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At least 865 records · Page 48Linked to original sources
PubMed2002

Effect of precursor feeding on alkaloid accumulation by a tryptophan decarboxylase over-expressing transgenic cell line T22 of Catharanthus roseus.

To obtain more insight into the regulation of terpenoid indole alkaloid (TIA) biosynthesis in Catharanthus roseus (L.) G. Don cell cultures and particularly to identify possible rate limiting steps, a transgenic cell line over-expressing tryptophan decarboxylase (Tdc), and thus having a high level of tryptamine, was fed with various amounts of precursors (tryptophan, tryptamine, loganin and secologanin) in different time schedules and analyzed for TIA production. When these precursors were added to this culture it was found that the optimal time for supplying the precursors was at inoculation of the cells into the production medium. Alkaloid accumulation by line T22 was enhanced by addition of loganin or secologanin; however, the secologanin feeding was less effective. Tryptamine or tryptophan alone had no effect on TIA accumulation. The over-expression of Tdc causes this cell line to produce quite large quantities of alkaloids after feeding loganin or secologanin. However, in combination with tryptophan or tryptamine, feeding of these precursors resulted in an even further increase of alkaloid accumulation and under optimal conditions line T22 accumulated around 1200 micromol l(-1) of TIAs whereas the control cultures accumulated less than 10 micromol l(-1) TIAs.

Alkaloids↗
PubMed1998

Synthesis of 2-iodo- and 2-phenyl-[11C]melatonin: potential PET tracers for melatonin binding sites.

Two 11C-labelled melatonin derivatives, 2-iodo-[11C]melatonin (2-iodo-5-methoxy-N[11C-acetyl]-tryptamine, an agonist) and 2-phenyl-[11C]melatonin (2-phenyl-5-methoxy-N[11C-acetyl]tryptamine, a putative antagonist) were synthesized from [11C]carbon dioxide. The reaction sequence was common to both compounds and consisted of three steps: (i) carbonylation of methyl magnesium bromide with [11C]carbon dioxide, (ii) conversion of the adduct to [11C]acetyl chloride, (iii) acetylation of the amine precursors (2-iodo-5-methoxy-tryptamine or 2-phenyl-5-methoxy-tryptamine) with [11C]acetyl chloride. The precursors were especially prepared. The radiochemical yield was 19% for 2-iodomelatonin and 32% for 2-phenymelatonin, based on [11C]carbon dioxide; the specific activity ranged from 300 to 600 mCi/mumol. Both labelled 2-substituted-melatonins are intended to be used as radiotracers to study melatonin binding sites in man with positron emission tomography.

Acetylation↗
PubMed1998

Influence of Precursor Availability on Alkaloid Accumulation by Transgenic Cell Line of Catharanthus roseus

We have used a transgenic cell line of Catharanthus roseus (L.) G. Don to study the relative importance of the supply of biosynthetic precursors for the synthesis of terpenoid indole alkaloids. Line S10 carries a recombinant, constitutively overexpressed version of the endogenous strictosidine synthase (Str) gene. Various concentrations and combinations of the substrate tryptamine and of loganin, the immediate precursor of secologanin, were added to suspension cultures of S10. Our results indicate that high rates of tryptamine synthesis can take place under conditions of low tryptophan decarboxylase activity, and that high rates of strictosidine synthesis are possible in the presence of a small tryptamine pool. It appears that the utilization of tryptamine for alkaloid biosynthesis enhances metabolic flux through the indole pathway. However, a deficiency in the supply of either the iridoid or the indole precursor can limit flux through the step catalyzed by strictosidine synthase. Precursor utilization for the synthesis of strictosidine depends on the availability of the cosubstrate; the relative abundance of these precursors is a cell-line-specific trait that reflects the metabolic status of the cultures.

Journal Article↗
PubMed1996

Selection of distinct conformational states of the 5-HT3 receptor by full and partial agonists.

1. 5-Hydroxytryptamine 5-HT3 receptor-mediated ion currents evoked by 5-HT, quaternary 5-HT (5-HTQ), meta-chlorophenylbiguanide (mCPBG), dopamine and tryptamine in N1E-115 mouse neuroblastoma cells have been investigated in whole-cell voltage clamp and single channel patch clamp experiments. 2. The concentration-dependent activation and desensitization of the ion currents evoked by the agonists yield the potency order: mCPBG > 5-HTQ approximately 5-HT >> tryptamine > dopamine, and the efficacy order: 5-HT approximately mCPBG approximately 5-HTQ >> dopamine approximately tryptamine. Thus, 5-HT, 5-HTQ and mCPBG are full agonists, whereas dopamine and tryptamine are partial agonists at the 5-HT3 receptor. 3. Full and partial agonists cause complete cross-desensitization and activate single channels with similar conductances and open lifetimes. This shows that full and partial agonists act on the same population of 5-HT3 receptors. 4. The time course of recovery from desensitization depends on the agonist used. Recovery from partial agonist-induced desensitization is single exponential, whereas the desensitization induced by full agonists recovers with sigmoid kinetics, suggesting at least 3 steps between 4 states. 5. During the process of recovery from cross-desensitization, the full agonists activate a larger fraction of the 5-HT3 receptors than the partial agonists, irrespective of the agonist used to induce desensitization. 6. It is concluded that full and partial agonists induce distinct desensitized states and, during recovery from desensitization, recognize distinct conformations of unoccupied 5-HT3 receptors. This conformational selection is likely to account for the different efficacies of full and partial 5-HT3, receptor agonists.

Animals↗
PubMed2003

Pharmacological characterization of a serotonin receptor (5-HT7) stimulating cAMP production in human corneal epithelial cells.

PURPOSE: To study the mRNA and pharmacology of a serotonin (5-HT) receptor positively coupled to adenylyl cyclase in normal, primary (P-CEPI), and immortalized human corneal epithelial cells (CEPI-17-CL4), by using numerous 5-HT agonists and antagonists. To determine and compare cloned human 5-HT7 receptor binding affinities of compounds with their functional potency data. METHODS: RT-PCR was used to detect the presence of an mRNA for the human 5-HT7 receptor in CEPI-17-CL4 cells. Receptor-mediated production of cAMP in cultured cells was measured using an enzyme immunoassay. Compound binding affinities were determined using [3H]-lysergic acid diethylamide ([3H]-LSD) binding to cell membranes of human embryonic kidney (HEK-293) cells expressing the cloned human 5-HT7 receptor. RESULTS: RT-PCR revealed the presence of a 5-HT7 receptor mRNA in CEPI-17-CL4 cells. Normal P-CEPI cells generated cAMP in response to 5-HT (-log EC50; pEC50=7.6), 5-carboxamidotryptamine (5-CT; pEC50=7.8), 5-methoxy-tryptamine (pEC50=7.0) and 5-methoxy-dimethyl-tryptamine (pEC50=5.7). In CEPI-17-CL4 cells, serotonergic agonists also stimulated cAMP production with different potencies (pEC50): 5-CT (7.4)>5-HT (6.5)> or =5-methoxy-tryptamine (6.1)>5-methoxy-dimethyl-tryptamine (5.4)> or =8-OH-DPAT (<5.0)=alpha-methyl-5-HT (<5.0). Various 5-HT receptor antagonists inhibited cAMP production induced by 5-CT in CEPI-17-CL4 cells with different potencies (pKi): methiothepin (8.5)>mesulergine (8.1)=metergoline (8.0)>spiperone (7.4)> or =clozapine (7.2)=SB-258719 (7.2)>mianserin (6.9)>ketanserin (6.3). Antagonist pKi values in P-CEPI cells were methiothepin (8.7), spiperone (7.4) and SB-258719 (6.6). The rank order of affinity for displacement of [3H]-LSD from the cloned human 5-HT7 receptor was: methiothepin>ritanserin>mesulergine=clozapine> or =metergoline=5-HT>SB-258719> or =spiperone>mianserin> or =ketanserin. The functional agonist and antagonist potency data obtained from CEPI-17-CL4 cells correlated well with cloned human 5-HT7 receptor binding affinity data (r=0.69), with P-CEPI cell functional data (r=0.85), and with functional potency data in the literature for the cloned human 5-HT7 receptor (r=0.88). CONCLUSIONS: These collective data support the presence of a pharmacologically defined, adenylyl cyclase-coupled 5-HT7 receptor in the CEPI-17-CL4 cells that may have relevance to physiological and/or pathologic functions of 5-HT7 receptors in the human cornea.

Adenylyl Cyclases↗
PubMed1984

Some interrelated properties of A and B form monoamine oxidase in monkey brain mitochondria.

The multiplicity of monoamine oxidase (MAO) in monkey brain was studied by comparing the relationship between the selective substrates of MAO and the pH-activity curves obtained using these substrates. When mitochondrial and A-form MAO were used as the enzyme preparations with serotonin (5-HT) and norepinephrine (NE), preferential substrates for A-form MAO, the pH optima were 8.8 and 7.8 with 5-HT and 8.5 and 7.2 with NE. These substrates were also oxidized by B-form MAO after changing the pH of the incubation medium (shift to alkaline); these pH optima were 9.0 and 8.2, respectively. When common substrates of MAO were used (tyramine, octopamine, dopamine and tryptamine), the pH activity curves obtained were all broad and bell-shaped with pH optima for the 3 species of enzyme (mitochondria, A-form and B-form MAO) at 8.0, 7.8, and 8.0 with tyramine; 8.3, 7.5, and 8.5 with octopamine; 7.8, 7.5, and 8.5 with dopamine; and 8.0, 8.3, and 6.9 with tryptamine, respectively. The pH optima were 6.6 with beta-phenylethylamine (beta-PEA) and 9.0 with benzylamine, preferential substrates for B-form MAO, for either mitochondria or B-form MAO. The Km values obtained for tryptamine and beta-PEA were lower than those for the other substrates of MAO, regardless of the enzyme preparations. The Km and Vmax values of both forms MAO for 5-HT and NE were similar to those of the A-form MAO. The differences in the Km and Vmax values of the A-form MAO and B-form MAO for common substrates were comparable. Tyramine, octopamine and dopamine were substrates for both forms MAO, with only a slight preference for B-form MAO over A-form MAO. However, tryptamine may be deaminated predominantly by A-form MAO.

Animals↗
PubMed2006

Precursor limitations in methyl jasmonate-induced Catharanthus roseus cell cultures.

Jasmonates enhance the expression of various genes involved in terpenoid indole alkaloid (TIA) biosynthesis in Catharanthus roseus. We applied precursor feeding to our C. roseus suspensions to determine how methyl jasmonate (MJ) alters the precursor availability for TIA biosynthesis. C. roseus suspensions were induced with MJ (100 microM) on day 6 and fed loganin (0.30 mM), tryptamine (0.15 mM), loganin plus tryptamine, or geraniol (0.1-1.0 mM) on day 7. While MJ increased ajmalicine production by 3-fold, induced cultures were still limited by terpenoid precursors. However, both induced and non-induced cultures became tryptamine-limited with excess loganin. Geraniol feeding also increased ajmalicine production in non-induced cultures. But MJ appeared to increase geraniol availability in induced cultures, due presumably to the increased expression of Dxs with MJ addition.

Acetates↗
PubMed1964

THE EFFECTS OF DRUGS ON THE UPTAKE OF AMINES BY MAST CELLS.

Neoplastic mast cells, taken from an ascitic tumour in mice and incubated in vitro, took up (14)C-labelled 5-hydroxytryptamine and histamine from the medium. Uptake during the first hour gave an approximate measure of the initial rate. The amount of each amine taken up in this time was determined by bioassay and by radioactivity, the two methods giving similar results. The curves obtained by plotting initial rate of uptake against concentration in the medium suggested that the uptake of 5-hydroxytryptamine was by an active process and also by diffusion, whereas uptake of histamine was by diffusion only. The cells also took up (14)C-labelled (+/-)-noradrenaline and tryptamine, apparently by diffusion. The active uptake of 5-hydroxytryptamine was inhibited by lowering the temperature to 25 degrees C or by increasing the pH to 8.9, procedures which had little effect on histamine uptake. The effects of cocaine, imipramine, chlorpromazine, mepyramine, promethazine, phenoxybenzamine, lysergic acid diethylamide, bromolysergic acid diethylamide, methysergide, guanethidine, dichloroisoprenaline and pronethalol on the uptake of amines were examined. In general, any antagonist which inhibited uptake of 5-hydroxytryptamine had little effect on uptake of histamine, and vice versa. Possible ways in which these antagonists produce their effects on amine uptake are discussed. A high concentration of 5-hydroxytryptamine, of tryptamine or of noradrenaline inhibited uptake of histamine, but only tryptamine decreased uptake of 5-hydroxytryptamine. These results, together with those from experiments with antagonists, suggest that there are specific binding sites for 5-hydroxtryptamine in these cells.

Amines↗
PubMed2002

X-ray crystallographic studies of serotonin N-acetyltransferase catalysis and inhibition.

The structure of serotonin N-acetyltransferase (also known as arylalkylamine N-acetyltransferase; AANAT) bound to a potent bisubstrate analog inhibitor has been determined at 2.0 A resolution using a two-edge (Se, Br) multiwavelength anomalous diffraction (MAD) experiment. This acetyl-CoA dependent enzyme is a member of the GCN5-related family of N-acetyltransferases (GNATs), which share four conserved sequence motifs (A-D). In serotonin N-acetyltransferase, motif A adopts an alpha/beta conformation characteristic of the phylogenetically invariant cofactor binding site seen in all previously characterized GNATs. Motif B displays a significantly lower level of conservation among family members, giving rise to a novel alpha/beta structure for the serotonin binding slot. Utilization of a brominated CoA-S-acetyl-tryptamine-bisubstrate analog inhibitor and the MAD method permitted conclusive identification of two radically different conformations for the tryptamine moiety in the catalytic site (cis and trans). A second high-resolution X-ray structure of the enzyme bound to a bisubstrate analog inhibitor, with a longer tether between the acetyl-CoA and tryptamine moieties, demonstrates only the trans conformation. Given a previous proposal that AANAT can catalyze an alkyltransferase reaction in a conformationally altered active site relative to its acetyltransferase activity, it is possible that the two conformations of the bisubstrate analog observed crystallographically correspond to these alternative reaction pathways. Our findings may ultimately lead to the design of analogs with improved AANAT inhibitory properties for in vivo applications.

Acetyl Coenzyme A↗
PubMed1999

Latest on enzymology of serotonin biosynthesis in walnut seeds.

Serotonin (5-HT) accumulation in walnut cotyledons is seen as a detoxification mechanism protecting the sensitive plant tissues of seeds from highly toxic ammonia concentrations following seed desiccation. Different metabolic pathways and cell compartments are involved in biosynthesis and storage of 5-HT. Ammonia fixation and incorporation into the indole moiety of tryptophan is followed by 5-HT biosynthesis via tryptamine in a two-step pathway with the adaptive tryptophan decarboxylase and the constitutive tryptamine 5-hydroxylase. Evidence is provided that tryptamine 5-hydroxylase is a member of the cytochrome P450 family which is involved in lipid hydroxylation processes in the very early period of seed development.

Ammonia↗
PubMed1977

Substrate-typic changes of platelet monoamine oxidase activity in sub-types of schizophrenia.

Monoamine oxidase (MAO) activity has been measured in the platelets of controls (n = 42) and schizophrenic patients (n = 49) of three subtypes, using beta-phenylethylamine, p-tyramine, and tryptamine as substrates. Characteristic differences of MAO activity were observed between platelets of patients and controls; the differences were substrate-typic: decreased enzyme activity was found with all three substrates in platelets of the parnaoid subtype. With tryptamine, MAO activity was decreased in the platelets of all three sub-types of schizophrenia. With p-tyramine, MAO was low in patients with affective psychoses and paranoid schizophrenia. The value of MAO activity measurements as a means for distinguishing sub-types of schizophrenic disorders is improved by using two substrates; tryptamine and p-tyramine. Possible mechanisms of the substrate-typic changes of platelet MAO activity in schizophrenia are discussed.

Adult↗
PubMed1982

Monoamine oxidase inhibition by tranylcypromine: assessment in human volunteers.

The inhibition of monoamine oxidase (MAO) by tranylcypromine was studied in 6 healthy volunteers given increasing doses of 10, 15, 20 and 25 mg/day over a 4-week period. Measurements were made of urinary tryptamine excretion, blood pressure response to tyramine (TY) and norepinephrine (NE), and subjective self-rating. A significant increase in urinary tryptamine, indicating the onset of MAO inhibition, occurred in all 6 subjects once the cumulative dose of 40 mg TC had been administered. Thereafter, urinary tryptamine increased up to 7-fold, dose-dependently with large interindividual variation (78 +/- 27 to 549 +/- 252 microgram/g creatinine). Within 4 days after stopping the drug, control values were reached again. The assessment of TY potentiation by comparison of equieffective doses (S dose) became up to 10 times more sensitive when both the height and the duration of the increase in systolic blood pressure (S AUC) were taken into account. The increases in tyramine sensitivity found with the highest cumulative doses of TC (5.4 +/- 0.8 mg/kg; n =6) were S dose from 8-16 and S AUC from 28-162, respectively. The pharmacodynamic half-life (Pd 1/2) of TC approximated a mean first fast Pd 1/2 of 1.3 d and a slower phase of 14.2 d. During treatment with the highest TC dose, resting blood pressure was significantly elevated from 120 to 128 mm Hg, and the pressor sensitivity to NE (S NE) in 4 of the 6 subjects rose, the mean was 1.7 (n = 6). In 3 volunteers NE sensitivity was normalized within 4 days after stopping TC. There was a significant correlation between increasing vigilance with TC dose in 5 volunteers (r = 0.81, n = 15, p less than 0.01). It is concluded that combination of the results of several tests has provided reliable information about the onset, extent and duration of MAO inhibition in healthy volunteers.

Adult↗
PubMed1984

Histochemical localization of monoamine oxidase in whole-body, freeze-dried sections of mice.

Monoamine oxidase was investigated histochemically in tissues of the mouse by incubating freeze-dried, whole-body sections with tryptamine, serotonin, tyramine, beta-phenylethylamine, or benzylamine as substrate and Nitroblue tetrazolium as the final electron acceptor. The most intense staining with tryptamine was exhibited by intestinal epithelium and adrenal cortex; moderate staining was noted in the epithelium of the nose, bronchi, oesophagus, and upper stomach and in preputial gland, pancreas, nerve, spinal cord and brain. Weak staining was seen in the lung, spleen, liver and kidney. The distribution of the formazan deposition was similar, but much less intense, when serotonin and tyramine were used as the substrates. Only very weak staining was observed when beta-phenylethylamine was the substrate; no staining was seen with benzylamine. Monoamine oxidase activities with tryptamine were greatly inhibited by pretreatment with clorgyline (10 microM), while deprenyl (10 microM) slightly inhibited activities in all tissues except liver. This staining technique should be useful in further studies on the identification of the multiple forms of monoamine oxidase in tissues of the mouse. Nicotine and nitrosonornicotine were not substrates in any of the tissues; consequently, this enzyme system does not appear to produce the proximal carcinogen from this nitrosamine.

Adrenal Cortex↗
PubMed1989

Possible mechanisms of inhibition and activation of rat N-acetyltransferase (EC 2.3.1.5.) by cations.

The possible mechanisms of inhibition and activation of various cations on rat pineal N-acetyltransferase (NAT) were elucidated. Copper was found to be a partial mixed noncompetitive inhibitor of NAT with respect to both substrates and this inhibition can be considered to result primarily from impairment of tryptamine (serotonin) binding to the enzyme. Both calcium and magnesium were found to activate NAT by a similar mechanism, with calcium being more effective than magnesium. It appears that the activation results from cation binding to the enzyme causing an increased affinity of tryptamine (serotonin) for binding to NAT and therefore enhancing catalytic activity. The monovalent cations, potassium and sodium, activated NAT by a similar mechanism which differed from the caused by the divalent cations. It can be suggested that tryptamine (serotonin) binds to the enzyme followed by the monovalent cation which enhances binding of the acetyl donor and thereby promotes catalysis. At high potassium or sodium concentration the affinity of acetyl coenzyme A for NAT begins to decrease suggesting that excess monovalent cations can be inhibitory and may represent an endogenous regulatory mechanism controlling in vivo NAT activity. It is possible that certain cations may be involved in regulation of melatonin synthesis although the physiological significance of such modulation remains unknown.

Acetyl Coenzyme A↗
PubMed1987

Elicitor-mediated induction of tryptophan decarboxylase and strictosidine synthase activities in cell suspension cultures of Catharanthus roseus.

Treatment of one cell line (No. 615) of Catharanthus roseus c.v. Little Delicata with an elicitor preparation of autoclaved and homogenized Pythium aphanidermatum culture resulted in rapid accumulation of indole alkaloids. Alkaloid formation was preceded by rapid transient increases in the extractable activities of the enzymes tryptophan decarboxylase and strictosidine synthase. The induction of these two enzyme activities occurred when cells were transferred to alkaloid production medium or treatment with fungal elicitors. Treatment of this cell line with translational or transcriptional inhibitors prevented the Pythium-induced increases of enzyme activity as well as alkaloid accumulation. When cells were transferred to alkaloid production medium the induction of strictosidine synthase activity preceded that of tryptophan decarboxylase by many hours even when cells were also treated with Pythium elicitor. Results suggested that tryptophan decarboxylase induction proceeds only when endogenous tryptamine levels were decreased by two-third. The internal cellular level of tryptamine, therefore, could regulate expression of tryptophan decarboxylase, whereas induction of strictosidine synthase or of another enzyme in the biosynthetic pathway could control channeling of tryptamine into alkaloids. The results demonstrate that fungal elicitors can be used to facilitate studies of the factors which regulate expression of indole alkaloid pathway enzymes and their ultimate pathway products.

Alkaloids↗
PubMed1993

The transport mechanisms of organic cations and their zwitterionic derivatives across rat intestinal brush-border membrane. 1. Binding characteristics to the bio- and lipid-membranes.

The uptake mechanisms of organic cations such as tryptamine, tyramine, 5-benzyloxytryptamine (BOTA) and their zwitterionic derivatives (tyrosine, tryptophan, 5-benzyloxytryptophan (BOTP)) by rat intestinal brush-border membrane vesicles and liposome containing phosphatidylserine were studied and compared. As compared to their zwitterionic derivatives, uptake rates by rat intestinal brush-border membrane of these three cations were far superior. The binding of cationic compounds to the brush-border membrane was also higher than those of their zwitterionic derivatives. Furthermore, the binding behaviour of BOTA and tryptamine to phospholipid liposome clearly amplified with increasing amounts of phosphatidylserine. In contrast, the contents of phosphatidylserine, a negatively charged phospholipid, exhibited no effects on the binding of zwitterionic derivatives (tryptophan and BOTP). The double-reciprocal plot of tryptamine binding with BOTA to liposome showed competitive inhibition. These results suggest that the binding of organic cations to the membrane lipid has a relatively high specificity despite the absence of membrane protein such as a transport-carrier in the liposome, and that the binding of cationic compounds play an important role in the uptake to the cell membrane systems.

Animals↗
PubMed1978

N-Acetyltransferase activity of the rat Harderian gland.

Harderian gland extracts from male rats catalyze the conversion of serotonin to N-acetylserotonin and of tryptamine to N-acetyltryptamine. The reaction is linear up to 14 mg tissue and departs from linearity after 10 min. The pH otpimum with tryptamine as substrate is between 8 and 9. Enzymic activity of the gland in vivo does not show diurnal variations. Enzymic activity of tissue in organ culture is not stimulated by 10 micrometer isoproterenol or 100 micrometer dibutyryl cyclic AMP. Harderian gland tissue in culture can acetylate tryptamine and serotonin and can O-methylate the N-acetylserotonin to form melatonin.

Acetylation↗
PubMed1975

Role of prostaglandins in tone and effector reactivity of the isolated rat stomach preparation.

The influence of indomethacin (2 mug/ml) on the tone and on the response to ACh, 5-HT and tryptamine of the stomach strip preparation from normal and Essential Fatty Acid Deficient (EFAD) rats was examined. The pD2 value of ACh and 5-HT, but not of tryptamine, was significantly lower on the preparations obtained from EFAD rats than on those from normal rats. Contradictory results were obtained with respect to the influence of indomethacin on the pD2 value of ACh, 5-HT and tryptamine. No significant difference in initial tone and contractility of the stomach strips of both groups of rats was observed. However, the tone of the strips from normal rats increased with time. Preparations from EFAD rats showed a gradual decrease of the tome with time. Pre-incubation with indomethacin reduced the tone of strips from both groups of rats to a comparable extent. Thus further support is provided for the proposed role of prostaglandins in the maintenance of the tone of isolated smooth muscle. The possibility is raised that prostaglandins might not be predominantly involved in the generation of the initial tone and also not substantially contribute to the effector reactivity of the organ.

Acetylcholine↗