalian systems are discussed.

Animals↗
PubMed1986

Sequence and structure of the dopa decarboxylase gene of Drosophila: evidence for novel RNA splicing variants.

In Drosophila, dopa decarboxylase (DDC) serves a dual role in neurotransmitter production and sclerotization of the cuticle. The Ddc gene is under complex hormonal and tissue-specific control and several sizes of Ddc RNA are observed at embryonic hatching, pupariation and adult eclosion. We present here the complete nucleotide sequence of the Drosophila dopa decarboxylase gene and the partial sequence of two corresponding Ddc cDNAs. The sequence allows us to account for the detailed structure of four of the five major Ddc RNA species observed. The cDNA sequence reveals the existence of previously undetected splicing events and provides evidence for two RNA splicing alternatives which appear to encode two protein isoforms. The structure, processing and developmental regulation of the Ddc transcripts and putative protein isoforms are discussed. Interestingly, the pyridoxal-binding peptide of porcine DDC matches the Drosophila sequence perfectly suggesting considerable selective pressure on at least portions of the sequence. This is the first available Ddc gene sequence from any organism and should serve as a basis of comparison for the related proteins of other species.

Amino Acid Sequence↗
PubMed1979

Studies on the enzymatic blood-brain barrier: quantitative measurements of DOPA decarboxylase in the wall of microvessels as related to the parenchyma in various CNS regions.

The presence of DOPA decarboxylase in cerebral microvessels (capillaries and venules) impedes the passage of circulating amine precursors into the brain. The relative amount of DOPA decarboxylase in this trapping mechanism as compared to the parenchyma per se was estimated in various CNS regions, measuring the formation of dopamine from L-DOPA in vitro or in vivo in two experimental models on rats and rabbits: (1) On the basis of the treatment with a peripheral decarboxylase inhibitor (carbidopa, which inhibits also microvascular DOPA decarboxylase in the CNS) it could be calculated that the enzyme in the microvessels of the caudate nucleus (rich in catecholamine nerve terminals), cerebellum (poor in catecholamine nerves), and spinal cord comprised 25, 91 and 79 per cent, respectively, of the total enzyme activity. (2) Measurement of dopamine formation in the spinal cord following transection at the midthoracic level (which causes degeneration of the catecholamine neurons caudal to the lesion since they are all descending) indicated that a similar fraction as found in the carbidopa model, 71%, of the total tissue decarboxylase activity resided in the microvessel walls. The results show that a considerable portion of tissue decarboxylase in the CNS is present in the microvessel walls, where it represents part of an enzymatic blood-brain barrier mechanism.

Animals↗
PubMed1997

cDNA cloning of L-dopa decarboxylase from the eclosion stage of the insect Ceratitis capitata. Evolutionary relationship to other species decarboxylases.

The cDNA encoding the L-dopa decarboxylase (ddc) from the eclosion stage of the insect Ceratitis capitata was isolated by PCR and a molecular cloning strategy. The isolated cDNA clone encoded a protein of 431 amino acids with a calculated molecular weight of 47,843 Da. Northern blot analysis of poly(A)+ RNA showed an approximately 2 kb transcript. The deduced protein sequence shares a high percentage of homology with Ddc protein sequences of other species. Furthermore, the molecular weight of the deduced protein agreed well with that of the purified Ddc from the same insect. Data base search revealed significant and extensive sequence similarities among prokaryotic and eukaryotic PLP-dependent decarboxylases including Ceratitis capitata and bacterial histidine decarboxylase (HDC), strongly suggesting an ancient and common origin for all PLP-dependent decarboxylases.

Amino Acid Sequence↗
PubMed1991

Pig kidney 3,4-dihydroxyphenylalanine (dopa) decarboxylase. Primary structure and relationships to other amino acid decarboxylases.

The complete amino acid sequence of pig kidney 3,4-dihydroxyphenylalanine (Dopa) decarboxylase is reported. The sequence was determined from analysis of peptides isolated after tryptic and cyanogen bromide cleavages of the enzyme. Each subunit is made up of 485 residues, corresponding to a molecular mass of 53858 Da. The N-terminus of the polypeptide chain is an acetylated methionyl residue. A number of structural features, previously shown to be important for the structure and function of the enzyme, could be localized along the polypeptide chain. Comparison of the primary structure with the known cDNA-deduced sequences of other Dopa decarboxylases (i.e. the human, bovine, rat, guinea-pig and Drosophila enzymes) reveals 50% identity. The identity increases to 73%, if the comparison is restricted to the mammalian sequences. Comparison with other aromatic and non-aromatic decarboxylases allows some consideration to be made in terms of structure/function and evolutionary relationships in this class of enzymes.

Amino Acid Sequence↗
PubMed1989

Pig kidney dopa decarboxylase: inactivation by iodoacetamide and sequence of the carboxyamidomethylcysteine-containing peptide.

Pig kidney 3,4-dihydroxyphenylalanine (Dopa) decarboxylase is inactivated by iodoacetamide following pseudo-first order reaction kinetics. The apparent first order rate constant for inactivation is proportional to the concentration of iodoacetamide and a second order rate constant of 37 M-1 min-1 is obtained at pH 6.8 and 25 degrees C. Cyanogen bromide fragmentation of iodo(1-14C)acetamide - modified inactivated Dopa decarboxylase followed by trypsin digestion yields a single radioactive peptide. Automated Edman degradation reveals a heptapeptide sequence which contains labeled carboxyamidomethylcysteine. This finding and the results of the incorporation of the label from ido (1-14C)acetamide into the enzyme clearly indicate that the modification of 1 mol of SH per mol of enzyme dimer is responsible for the inactivation process. The labeled peptide, which was located by means of limited proteolysis on the fragment corresponding to the COOH-terminal third of the enzyme, has been aligned with a 7 amino acid stretch of Drosophila enzyme. Although this region appears highly conserved in the Dopa decarboxylase enzymes, the cysteinyl residue is not conserved. This observation together with the spectral binding properties of the iodoacetamide inactivated enzyme argue against a functional role for the modifiable cysteine in the mechanism of action of pig kidney enzyme. It is suggested that the loss of pig kidney decarboxylase activity produced by iodoacetamide modification might be attributable to steric hindrance. This could be due to the presence of the bulky acetamidic group on a cysteine residue at, or near, the active center or in a site of strategic importance to the maintenance of the active site topography.

Amino Acid Sequence↗
PubMed1990

Serotonin synthesis and distribution in Drosophila dopa decarboxylase genetic mosaics.

In Drosophila, the enzyme dopa decarboxylase (DDC) catalyzes the last step in the biosynthesis of serotonin (5HT) and dopamine. In the present study, the distribution of DDC and one of its biosynthetic products (5HT) was determined in CNSs that were genetic mosaics, composed of neurons that have DDC activity and neurons that lack DDC activity. Phenotypic mosaicism, that is, immunoreactive (IR) and non-IR neurons within the same nervous system, was observed for both DDC and 5HT immunoreactivity. DDC-IR neurons were always 5HT-IR, but some 5HT-IR neurons devoid of DDC immunoreactivity were also observed. 5HT-IR neurons devoid of DDC immunoreactivity were always in close apposition to other DDC-IR neurons. We suggest that in vivo uptake mechanisms are responsible for 5HT accumulation in neurons devoid of DDC immunoreactivity.

Animals↗
PubMed2003

Possible parent-of-origin effect of Dopa decarboxylase in susceptibility to bipolar affective disorder.

Dopa decarboxylase (DDC) catalyses the synthesis of both dopamine and serotonin as well as trace amines suggested to possess neuromodulating capabilities. We have previously reported evidence suggesting an association between DDC and bipolar affective disorder (BPAD) [Børglum et al., 1999]. To further investigate the possible role of DDC in BPAD, we analyzed a 1- and a 4-bp deletion variant-both of putative functional significance-in two new samples: a case-control sample with 140 cases and 204 controls, and 100 case-parents trios. We also tested for association in subjects with familial disease in both the new and the previously investigated samples. The previously reported association was not replicated in either of the new samples. However, a preponderance of the 1-bp deletion was increased by analysis of the familial cases separately for all case-control samples investigated, indicating a possible association with familial disease (combined analysis, P = 0.02). In the trio sample, a preferential paternal transmission of the 4-bp deletion was observed (P = 0.006). DDC is located next to the imprinted gene GRB10, which is expressed specifically from the paternal allele in fetal brains. Increased transmission of paternal DDC alleles has also been suggested in attention deficit hyperactivity disorder. We suggest that DDC might confer susceptibility to BPAD predominantly when paternally transmitted.

Bipolar Disorder↗
PubMed1999

Two novel variants in the DOPA decarboxylase gene: association with bipolar affective disorder.

DOPA decarboxylase (DDC), also known as aromatic L-amino acid decarboxylase (AADC), is an enzyme involved in the synthesis of the important neurotransmitters dopamine, norepinephrine, and serotonin. In addition, it participates in the synthesis of trace amines; compounds suggested to act as endogenous modulators of central neurotransmission. Thus, DDC is regarded as a potential susceptibility gene for a variety of neuropsychiatric disorders. The aim of the present study was to examine the role of DDC in bipolar affective disorder (BPAD). By screening 10 individuals for sequence variations in the coding region of the DDC gene as well as in the neuron-specific promoter and 5' untranslated regions we were able to identify two fairly frequent variants: a 1-bp deletion in the promoter and a 4-bp deletion in the untranslated exon 1. Both deletions affect putative binding sites for known transcription factors, suggesting a possible functional impact at the level of expression. The two variants were applied in an association study including 80 Danish bipolar patients, 112 English bipolar patients, 223 Danish controls, and 349 English controls. Analyzing the combined material, a significant association was found between the 1-bp deletion and BPAD with P-values of 0.037 (allelic) and 0.021 (genotypic). The frequency of the 1-bp deletion was 13.3% in patients and 9.4% in controls with a corresponding odds ratio of 1. 48 (95% CI: 1.02-2.15). The results presented suggest that DDC may act as a minor susceptibility gene for bipolar affective disorder.

Alleles↗
PubMed1984

DOPA decarboxylase activity in the nervous system and the ctenidium of the freshwater clam, Musculium (Sphaerium) transversum.

Dopa decarboxylase was measured in ganglia, connectives, branchial nerve and ctenidium of the clam, Musculium transversum. DOPA decarboxylase inhibitors (STH, HMD, and alpha-methyl-DOPA) reduced the enzymatic activity in all extracts. Ligation and extirpation of the visceral ganglion and branchial nerve significantly decreased the enzymatic activity in the ctenidium. Scanning electron microscopic observations showed numerous degenerative changes in nerve cells with progressive destruction of axons within the branchial nerve. In conclusion, it appears that lateral ctenidial cilia are dependent upon the decarboxylase activity of the visceral ganglion and branchial nerve.

Animals↗
PubMed2002

Behavior of fluorinated analogs of L-(3,4-dihydroxyphenyl)alanine and L-threo-(3,4-dihydroxyphenyl)serine as substrates for Dopa decarboxylase.

We have determined the kinetic parameters for Dopa decarboxylase (DDC) of three ring-fluorinated analogs of 3,4-dihydroxyphenylalanine (Dopa). The rank order of catalytic efficiency of decarboxylation (k(cat)/K(m)) is Dopa>6-F-Dopa>2-F-Dopa>5-F-Dopa. This rank is consistent with previous in vivo and in vitro studies which indicate that, of the fluorinated analogs, 6-F-Dopa has pharmacokinetics that are most suited for positron emission tomographic (PET) evaluation of dopamine function. The effectiveness of PET as a diagnostic tool, the convenient half-life of (18)F (110 min) and the favorable pharmacokinetics of 6-[(18)F]FDOPA have combined to make this an extremely valuable reagent to study dopaminergic activity. The reactions of the related fluorinated DOPS analogs show that, while 6-F-threo-3,4-(dihydroxyphenyl)serine (DOPS) is decarboxylated at approximately the same rate as the non-fluorinated substrate, 2-F-threo-DOPS is not converted into the corresponding amine. In both cases a Pictet-Spengler condensation with the pyridoxal 5(')-phosphate (PLP) cofactor occurs to produce tetrahydroisoquinolines. Condensation of fluorinated catecholamines and catechol amino acids with endogenous aldehydes will be investigated as an approach to study possible mechanisms of L-Dopa-linked neurotoxicity.

Dihydroxyphenylalanine↗
PubMed1987

Two classes of sympathetic nerves with different dopa decarboxylase immunoreactivities exist in dog vas deferens.

To determine whether dihydroxyphenylalanine (DOPA) decarboxylase (DDC) activity in the terminal regions of noradrenergic axons varies with axonal length, we compared the pattern of immunohistochemical staining for DDC in the 'short' terminal nerves of dog vas deferens with that in the 'long' nerves of spleen and atrium. The terminal nerves supplying the muscular coats of the vas deferens were, like those in spleen and heart, devoid of DDC immunoreactivity. The presence of this enzyme is therefore not characteristic of either short or long noradrenergic axons, in support of previous evidence that it is a specific marker for dopaminergic terminal nerves. Many axons supplying the mucosal epithelial cells in the vas deferens were DDC-positive, suggesting the existence of a dopaminergic innervation.

Animals↗
PubMed1986

Evidence for evolutionary duplication of genes in the dopa decarboxylase region of Drosophila.

The region surrounding the dopa decarboxylase gene (Ddc) of Drosophila contains a cluster of genes, many of which appear to be functionally related by virtue of their effects on cuticle development and/or catecholamine metabolism. In this report we describe evidence that the Ddc gene and the closely linked alpha-methyldopa hypersensitive (amd) gene share extensive sequence homology and are the products of a gene duplication event. The two genes are transcribed convergently and are separated by 2.4 kb. A gene located between Ddc and amd expresses a 2.0-kb mRNA and appears to partially overlap the Ddc gene. The organization of these transcripts implies a complex series of events giving rise to the present pattern. The patterns of expression of these genes do not support a model of coordinate regulation, but are more consistent with a pattern of duplication and divergence to various related metabolic subspecialties. These data provide the first evidence for structural relationships among genes in the 37C cluster.

Amino Acid Sequence↗
PubMed1984

Molecular mapping of a gene cluster flanking the Drosophila Dopa decarboxylase gene.

Nine lethal complementation groups flanking the Drosophila Dopa decarboxylase (Ddc) gene, have been localized within 100 kb of cloned chromosomal DNA. Six of these complementation groups are within 23 kb of DNA, and all ten complementation groups, including Ddc, lie within 78-82 kb of DNA. The potential significance of this unusually high gene density is discussed.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed1995

No evidence of linkage between manic depressive illness and the dopa decarboxylase gene or nearby region on chromosome 7p.

Dopa decarboxylase (DDC) is involved directly in the synthesis of dopamine and serotonin and indirectly in the synthesis of noradrenaline. The present study investigated two Danish families for linkage between manic depressive illness, a marker at the DDC locus which has been mapped to 7p11-p13 and 10 microsatellite markers covering chromosome 7q11-p15. No evidence of linkage was found assuming a dominant or a recessive mode of inheritance. We have earlier reported evidence against linkage between manic depressive illness and tyrosine hydroxylase and dopamine beta-hydroxylase. Mutations of major importance in the genes encoding the three enzymes involved in the synthesis of dopamine and noradrenaline seem less likely in the families we have studied. Further investigations of genetic and other pathophysiological mechanisms in relation to the monoamine hypotheses for manic depressive illness are still of relevance. There is a need for further linkage and association studies as well as a search for possible mutations in the relevant genes involved in the monoaminergic pathways to clarify their possible role in the aetiology of manic depressive illness.

Bipolar Disorder↗