Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.3.1.107 (DAT)
 1,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The monoamines, serotonin, dopamine, norepinephrine, epinephrine and histamine, play a critical role in the function of the hypothalamic-pituitary-adrenal axis and in the integration of information in sensory, limbic, and motor systems. The primary mechanism for termination of monoaminergic neurotransmission is through reuptake of released neurotransmitter by Na+, CI-dependent plasma membrane transporters. A second family of transporters packages monoamines into synaptic and secretory vesicles by exchange of protons. Identification of those cells which express these two families of neurotransmitter transporters is an initial step in understanding what adaptive strategies cells expressing monoamine transporters use to establish the appropriate level of transport activity and thus attain the appropriate efficiency of monoamine storage and clearance. The most recent advances in this field have yielded several surprises about their function, cellular and subcellular localization, and regulation, suggesting that these molecules are not static and most likely are the most important determinants of extracellular levels of monoamines. Here, information on the localization of mRNAs for these transporters in rodent and human brain is summarized along with immunohistochemical information at the light and electron microscopic levels. Regulation of transporters at the mRNA level by manipulation in rodents and differences in transporter site densities by tomographic techniques as an index of regulation in human disease and addictive states are also reviewed. These studies have highlighted the presence of monoamine neurotransmitter transporters in neurons but not in glia in situ. The norepinephrine transporter is present in all cells which are both tyrosine hydroxylase (TH)- and dopamine beta-hydroxylase-positive but not in those cells which are TH- and phenyl-N-methyltransferase-positive, suggesting that epinephrine cells may have their own, unique transporter. In most dopaminergic cells, dopamine transporter mRNA completely overlaps with TH mRNA-positive neurons. However, there are areas in which there is a lack of one to one correspondence. The serotonin transporter (5-HTT) mRNA is found in all raphe nuclei and in the hypothalamic dorsomedial nucleus where the 5-HTT mRNA is dramatically reduced following immobilization stress. The vesicular monoamine transporter 2 (VMAT2) is present in all monoaminergic neurons including epinephrine- and histamine-synthesizing cells. Immunohistochemistry demonstrates that the plasma membrane transporters are present along axons, soma, and dendrites. Subcellular localization of DAT by electron microscopy suggests that these transporters are not at the synaptic density but are confined to perisynaptic areas, implying that dopamine diffuses away from the synapse and that contribution of diffusion to dopamine signalling may vary between brain regions. Interestingly, the presence of VMAT2 in vesicles underlying dendrites, axons, and soma suggests that monoamines may be released at these cellular domains. An understanding of the regulation of transporter function may have important therapeutic consequences for neuroendocrine function in stress and psychiatric disorders.
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PMID:Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system. 966 36

Salutaridinol 7-O-acetyltransferase (EC ) catalyzes the conversion of the phenanthrene alkaloid salutaridinol to salutaridinol-7-O-acetate, the immediate precursor of thebaine along the morphine biosynthetic pathway. We have isolated a cDNA clone that corresponds to the internal amino acid sequences of the native enzyme purified from a cell suspension culture of opium poppy Papaver somniferum. The recombinant enzyme acetylated the 7-hydroxyl moiety of salutaridinol in the presence of acetyl-CoA. The apparent K(m) value for salutaridinol was determined to be 9 microm and 54 microm for acetyl-CoA. The gene transcript was detected in extracts from Papaver orientale and Papaver bracteatum in addition to P. somniferum. Genomic DNA gel blot analysis indicated that there is likely a single copy of this gene in the P. somniferum genome. The amino acid sequence of salutaridinol 7-O-acetyltransferase is most similar (37% identity) to that of deacetylvindoline acetyltransferase of Catharanthus roseus. Salutaridinol 7-O-acetyltransferase is the second enzyme specific to morphine biosynthesis for which we have isolated a cDNA. Taken together with the other cDNAs cloned encoding norcoclaurine 6-O-methyltransferase, (S)-N-methylcoclaurine 3'-hydroxylase, the cytochrome P-450 reductase, and codeinone reductase, significant progress has been made toward accumulating genes of this pathway to enable the end goal of a biotechnological production of morphinan alkaloids.
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PMID:Molecular characterization of the salutaridinol 7-O-acetyltransferase involved in morphine biosynthesis in opium poppy Papaver somniferum. 1140 55

Developing seedlings of Catharanthus roseus were analyzed for appearance of tryptophan decarboxylase (TDC), strictosidine synthase (SS), N-methyltransferase (NMT) and O-acetyltransferase (DAT) enzyme activities. SS enzyme activity appeared early after germination and was present throughout most of the developmental study. TDC activity was highly regulated and peaked over a 48 hour period achieving a maximum by day of 5 of seedling development. Both TDC and SS were present in all tissues of the seedling. NMT and DAT enzyme activities were induced after TDC and SS had peaked and these activities could only be found in hypocotyls and cotyledons. TDC, SS, and NMT did not require light for induction whereas DAT enzyme activity was increased approximately 10-fold after light treatment of dark grown seedlings.
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PMID:Developmental Regulation of Enzymes of Indole Alkaloid Biosynthesis in Catharanthus roseus. 1666 28

The purpose of the present paper was to review studies of two candidate genes for attention deficit-hyperactivity disorder (ADHD) and to separate aetiological from therapeutic effects. Genomic studies of ADHD were reviewed for candidate dopamine genes and studies selected to distinguish catechol-o-methyltransferase (COMT) and dopamine transporter (DAT-1) effects. Pharmacogenomic findings for the COMT gene were in agreement with the 1977 observations of Sprague and Sleator, who reported that at low psychostimulant doses, children with ADHD showed a remarkable improvement on a short-term memory test at all levels of task load, whereas at higher doses, there was a significant decrement in performance on the more difficult versions of the task, corresponding to an 'inverted 'U' shaped curve'. Recent studies show that individuals with the homozygous COMT (valine/valine) genotype demonstrated improvement following psychostimulant treatment, because their tonic dopamine (DA) levels were low, whereas the homozygous COMT (methionine/methionine) individuals, who already have high initial prefrontal cortex (PFC) dopamine levels performed more poorly after medication, in tasks with high working memory load. On the other hand aetiological findings for DAT-1 gene were heterogenous, but more often positive than for COMT. Contrasting findings for COMT and DAT-1 may best be considered in terms of prediction of medication response in ADHD in the case of COMT, but in aetiological terms in the case of DAT-1, which is abundant in the striatum and possibly plays a greater role in determining hyperactivity and impulsivity, than working memory deficiencies.
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PMID:What do dopamine transporter and catechol-o-methyltransferase tell us about attention deficit-hyperactivity disorder? Pharmacogenomic implications. 1746 76

We tested human participants on a modified peak procedure in order to investigate the relation between interval timing and reward processing, and examine the interaction of this relation with three different dopamine-related gene polymorphisms. These gene polymorphisms affected the expression of catechol-o-methyltransferase, which catabolizes synaptic dopamine primarily in the prefrontal cortex (COMT Val158Met polymorphism), D2 dopamine receptors primarily in the striatum (DRD2/ANKK1-Taq1a polymorphism), and dopamine transporters, which clear synaptic dopamine in the striatum (DAT 3' VNTR variant). The inclusion of these polymorphisms allowed us to investigate dissociable aspects of the dopamine system and their interaction with reward magnitude manipulations in shaping timed behavior. These genes were chosen for their roles in reward processing and cortico-striatal information processing that have been implicated for interval timing. Consistent with recent animal studies, human participants initiated their timed anticipatory responding earlier when expecting a larger reward in the absence of any changes in the timing of response termination or perceived time. This effect however was specific to two out of four evaluated COMT and DRD2 polymorphism combinations that lead to high prefrontal dopamine coupled with high D2 density and low prefrontal dopamine coupled with low D2 density. Larger rewards also decreased timing precision indices, some of which interacted with the COMT polymorphism. Furthermore, the COMT polymorphism that leads to higher prefrontal dopamine resulted in weaker manifestation of memory variability (relative to threshold variability) in timed behavior. There was no effect of DAT polymorphisms on any of the core behavioral measures. These results suggest that the reward modulates decision thresholds rather than clock speed, and that these effects are specific to COMT and DRD2 epistasis effects that presumably constitute a balanced prefrontal and striatal dopamine transmission.
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PMID:Epistasis effects of dopamine genes on interval timing and reward magnitude in humans. 2290 38

Young leaves from Catharanthus roseus plants contain a novel N-methyltransferase which transfers the methyl group from S-adenosyl-L-methionine specifically to position 1 of (2R, 3R)-2,3-dihydro-3-hydroxytabersonine, producing the N-methylated product. The enzyme shows a high degree of specificity toward substrates containing a reduced double bond at position 2,3 of tabersonine derivatives but the more substituted N-desmethyldeacetylvindoline did not act as a substrate. The enzyme catalyses the third last step in vindorosine and vindoline biosynthesis, and is associated with chlorophyll-containing fractions in partially purified enzyme preparations. The lack of vindoline accumulation in cell suspension cultures is correlated with the lack of expression of this enzyme activity as well as that of an acetyltransferase which catalyses the last step in vindoline biosynthesis. Neither fungal elicitor treatment of cell line #615 nor transfer to alkaloid production medium resulted in expression of these two enzyme activities, nor was either enzyme activity detected in photoautotrophic or hormone autotrophic cultures. Cell lines #200, 615-767 and 916 could not be induced to produce DAT or NMT enzyme activities.
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PMID:Characterization of a novel N-methyltransferase (NMT) from Catharanthus roseus plants : Detection of NMT and other enzymes of the indole alkaloid biosynthetic pathway in different cell suspension culture systems. 2424 32