702 results on '"5-Methoxytryptamine"'
Search Results
2. Escherichia coli RimI Encodes Serotonin N -Acetyltransferase Activity and Its Overexpression Leads to Enhanced Growth and Melatonin Biosynthesis.
- Author
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Lee, Kyungjin and Back, Kyoungwhan
- Subjects
- *
BIOSYNTHESIS , *ESCHERICHIA coli , *SEROTONIN , *GENETIC overexpression , *MELATONIN , *SEROTONIN receptors , *ENZYME kinetics , *PHYTOCHELATINS - Abstract
Serotonin N-acetyltransferase (SNAT) functions as the penultimate or final enzyme in melatonin biosynthesis, depending on the substrate. The Escherichia coli orthologue of archaeal SNAT from Thermoplasma volcanium was identified as RimI (EcRimI), with 42% amino acid similarity to archaeal SNAT. EcRimI has been reported to be an N-acetyltransferase enzyme. Here, we investigated whether EcRimI also exhibits SNAT enzyme activity. To achieve this goal, we purified recombinant EcRimI and examined its SNAT enzyme kinetics. As expected, EcRimI showed SNAT activity toward various amine substrates including serotonin and 5-methoxytryptamine, with Km and Vmax values of 531 μM and 528 pmol/min/mg protein toward serotonin and 201 μM and 587 pmol/min/mg protein toward 5-methoxytryptamine, respectively. In contrast to the rimI mutant E. coli strain that showed no growth defect, the EcRimI overexpression strain exhibited a 2-fold higher growth rate than the control strain after 24 h incubation in nutrient-rich medium. The EcRimI overexpression strain produced more melatonin than the control strain in the presence of 5-methoxytryptamine. The enhanced growth effect of EcRimI overexpression was also observed under cadmium stress. The higher growth rate associated with EcRimI expression was attributed to increased protein N-acetyltransferase activity, increased synthesis of melatonin, or the combined effects of both. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
3. The Role of the PAA1 Gene on Melatonin Biosynthesis in Saccharomyces cerevisiae : A Search of New Arylalkylamine N -Acetyltransferases.
- Author
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Bisquert, Ricardo, Planells-Cárcel, Andrés, Alonso-del-Real, Javier, Muñiz-Calvo, Sara, and Guillamón, José Manuel
- Subjects
SACCHAROMYCES cerevisiae ,ARYLALKYLAMINE N-acetyltransferase ,BIOSYNTHESIS ,ESCHERICHIA coli ,MELATONIN ,SEROTONIN receptors - Abstract
Recently, the presence of melatonin in fermented beverages has been correlated with yeast metabolism during alcoholic fermentation. Melatonin, originally considered a unique product of the pineal gland of vertebrates, has been also identified in a wide range of invertebrates, plants, bacteria, and fungi in the last two decades. These findings bring the challenge of studying the function of melatonin in yeasts and the mechanisms underlying its synthesis. However, the necessary information to improve the selection and production of this interesting molecule in fermented beverages is to disclose the genes involved in the metabolic pathway. So far, only one gene has been proposed as involved in melatonin production in Saccharomyces cerevisiae, PAA1, a polyamine acetyltransferase, a homolog of the vertebrate's aralkylamine N-acetyltransferase (AANAT). In this study, we assessed the in vivo function of PAA1 by evaluating the bioconversion of the different possible substrates, such as 5-methoxytryptamine, tryptamine, and serotonin, using different protein expression platforms. Moreover, we expanded the search for new N-acetyltransferase candidates by combining a global transcriptome analysis and the use of powerful bioinformatic tools to predict similar domains to AANAT in S. cerevisiae. The AANAT activity of the candidate genes was validated by their overexpression in E. coli because, curiously, this system evidenced higher differences than the overexpression in their own host S. cerevisiae. Our results confirm that PAA1 possesses the ability to acetylate different aralkylamines, but AANAT activity does not seem to be the main acetylation activity. Moreover, we also prove that Paa1p is not the only enzyme with this AANAT activity. Our search of new genes detected HPA2 as a new arylalkylamine N-acetyltransferase in S. cerevisiae. This is the first report that clearly proves the involvement of this enzyme in AANAT activity. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
4. The Role of the PAA1 Gene on Melatonin Biosynthesis in Saccharomyces cerevisiae: A Search of New Arylalkylamine N-Acetyltransferases
- Author
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Ricardo Bisquert, Andrés Planells-Cárcel, Javier Alonso-del-Real, Sara Muñiz-Calvo, and José Manuel Guillamón
- Subjects
yeast ,E. coli ,melatonin ,tryptophan metabolism ,N-acetylserotonin ,5-methoxytryptamine ,Biology (General) ,QH301-705.5 - Abstract
Recently, the presence of melatonin in fermented beverages has been correlated with yeast metabolism during alcoholic fermentation. Melatonin, originally considered a unique product of the pineal gland of vertebrates, has been also identified in a wide range of invertebrates, plants, bacteria, and fungi in the last two decades. These findings bring the challenge of studying the function of melatonin in yeasts and the mechanisms underlying its synthesis. However, the necessary information to improve the selection and production of this interesting molecule in fermented beverages is to disclose the genes involved in the metabolic pathway. So far, only one gene has been proposed as involved in melatonin production in Saccharomyces cerevisiae, PAA1, a polyamine acetyltransferase, a homolog of the vertebrate’s aralkylamine N-acetyltransferase (AANAT). In this study, we assessed the in vivo function of PAA1 by evaluating the bioconversion of the different possible substrates, such as 5-methoxytryptamine, tryptamine, and serotonin, using different protein expression platforms. Moreover, we expanded the search for new N-acetyltransferase candidates by combining a global transcriptome analysis and the use of powerful bioinformatic tools to predict similar domains to AANAT in S. cerevisiae. The AANAT activity of the candidate genes was validated by their overexpression in E. coli because, curiously, this system evidenced higher differences than the overexpression in their own host S. cerevisiae. Our results confirm that PAA1 possesses the ability to acetylate different aralkylamines, but AANAT activity does not seem to be the main acetylation activity. Moreover, we also prove that Paa1p is not the only enzyme with this AANAT activity. Our search of new genes detected HPA2 as a new arylalkylamine N-acetyltransferase in S. cerevisiae. This is the first report that clearly proves the involvement of this enzyme in AANAT activity.
- Published
- 2023
- Full Text
- View/download PDF
5. Investigators at Icahn School of Medicine at Mount Sinai Describe Findings in Life Science (Structural Pharmacology and Therapeutic Potential of 5-methoxytryptamines).
- Abstract
A recent study conducted at the Icahn School of Medicine at Mount Sinai explores the structural pharmacology and therapeutic potential of 5-methoxytryptamines, a class of psychedelic substances. The research focuses on the serotonin receptor 5-HT1A and its role in the behavioral effects of tryptamine hallucinogens, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). Through cryogenic electron microscopy and other techniques, the study identifies the molecular determinants of 5-HT1A signaling potency, efficacy, and selectivity. The findings may contribute to the development of new medications for neuropsychiatric disorders. [Extracted from the article]
- Published
- 2024
6. The Role of the PAA1 Gene on Melatonin Biosynthesis in Saccharomyces cerevisiae: A Search of New Arylalkylamine N-Acetyltransferases
- Author
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Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Ministerio de Educación, Cultura y Deporte (España), European Commission, Bisquert, Ricardo [0000-0001-6381-8852], Alonso del Real, Javier [0000-0002-6474-9040], Muñiz Calvo, Sara [0000-0003-4689-6589], Guillamón, José Manuel [0000-0001-5414-0787], Bisquert, Ricardo, Planells-Cárcel, Andrés, Alonso del Real, Javier, Muñiz Calvo, Sara, Guillamón, José Manuel, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Ministerio de Educación, Cultura y Deporte (España), European Commission, Bisquert, Ricardo [0000-0001-6381-8852], Alonso del Real, Javier [0000-0002-6474-9040], Muñiz Calvo, Sara [0000-0003-4689-6589], Guillamón, José Manuel [0000-0001-5414-0787], Bisquert, Ricardo, Planells-Cárcel, Andrés, Alonso del Real, Javier, Muñiz Calvo, Sara, and Guillamón, José Manuel
- Abstract
Recently, the presence of melatonin in fermented beverages has been correlated with yeast metabolism during alcoholic fermentation. Melatonin, originally considered a unique product of the pineal gland of vertebrates, has been also identified in a wide range of invertebrates, plants, bacteria, and fungi in the last two decades. These findings bring the challenge of studying the function of melatonin in yeasts and the mechanisms underlying its synthesis. However, the necessary information to improve the selection and production of this interesting molecule in fermented beverages is to disclose the genes involved in the metabolic pathway. So far, only one gene has been proposed as involved in melatonin production in Saccharomyces cerevisiae, PAA1, a polyamine acetyltransferase, a homolog of the vertebrate’s aralkylamine N-acetyltransferase (AANAT). In this study, we assessed the in vivo function of PAA1 by evaluating the bioconversion of the different possible substrates, such as 5-methoxytryptamine, tryptamine, and serotonin, using different protein expression platforms. Moreover, we expanded the search for new N-acetyltransferase candidates by combining a global transcriptome analysis and the use of powerful bioinformatic tools to predict similar domains to AANAT in S. cerevisiae. The AANAT activity of the candidate genes was validated by their overexpression in E. coli because, curiously, this system evidenced higher differences than the overexpression in their own host S. cerevisiae. Our results confirm that PAA1 possesses the ability to acetylate different aralkylamines, but AANAT activity does not seem to be the main acetylation activity. Moreover, we also prove that Paa1p is not the only enzyme with this AANAT activity. Our search of new genes detected HPA2 as a new arylalkylamine N-acetyltransferase in S. cerevisiae. This is the first report that clearly proves the involvement of this enzyme in AANAT activity.
- Published
- 2023
7. Comparative genomics of N-acetyl-5-methoxytryptamine members in four Prunus species with insights into bud dormancy and abiotic stress responses in Prunus avium.
- Author
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Manzoor MA, Xu Y, Lv Z, Xu J, Wang Y, Sun W, Liu X, Wang L, Abdullah M, Liu R, Jiu S, and Zhang C
- Subjects
- 5-Methoxytryptamine, Phylogeny, Acetylserotonin O-Methyltransferase chemistry, Acetylserotonin O-Methyltransferase genetics, Acetylserotonin O-Methyltransferase metabolism, Genomics, Stress, Physiological genetics, Prunus avium genetics, Prunus avium metabolism, Prunus genetics, Prunus metabolism, Melatonin genetics, Melatonin metabolism, Arabidopsis genetics
- Abstract
Key Message: This study provides novel insights into the evolution, diversification, and functions of melatonin biosynthesis genes in Prunus species, highlighting their potential role in regulating bud dormancy and abiotic stresses. The biosynthesis of melatonin (MEL) in plants is primarily governed by enzymatic reactions involving key enzymes such as serotonin N-acetyltransferase (SNAT), tryptamine 5-hydroxylase (T5H), N-acetylserotonin methyltransferase (ASMT) and tryptophan decarboxylase (TDC). In this study, we analyzed Melatonin genes in four Prunus species such as Prunus avium (Pavi), Prunus pusilliflora (Ppus), Prunus serulata (Pser), and Prunus persica (Pper) based on comparative genomics approach. Among the four Prunus species, a total of 29 TDCs, 998 T5Hs, 16 SNATs, and 115 ASMTs within the genome of four Prunus genomes. A thorough investigation of melatonin-related genes was carried out using systematic biological methods and comparative genomics. Through phylogenetic analysis, orthologous clusters, Go enrichment, syntenic relationship, and gene duplication analysis, we discovered both similarities and variations in Melatonin genes among these Prunus species. Additionally, our study revealed the existence of unique subgroup members in the Melatonin genes of these species, which were distinct from those found in Arabidopsis genes. Furthermore, the transcriptomic expression analysis revealed the potential significance of melatonin genes in bud dormancy regulation and abiotic stresses. Our extensive results offer valuable perspectives on the evolutionary patterns, intricate expansion, and functions of PavMEL genes. Given their promising attributes, PavTDCs, PavT5H, PavNAT, and three PavASMT genes warrant in-depth exploration as prime candidates for manipulating dormancy in sweet cherry. This was done to lay the foundation for future explorations into the structural and functional aspects of these factors in Prunus species. This study offers significant insights into the functions of ASMT, SNAT, T5H, and TDC genes and sheds light on their roles in Prunus avium. Moreover, it established a robust foundation for further exploration functional characterization of melatonin genes in fruit species., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2024
- Full Text
- View/download PDF
8. Functions and prospects of melatonin in plant growth, yield, and quality
- Author
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Kaixin Wang, Qufan Xing, Golam Jalal Ahammed, and Jie Zhou
- Subjects
5-Methoxytryptamine ,Crops, Agricultural ,Free Radicals ,Physiology ,Animals ,Plant Science ,Plant Physiological Phenomena ,Melatonin - Abstract
Melatonin (N-acetyl-5-methoxytryptamine) is an indole molecule widely found in animals and plants. It is well known that melatonin improves plant resistance to various biotic and abiotic stresses due to its potent free radical scavenging ability while being able to modulate plant signaling and response pathways through mostly unknown mechanisms. In recent years, an increasing number of studies have shown that melatonin plays a crucial role in improving crop quality and yield by participating in the regulation of various aspects of plant growth and development. Here, we review the effects of melatonin on plant vegetative growth and reproductive development, and systematically summarize its molecular regulatory network. Moreover, the effective concentrations of exogenously applied melatonin in different crops or at different growth stages of the same crop are analysed. In addition, we compare endogenous phytomelatonin concentrations in various crops and different organs, and evaluate a potential function of phytomelatonin in plant circadian rhythms. The prospects of different approaches in regulating crop yield and quality through exogenous application of appropriate concentrations of melatonin, endogenous modification of phytomelatonin metabolism-related genes, and the use of nanomaterials and other technologies to improve melatonin utilization efficiency are also discussed.
- Published
- 2022
- Full Text
- View/download PDF
9. The cutaneous stress response system in three-spined stickleback and European flounder exposed to oxidative stress: Different mode of action.
- Author
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Pomianowski, Konrad, Gozdowska, Magdalena, Sokołowska, Ewa, and Kulczykowska, Ewa
- Subjects
- *
THREESPINE stickleback , *EUROPEAN flounder , *OXIDATIVE stress , *POTASSIUM dichromate , *STICKLEBACKS , *HUMAN skin color , *PARALICHTHYS - Abstract
In fish, the skin is directly exposed to multiple environmental stressors and provides the first line of defense against harmful external factors. It turned out that cortisol and melatonin (Mel) are involved in fish cutaneous stress response system (CSRS) similar to mammalian. This study investigates the mode of action of CSRS in two teleost species of different biology and skin characteristics, the three-spined stickleback and the European flounder, after exposure to oxidative stress induced by a potassium dichromate solution. The cutaneous stress response system presents different ways of action in two studied species: Mel concentration increases in the skin of both species, but cortisol concentration increases in the skin only in sticklebacks. Data suggest that stickleback skin cells can produce cortisol. However, cortisol is not involved in the response to oxidative stress in flounders. In stickleback skin, two genes encoding AANAT and ASMT/HIOMT (enzymes involved in Mel synthesis), aanat1a and asmt2 , are expressed, but in flounder skin, only one, asmtl. Because gene expression does not change in stickleback skin after exposure to stress, the source of increased Mel is probably outside the skin. A lack of expression of the gene encoding AANAT in flounder skin strongly suggests that Mel is transported to the skin by the bloodstream from other sites of synthesis. Pigment dispersion in the skin after exposure to oxidative stress is found only in sticklebacks. [Display omitted] • Mel concentration increases in the skin of sticklebacks and flounders exposed to oxidative stress. • Mel is not synthesized in flounder's skin. • The source of increased skin Mel in sticklebacks and flounders exposed to oxidative stress is outside the skin. • Cortisol is involved in the response to oxidative stress in sticklebacks but not in flounders. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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10. Cyclopeptide-β-cyclodextrin/γ-glycerol methoxytrimethoxysilane film for potential vascular tissue engineering scaffolds
- Author
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Heyi, Mao, Yidan, Zhang, Lei, Wang, Anduo, Zhou, Shanfeng, Zhang, Jing, Cao, and Huang, Xia
- Subjects
Glycerol ,Calorimetry, Differential Scanning ,Tissue Engineering ,Tissue Scaffolds ,beta-Cyclodextrins ,Biomedical Engineering ,Biophysics ,Membranes, Artificial ,Bioengineering ,Cardiovascular System ,Peptides, Cyclic ,5-Methoxytryptamine ,Biomaterials ,X-Ray Diffraction ,Cardiovascular Diseases ,Spectroscopy, Fourier Transform Infrared ,Microscopy, Electron, Scanning ,Humans ,Porosity - Abstract
The mortality rate of cardiovascular diseases is the highest among all mortality rates worldwide. Allotransplantation and autotransplantation are limited by rejection reaction and availability. Tissue engineering provides new avenues for the treatment of cardiovascular diseases. However, the current small-diameter (6 mm) vascular tissue-engineered scaffolds have many challenges, including thrombosis, stenosis, and infection. Small-diameter vascular scaffolds have structural and compositional requirements such as biocompatibility, porosity, and appropriate phase separation. We used liquid-crystal cyclopeptide(CYC)to modify β-cyclodextrin and mixed it with γ-glycerol methoxytrimethoxysilane (GPTMS) to prepare CYC-β-cyclodextrin (βCD)/GPTMS film by sol-gel. The chemical structure of CYC-βCD was confirmed by Fourier transform infrared spectroscopy and
- Published
- 2022
- Full Text
- View/download PDF
11. Pharmacological manipulation of serotonin receptors during brain embryogenesis favours stress resiliency in female rats
- Author
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Gianluca Lavanco, Angela Cavallaro, Emanuele Cannizzaro, Marco Giammanco, Danila Di Majo, and Anna Brancato
- Subjects
5-methoxytryptamine ,development ,stress reactivity ,female rats ,Biology (General) ,QH301-705.5 - Abstract
Manipulations of the serotonin transmission during early development induce long-lasting changes in the serotonergic circuitry throughout the brain. However, little is known on the developmental consequences in the female progeny. Therefore, this study aimed at exploring the behavioural effects of pre- and postnatal stimulation of the serotonergic system by 5-methoxytryptamine in adolescent female rats on behavioural reactivity and anxiety- like phenotype. Our results show that perinatal 5- methoxythyptamine decreased total distance travelled and rearing frequency in the novel enviroment, and increased the preference for the centre of the arena in the open field test. Moreover, perinatal 5-methoxytryptamine increased the percentages of entries and time spent on the open arms of the elevated plus maze, with respect to perinatally vehicle-exposed rats. Thus, perinatal stimulation of serotonin receptors does not impair the functional response to the emotional challenges in female rats, favouring the occurrence of a stress-resilient phenotype.
- Published
- 2018
- Full Text
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12. Melanogenesis Is Directly Affected by Metabolites of Melatonin in Human Melanoma Cells.
- Author
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Möller JKS, Linowiecka K, Gagat M, Brożyna AA, Foksiński M, Wolnicka-Glubisz A, Pyza E, Reiter RJ, Tulic MK, Slominski AT, Steinbrink K, and Kleszczyński K
- Subjects
- Humans, Melanins, 5-Methoxytryptamine, Receptor, Melatonin, MT2, Monophenol Monooxygenase, Melatonin metabolism, Melanoma metabolism
- Abstract
Melatonin ( N -acetyl-5-methoxytryptamine, MEL), its kynurenic ( N
1 -formyl-5-methoxykynurenine, AFMK) and indolic derivatives (6-hydroxymelatonin, 6(OH)MEL and 5-methoxytryptamine, 5-MT) are endogenously produced in human epidermis. Melatonin, produced by the pineal gland, brain and peripheral organs, displays a diversity of physiological functions including anti-inflammatory, immunomodulatory, and anti-tumor capacities. Herein, we assessed their regulatory effect on melanogenesis using amelanotic (A375, Sk-Mel-28) and highly pigmented (MNT-1, melanotic) human melanoma cell lines. We discovered that subjected compounds decrease the downstream pathway of melanin synthesis by causing a significant drop of cyclic adenosine monophosphate (cAMP) level, the microphthalmia-associated transcription factor (MITF) and resultant collapse of tyrosinase (TYR) activity, and melanin content comparatively to N2 -formyl-5-methoxykynurenine, AFMK) and indolic derivatives (6-hydroxymelatonin, 6(OH)MEL and 5-methoxytryptamine, 5-MT) are endogenously produced in human epidermis. Melatonin, produced by the pineal gland, brain and peripheral organs, displays a diversity of physiological functions including anti-inflammatory, immunomodulatory, and anti-tumor capacities. Herein, we assessed their regulatory effect on melanogenesis using amelanotic (A375, Sk-Mel-28) and highly pigmented (MNT-1, melanotic) human melanoma cell lines. We discovered that subjected compounds decrease the downstream pathway of melanin synthesis by causing a significant drop of cyclic adenosine monophosphate (cAMP) level, the microphthalmia-associated transcription factor (MITF) and resultant collapse of tyrosinase (TYR) activity, and melanin content comparatively to N -phenylthiourea (PTU, a positive control). We observed a reduction in pigment in melanosomes visualized by the transmission electron microscopy. Finally, we assessed the role of G-protein-coupled seven-transmembrane-domain receptors. Obtained results revealed that nonselective MT1 and MT2 receptor antagonist (luzindole) or selective MT2 receptor antagonist (4-P-PDOT) did not affect dysregulation of the melanin pathway indicating a receptor-independent mechanism. Our findings, together with the current state of the art, provide a convenient experimental model to study the complex relationship between metabolites of melatonin and the control of pigmentation serving as a future and rationale strategy for targeted therapies of melanoma-affected patients.- Published
- 2023
- Full Text
- View/download PDF
13. Alternative Ligands at Melatonin Receptors
- Author
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Céline, Legros, Said, Yous, Jean A, Boutin, Institut de Recherches SERVIER (IRS), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Pharmacochimie et Biologie pour le Développement (PHARMA-DEV), Institut de Recherche pour le Développement (IRD)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)
- Subjects
5-Methoxytryptamine ,Iodine Radioisotopes ,Mammals ,Iodination ,[SDV]Life Sciences [q-bio] ,Receptors, Melatonin ,Animals ,Radioligands ,Binding ,Iodinated radioligand ,Ligands ,Tritiated ligand ,Melatonin - Abstract
International audience; Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that possesses a wide range of biological effects. Most of the main recognized effects of this hormone in mammals are due to its interaction with two G protein-coupled receptors, MT1 and MT2. Ligand-binding studies have been based on the use of its radioligand analog, 2[125I]-iodomelatonin, a super agonist discovered in the early 1990s. This compound has been used in most of the binding studies reported in the literature. Nevertheless, more recently other possibilities arose. This chapter is a brief summary of those alternative radioligands and of their benefits one can find in using them.
- Published
- 2022
- Full Text
- View/download PDF
14. Cloning, Expression, Purification, Crystallization, and X-Ray Structural Determination of the Human NQO2 in Complex with Melatonin
- Author
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Barbara, Calamini, Gilles, Ferry, and Jean A, Boutin
- Subjects
5-Methoxytryptamine ,Mammals ,X-Rays ,Receptors, Melatonin ,Animals ,Humans ,Cloning, Molecular ,Quinone Reductases ,Crystallization ,Ligands ,Antioxidants ,Melatonin - Abstract
Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone which possesses a wide range of biological effects. The effects mediated by melatonin are in part attributed to the antioxidant properties of the molecule, which may act as scavenger of free radicals, and also to the binding of melatonin to its protein targets. For a long time, melatonin had been described as a ligand of a putative "receptor" present in the mammalian brain. Several studies were thus carried out with the goal of clarifying the nature of this melatonin "receptor," which led to the discovery of MT3 as the third melatonin binding site. This binding site was confirmed independently by several groups, and it was eventually demonstrated that MT3 was the enzyme quinone reductase 2 (NQO2). Among the different approaches used to validate that MT3 was indeed NQO2, the co-crystallization of NQO2 with melatonin was key in demonstrating the exact binding site and mode of melatonin to the enzyme and led to a clear understanding of the residues important for protein binding and inhibition. In this chapter, we described the details for the cloning, expression, and purification of the human enzyme NQO2. We also describe a detailed protocol for the crystallization of melatonin with this protein.
- Published
- 2022
15. Measuring Binding at the Putative Melatonin Receptor MT3
- Author
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Céline, Legros, Philippe, Dupuis, Gilles, Ferry, and Jean A, Boutin
- Subjects
5-Methoxytryptamine ,Mammals ,Binding Sites ,Receptors, Melatonin ,Animals ,Quinone Reductases ,Ligands ,Antioxidants ,Melatonin - Abstract
Melatonin, (N-acetyl-5-methoxytryptamine), is a neurohormone which possesses a wide range of biological effects. The effects mediated by melatonin are in part attributed to the antioxidant properties of the molecule. For a long time, melatonin had been described as a ligand of a putative "receptor" present in mammalian brains named MT
- Published
- 2022
16. Changes in the Metabolic Profile of Melatonin Synthesis-Related Indoles during Post-Embryonic Development of the Turkey Pineal Organ
- Author
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Bogdan Lewczuk, Kamila Martyniuk, and Maria Hanuszewska - Dominiak
- Subjects
Serotonin ,Indoles ,Organic Chemistry ,Tryptophan ,Embryonic Development ,General Medicine ,Hydroxyindoleacetic Acid ,Pineal Gland ,Catalysis ,Computer Science Applications ,Circadian Rhythm ,Inorganic Chemistry ,5-Hydroxytryptophan ,5-Methoxytryptamine ,Metabolome ,pineal organ ,melatonin ,serotonin ,indoles ,development ,turkey ,birds ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Melatonin - Abstract
Research on age-dependent changes in pineal activity has been limited almost exclusively to melatonin (MLT). This study determined, for the first time, the alterations occurring in the metabolic profile of MLT synthesis-related indoles during the post-embryonic development period in birds. Turkeys reared under a 12 h light/dark cycle were euthanized at 2 h intervals for 24 h at the ages of 2, 7, 14, and 28 days and 10, 20, 30, and 45 weeks. The results showed prominent changes in the metabolic profile of indoles during development and could be distinguished in four stages. The first stage, from hatching to the age of 2 weeks, was characterized by a decrease in the 5-hydroxytryptophan concentration and an increase in the concentrations of serotonin (5-HT), MLT, 5-methoxyindoleacetic acid, and 5-methoxytryptamine (5-MTAM). During the second stage, around the age of 1 month, the concentrations of N-acetylserotonin (NAS) and MLT reached a maximum. The synthesis and degradation of 5-HT were also the highest. The third stage, around the age of 10 weeks, was characterized by decreased levels of 5-HT (approximately 50%) and 5-hydroxyindoleacetic acid and a high level of 5-MTAM. The last stage, covering the age of 20 to 45 weeks, was characterized by a large decrease in the synthesis, content, and degradation of 5-HT. Despite these changes, there were no prominent differences in the nocturnal levels of NAS and MLT between the third and fourth stages. The concentrations of all tryptophan derivatives showed daily fluctuations until the age of 45 weeks.
- Published
- 2022
17. Structural and Molecular Dynamics Analysis of Plant Serotonin N ‐Acetyltransferase Reveal an Acid/Base‐Assisted Catalysis in Melatonin Biosynthesis
- Author
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Yucheng Zhao, Youdong Xu, Yuhao Zhang, Xikai Liu, Zhixiong Zeng, Yuanze Zhou, Xinxin Chen, Lijing Liao, Biao Liu, and Yan Guo
- Subjects
Serotonin ,AANAT ,Molecular Dynamics Simulation ,Crystallography, X-Ray ,010402 general chemistry ,Arylalkylamine N-Acetyltransferase ,01 natural sciences ,Catalysis ,5-Methoxytryptamine ,Acetyl Coenzyme A ,Catalytic Domain ,Ternary complex ,Plant Proteins ,chemistry.chemical_classification ,010405 organic chemistry ,Mutagenesis ,Hydrogen Bonding ,Oryza ,General Chemistry ,Protein engineering ,General Medicine ,0104 chemical sciences ,Enzyme ,chemistry ,Biochemistry ,Acetyltransferase ,Mutation ,Biocatalysis ,Mutagenesis, Site-Directed ,Arylalkylamine ,Function (biology) ,Protein Binding - Abstract
Serotonin N -acetyltransferase (SNAT) is the key rate-limiting enzyme in melatonin biosynthesis. SNAT mediates dual pathways of melatonin biosynthesis in plants by using serotonin and 5-methoxytryptamine (5-MT) as substrates, and a high reaction pH and temperature are essential to its activity. However, little is known of its underlying mechanisms. Herein, we present a detailed reaction mechanism of a SNAT from Oryza sativa through combined structural and molecular dynamics (MD) analysis. We report for the first time the crystal structures of plant SNAT in the apo and binary/ternary complex forms with acetyl-CoA (AcCoA), serotonin, and 5-MT. These structures reveal that Os SNAT exhibits a unique enzymatically active dimeric fold that is not found in all the known structures of arylalkylamine N-acetyltransferase (AANAT) family. The key residues W188, D189, D226, N220, and Y233 located around the active pocket have important role in catalysis which is subsequently confirmed by site-directed mutagenesis. Combined with MD simulations, we hypothesize a novel plausible catalytic mechanism in which D226 and Y233 function as catalytic base and acid during the acetyl-transfer reaction. This work provides a molecular framework for understanding the catalytic mechanisms of plant SNAT and has implications for future protein engineering and biocatalytic applications.
- Published
- 2021
- Full Text
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18. 'Foxtrot' fumarate: a water-soluble salt of N,N-diallyl-5-methoxytryptamine (5-MeO-DALT)
- Author
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Vamshikrishna Reddy Sammeta, James A. Golen, Duyen N. K. Pham, Andrew R. Chadeayne, and David R. Manke
- Subjects
crystal structure ,Salt (chemistry) ,Crystal structure ,010402 general chemistry ,010403 inorganic & nuclear chemistry ,01 natural sciences ,Medicinal chemistry ,Research Communications ,chemistry.chemical_compound ,medicine ,General Materials Science ,chemistry.chemical_classification ,5-MeO-DALT ,Crystallography ,Hydrogen bond ,tryptamines ,General Chemistry ,indoles ,Condensed Matter Physics ,hydrogen bonding ,0104 chemical sciences ,Water soluble ,chemistry ,5-Methoxytryptamine ,QD901-999 ,medicine.drug - Abstract
The synthesis and solid-state structure of the fumarate salt of the synthetic psychedelic 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) is reported., The title compound, bis(N,N-diallyl-5-methoxytryptammonium) (5-MeO-DALT) fumarate (systematic name: bis{N-[2-(5-methoxy-1H-indol-3-yl)ethyl]- N-(prop-2-en-1-yl)prop-2-en-1-aminium} (E)-but-2-enedioate), 2C17H23N2O+·C4H2O4 2−, has a single tryptammonium cation and half of a fumarate dianion in the asymmetric unit. The tryptammonium and fumarate ions are held together in one-dimensional chains by a series of N—H⋯O hydrogen bonds. These chains are combinations of R 4 4(22) rings, and C 2 2(14) and C 4 4(28) parallel chains along [111].
- Published
- 2021
19. Escherichia coli RimI Encodes Serotonin N-Acetyltransferase Activity and Its Overexpression Leads to Enhanced Growth and Melatonin Biosynthesis
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Kyungjin Lee and Kyoungwhan Back
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archaea ,Escherichia coli ,N-acetylserotonin ,protein acetylation ,RimI ,melatonin ,5-methoxytryptamine ,Molecular Biology ,Biochemistry - Abstract
Serotonin N-acetyltransferase (SNAT) functions as the penultimate or final enzyme in melatonin biosynthesis, depending on the substrate. The Escherichia coli orthologue of archaeal SNAT from Thermoplasma volcanium was identified as RimI (EcRimI), with 42% amino acid similarity to archaeal SNAT. EcRimI has been reported to be an N-acetyltransferase enzyme. Here, we investigated whether EcRimI also exhibits SNAT enzyme activity. To achieve this goal, we purified recombinant EcRimI and examined its SNAT enzyme kinetics. As expected, EcRimI showed SNAT activity toward various amine substrates including serotonin and 5-methoxytryptamine, with Km and Vmax values of 531 μM and 528 pmol/min/mg protein toward serotonin and 201 μM and 587 pmol/min/mg protein toward 5-methoxytryptamine, respectively. In contrast to the rimI mutant E. coli strain that showed no growth defect, the EcRimI overexpression strain exhibited a 2-fold higher growth rate than the control strain after 24 h incubation in nutrient-rich medium. The EcRimI overexpression strain produced more melatonin than the control strain in the presence of 5-methoxytryptamine. The enhanced growth effect of EcRimI overexpression was also observed under cadmium stress. The higher growth rate associated with EcRimI expression was attributed to increased protein N-acetyltransferase activity, increased synthesis of melatonin, or the combined effects of both.
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- 2023
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20. Taxon- and Site-Specific Melatonin Catabolism.
- Author
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Hardeland, Rüdiger
- Subjects
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MELATONIN , *HORMONES , *FREE radicals , *RADICALS (Chemistry) , *PEROXYNITRITE - Abstract
Melatonin is catabolized both enzymatically and nonenzymatically. Nonenzymatic processes mediated by free radicals, singlet oxygen, other reactive intermediates such as HOCl and peroxynitrite, or pseudoenzymatic mechanisms are not species- or tissue-specific, but vary considerably in their extent. Higher rates of nonenzymatic melatonin metabolism can be expected upon UV exposure, e.g., in plants and in the human skin. Additionally, melatonin is more strongly nonenzymatically degraded at sites of inflammation. Typical products are several hydroxylated derivatives of melatonin and N¹-acetyl-N²-formyl-5-methoxykynuramine (AFMK). Most of these products are also formed by enzymatic catalysis. Considerable taxon- and site-specific differences are observed in the main enzymatic routes of catabolism. Formation of 6-hydroxymelatonin by cytochrome P450 subforms are prevailing in vertebrates, predominantly in the liver, but also in the brain. In pineal gland and non-mammalian retina, deacetylation to 5-methoxytryptamine (5-MT) plays a certain role. This pathway is quantitatively prevalent in dinoflagellates, in which 5-MT induces cyst formation and is further converted to 5-methoxyindole-3-acetic acid, an end product released to the water. In plants, the major route is catalyzed by melatonin 2-hydroxylase, whose product is tautomerized to 3-acetamidoethyl-3-hydroxy-5-methoxyindolin-2-one (AMIO), which exceeds the levels of melatonin. Formation and properties of various secondary products are discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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21. Chloroplast overexpression of rice caffeic acid O-methyltransferase increases melatonin production in chloroplasts via the 5-methoxytryptamine pathway in transgenic rice plants.
- Author
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Choi, Geun‐Hee, Lee, Hyoung Yool, and Back, Kyoungwhan
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- *
MELATONIN , *ENZYME regulation , *PHYSIOLOGICAL effects of cadmium , *METHYLTRANSFERASES , *SEROTONIN , *CHLOROPLASTS - Abstract
Recent analyses of the enzymatic features of various melatonin biosynthetic genes from bacteria, animals, and plants have led to the hypothesis that melatonin could be synthesized via the 5-methoxytryptamine (5- MT) pathway. 5- MT is known to be synthesized in vitro from serotonin by the enzymatic action of O-methyltransferases, including N-acetylserotonin methyltransferase ( ASMT) and caffeic acid O-methyltransferase ( COMT), leading to melatonin synthesis by the subsequent enzymatic reaction with serotonin N-acetyltransferase ( SNAT). Here, we show that 5- MT was produced and served as a precursor for melatonin synthesis in plants. When rice seedlings were challenged with senescence treatment, 5- MT levels and melatonin production were increased in transgenic rice seedlings overexpressing the rice COMT in chloroplasts, while no such increases were observed in wild-type or transgenic seedlings overexpressing the rice COMT in the cytosol, suggesting a 5- MT transport limitation from the cytosol to chloroplasts. In contrast, cadmium treatment led to results different from those in senescence. The enhanced melatonin production was not observed in the chloroplast COMT lines relative over the cytosol COMT lines although 5- MT levels were equally induced in all genotypes upon cadmium treatment. The transgenic seedlings with enhanced melatonin in their chloroplasts exhibited improved seedling growth vs the wild type under continuous light conditions. This is the first report describing enhanced melatonin production in chloroplasts via the 5- MT pathway with the ectopic overexpression of COMT in chloroplasts in plants. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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- View/download PDF
22. Pharmacological manipulation of serotonin receptors during brain embryogenesis favours stress resiliency in female rats.
- Author
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Lavanco, Gianluca, Cavallaro, Angela, Cannizzaro, Emanuele, Giammanco, Marco, Di Majo, Danila, and Brancato, Anna
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- *
SEROTONINERGIC mechanisms , *EMBRYOLOGY , *LABORATORY rats , *PHENOTYPES , *MENTAL depression - Abstract
Manipulations of the serotonin transmission during early development induce long-lasting changes in the serotonergic circuitry throughout the brain. However, little is known on the developmental consequences in the female progeny. Therefore, this study aimed at exploring the behavioural effects of pre- and postnatal stimulation of the serotonergic system by 5-methoxytryptamine in adolescent female rats on behavioural reactivity and anxiety-like phenotype. Our results show that perinatal 5-methoxythyptamine decreased total distance travelled and rearing frequency in the novel enviroment, and increased the preference for the centre of the arena in the open field test. Moreover, perinatal 5-methoxytryptamine increased the percentages of entries and time spent on the open arms of the elevated plus maze, with respect to perinatally vehicle-exposed rats. Thus, perinatal stimulation of serotonin receptors does not impair the functional response to the emotional challenges in female rats, favouring the occurrence of a stress-resilient phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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23. Rice N-acetylserotonin deacetylase regulates melatonin levels in transgenic rice
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Kyungjin Lee, Kyoungwhan Back, and Ok Jin Hwang
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biology ,Chemistry ,Wild type ,food and beverages ,Genetically modified rice ,Enzyme assay ,Melatonin ,chemistry.chemical_compound ,Biochemistry ,5-Methoxytryptamine ,N-Acetylserotonin ,Caffeic acid ,medicine ,biology.protein ,Serotonin ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
A reverse melatonin biosynthetic pathway was recently discovered in plants, by which N-acetylserotonin (NAS) is converted into serotonin by N-acetylserotonin deacetylase (ASDAC) rather than into melatonin by N-acetylserotonin O-methyltransferase (ASMT). In this study, we generated transgenic rice plants in which ASDAC was either suppressed or overexpressed to determine whether ASDAC is functionally involved in melatonin biosynthesis. ASDAC-suppressed rice showed increased levels of NAS, 5-methoxytryptamine (5-MT), and melatonin, whereas ASDAC-overexpressed rice exhibited less melatonin synthesis than observed in the wild type. This finding is strong evidence of the role of ASDAC in melatonin biosynthesis in rice. The increased levels of 5-MT, which is produced either by ASDAC from melatonin or by serotonin O-methyltransferase (SOMT) from serotonin in ASDAC-suppressed rice, was ascribed to enhanced SOMT enzyme activity rather than increased transcripts, such as ASMT or caffeic acid O-methyltransferase (COMT) encoding SOMT activity.
- Published
- 2020
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24. Melatonin biosynthesis in plants: multiple pathways catalyze tryptophan to melatonin in the cytoplasm or chloroplasts.
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Back, Kyoungwhan, Tan, Dun‐Xian, and Reiter, Russel J.
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- *
MELATONIN , *BIOSYNTHESIS , *TRYPTOPHAN , *CHLOROPLASTS , *SEROTONIN , *TRYPTAMINE - Abstract
Melatonin is an animal hormone as well as a signaling molecule in plants. It was first identified in plants in 1995, and almost all enzymes responsible for melatonin biosynthesis had already been characterized in these species. Melatonin biosynthesis from tryptophan requires four-step reactions. However, six genes, that is, TDC, TPH, T5H, SNAT, ASMT, and COMT, have been implicated in the synthesis of melatonin in plants, suggesting the presence of multiple pathways. Two major pathways have been proposed based on the enzyme kinetics: One is the tryptophan/tryptamine/serotonin/ N-acetylserotonin/melatonin pathway, which may occur under normal growth conditions; the other is the tryptophan/tryptamine/serotonin/5-methoxytryptamine/melatonin pathway, which may occur when plants produce large amounts of serotonin, for example, upon senescence. The melatonin biosynthetic capacity associated with conversion of tryptophan to serotonin is much higher than that associated with conversion of serotonin to melatonin, which yields a low level of melatonin synthesis in plants. Many melatonin intermediates are produced in various subcellular compartments, such as the cytoplasm, endoplasmic reticulum, and chloroplasts, which either facilitates or impedes the subsequent enzymatic steps. Depending on the pathways, the final subcellular sites of melatonin synthesis vary at either the cytoplasm or chloroplasts, which may differentially affect the mode of action of melatonin in plants. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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- View/download PDF
25. On the significance of an alternate pathway of melatonin synthesis via 5-methoxytryptamine: comparisons across species.
- Author
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Tan, Dun‐Xian, Hardeland, Rüdiger, Back, Kyoungwhan, Manchester, Lucien C., Alatorre‐Jimenez, Moises A., and Reiter, Russel J.
- Subjects
- *
MELATONIN , *TRYPTAMINE , *PHOTOSYNTHESIS , *ACETYLTRANSFERASES , *ANTIOXIDANTS - Abstract
Melatonin is a phylogenetically ancient molecule. It is ubiquitously present in almost all organisms from primitive photosynthetic bacteria to humans. Its original primary function is presumable to be that of an antioxidant with other functions of this molecule having been acquired during evolution. The synthetic pathway of melatonin in vertebrates has been extensively studied. It is common knowledge that serotonin is acetylated to form N-acetylserotonin by arylalkylamine N-acetyltransferase ( AANAT) or arylamine N-acetyltransferase ( SNAT or NAT) and N-acetylserotonin is, subsequently, methylated to melatonin by N-acetylserotonin O-methyltransferase ( ASMT; also known as hydroxyindole-O-methyltransferase, HIOMT). This is referred to as a classic melatonin synthetic pathway. Based on new evidence, we feel that this classic melatonin pathway is not generally the prevailing route of melatonin production. An alternate pathway is known to exist, in which serotonin is first O-methylated to 5-methoxytryptamine (5- MT) and, thereafter, 5- MT is N-acetylated to melatonin. Here, we hypothesize that the alternate melatonin synthetic pathway may be more important in certain organisms and under certain conditions. Evidence strongly supports that this alternate pathway prevails in some plants, bacteria, and, perhaps, yeast and may also occur in animals. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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- View/download PDF
26. Taxon- and Site-Specific Melatonin Catabolism
- Author
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Rüdiger Hardeland
- Subjects
5-methoxytryptamine ,CNS ,dinoflagellates ,indole metabolism ,kynuramines ,plants ,yeast ,Organic chemistry ,QD241-441 - Abstract
Melatonin is catabolized both enzymatically and nonenzymatically. Nonenzymatic processes mediated by free radicals, singlet oxygen, other reactive intermediates such as HOCl and peroxynitrite, or pseudoenzymatic mechanisms are not species- or tissue-specific, but vary considerably in their extent. Higher rates of nonenzymatic melatonin metabolism can be expected upon UV exposure, e.g., in plants and in the human skin. Additionally, melatonin is more strongly nonenzymatically degraded at sites of inflammation. Typical products are several hydroxylated derivatives of melatonin and N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK). Most of these products are also formed by enzymatic catalysis. Considerable taxon- and site-specific differences are observed in the main enzymatic routes of catabolism. Formation of 6-hydroxymelatonin by cytochrome P450 subforms are prevailing in vertebrates, predominantly in the liver, but also in the brain. In pineal gland and non-mammalian retina, deacetylation to 5-methoxytryptamine (5-MT) plays a certain role. This pathway is quantitatively prevalent in dinoflagellates, in which 5-MT induces cyst formation and is further converted to 5-methoxyindole-3-acetic acid, an end product released to the water. In plants, the major route is catalyzed by melatonin 2-hydroxylase, whose product is tautomerized to 3-acetamidoethyl-3-hydroxy-5-methoxyindolin-2-one (AMIO), which exceeds the levels of melatonin. Formation and properties of various secondary products are discussed.
- Published
- 2017
- Full Text
- View/download PDF
27. Chloroplastic and cytoplasmic overexpression of sheep serotonin N-acetyltransferase in transgenic rice plants is associated with low melatonin production despite high enzyme activity.
- Author
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Byeon, Yeong, Lee, Hyoung Yool, and Back, Kyoungwhan
- Subjects
- *
CHLOROPLASTS , *CYTOPLASM , *ARYLALKYLAMINE N-acetyltransferase , *GENE expression in plants , *TRANSGENIC rice , *MELATONIN , *ENZYME kinetics - Abstract
Serotonin N-acetyltransferase ( SNAT), the penultimate enzyme in melatonin biosynthesis, catalyzes the conversion of serotonin into N-acetylserotonin. Plant SNAT is localized in chloroplasts. To test SNAT localization effects on melatonin synthesis, we generated transgenic rice plants overexpressing a sheep ( Ovis aries) SNAT ( Oa SNAT) in their chloroplasts and compared melatonin biosynthesis with that of transgenic rice plants overexpressing Oa SNAT in their cytoplasm. To localize the Oa SNAT in chloroplasts, we used a chloroplast targeting sequence ( CTS) from tobacco protoporphyrinogen IX oxidase ( PPO), which expresses in chloroplasts. The purified recombinant CTS: Oa SNAT fusion protein was enzymatically functional and localized in chloroplasts as confirmed by confocal microscopic analysis. The chloroplast-targeted CTS: Oa SNAT lines and cytoplasm-expressed Oa SNAT lines had similarly high SNAT enzyme activities. However, after cadmium and butafenacil treatments, melatonin production in rice leaves was severalfold lower in the CTS: Oa SNAT lines than in the Oa SNAT lines. Notably, enhanced SNAT enzyme activity was not directly proportional to the production of N-acetylserotonin, melatonin, or 2-hydroxymelatonin, suggesting that plant SNAT has a role in the homeostatic regulation of melatonin rather than in accelerating melatonin synthesis. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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- View/download PDF
28. Melatonin and its metabolites accumulate in the human epidermis in vivo and inhibit proliferation and tyrosinase activity in epidermal melanocytes in vitro.
- Author
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Kim, Tae-Kang, Lin, Zongtao, Tidwell, William J., Li, We, and Slominski, Andrzej T.
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- *
MELATONIN , *METABOLITES , *EPIDERMIS , *PHENOL oxidase , *MELANOCYTES , *AFRICAN Americans - Abstract
Melatonin and its metabolites including 6-hydroxymelatonin (6(OH)M), N 1 -acetyl- N 2 -formyl-5-methoxykynuramine (AFMK) and 5-methoxytryptamine (5MT) are endogenously produced in human epidermis. This production depends on race, gender and age. The highest melatonin levels are in African-Americans. In each racial group they are highest in young African-Americans [30–50 years old (yo)], old Caucasians (60–90 yo) and Caucasian females. AFMK levels are the highest in African-Americans, while 6(OH)M and 5MT levels are similar in all groups. Testing of their phenotypic effects in normal human melanocytes show that melatonin and its metabolites (10 −5 M) inhibit tyrosinase activity and cell growth, and inhibit DNA synthesis in a dose dependent manner with 10 −9 M being the lowest effective concentration. In melanoma cells, they inhibited cell growth but had no effect on melanogenesis, except for 5MT which enhanced L-tyrosine induced melanogenesis. In conclusion, melatonin and its metabolites [6(OH)M, AFMK and 5MT] are produced endogenously in human epidermis and can affect melanocyte and melanoma behavior. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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- View/download PDF
29. Dual actions of 5-MeO-DIPT at the serotonin transporter and serotonin 5-HT
- Author
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Yoko, Hagino, Frank Scott, Hall, George R, Uhl, Ichiro, Sora, and Kazutaka, Ikeda
- Subjects
Male ,Mice, Knockout ,Serotonin Plasma Membrane Transport Proteins ,8-Hydroxy-2-(di-n-propylamino)tetralin ,5‐MeO‐DIPT ,prefrontal cortex ,Pyridines ,Microdialysis ,striatum ,serotonin transporter ,Prefrontal Cortex ,Original Articles ,Serotonin 5-HT1 Receptor Agonists ,Serotonin 5-HT1 Receptor Antagonists ,5‐HT1A serotonin receptor ,Corpus Striatum ,Piperazines ,5-Methoxytryptamine ,Mice ,Receptor, Serotonin, 5-HT1A ,Animals ,Female ,Original Article - Abstract
Aims 5‐Methoxy‐N,N‐diisopropyltryptamine (5‐MeO‐DIPT) is a synthetic orally active hallucinogenic tryptamine analogue. The present study examined whether the effects of 5‐MeO‐DIPT involve the serotonin transporter (SERT) and serotonin 5‐hydroxytryptamine‐1A (5‐HT1A) receptor in the striatum and prefrontal cortex (PFC). Methods We investigated the effects of 5‐MeO‐DIPT on extracellular 5‐HT (5‐HTex) and dopamine (DAex) levels in the striatum and PFC in wildtype and SERT knockout (KO) mice using in vivo microdialysis, and for comparison the effects of the 5‐HT1A receptor antagonist WAY100635 and the 5‐HT1A receptor agonist 8‐OH‐DPAT on 5‐HTex. Results 5‐MeO‐DIPT decreased 5‐HTex levels in the striatum, but not PFC. In SERT‐KO mice, 5‐MeO‐DIPT did not affect 5‐HTex levels in the striatum or PFC. In the presence of WAY100635, 5‐MeO‐DIPT substantially increased 5‐HTex levels, suggesting that 5‐MeO‐DIPT acts on SERT and these effects are masked by its 5‐HT1A actions in the absence of WAY100635. 8‐OH‐DPAT decreased 5‐HTex levels in the striatum and PFC in wildtype mice. WAY100635 antagonized the 8‐OH‐DPAT‐induced decrease in 5‐HTex levels. In SERT‐KO mice, 8‐OH‐DPAT did not decrease 5‐HTex levels in the striatum and PFC. 5‐MeO‐DIPT dose‐dependently increased DAex levels in the PFC, but not striatum, in wildtype and SERT‐KO mice. The increase in DAex levels that was induced by 5‐MeO‐DIPT was not antagonized by WAY100635. Conclusion 5‐MeO‐DIPT influences both 5‐HTex and DAex levels in the striatum and PFC. 5‐MeO‐DIPT dually acts on SERT and 5‐HT1A receptors so that elevations in 5‐HTex levels produced by reuptake inhibition are limited by actions of the drug on 5‐HT1A receptors., 5‐MeO‐DIPT influences both 5‐HTex and DAex levels in the striatum and PFC. 5‐MeO‐DIPT dually acts on SERT and 5‐HT1A receptors so that elevations in 5‐HTex levels produced by reuptake inhibition are limited by actions of the drug on 5‐HT1A receptors.
- Published
- 2021
30. Cloning of Arabidopsis serotonin N-acetyltransferase and its role with caffeic acid O-methyltransferase in the biosynthesis of melatonin in vitro despite their different subcellular localizations.
- Author
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Lee, Hyoung Yool, Byeon, Yeong, Lee, Kyungjin, Lee, Hye‐Jung, and Back, Kyoungwhan
- Subjects
- *
PLANT clones , *ARABIDOPSIS , *SEROTONIN , *ACETYLTRANSFERASES , *CAFFEIC acid , *METHYLTRANSFERASES , *PLANT product synthesis - Abstract
Serotonin N-acetyltransferase (SNAT) is the penultimate enzyme in melatonin biosynthesis. We cloned SNAT from Arabidopsis thaliana (AtSNAT) and functionally characterized this enzyme for the first time from dicotyledonous plants. Similar to rice SNAT, AtSNAT was found to localize to chloroplasts with peak enzyme activity at 45°C (Km, 309 μM; Vmax, 1400 pmol/min/mg protein). AtSNAT also catalyzed 5-methoxytryptamine (5-MT) into melatonin with high catalytic activity (Km, 51 μM; Vmax, 5300 pmol/min/mg protein). In contrast, Arabidopsis caffeic acid O-methyltransferase (AtCOMT) localized to the cytoplasm. Interestingly, AtCOMT can methylate serotonin into 5-MT with low catalytic activity (Km, 3.396 mM; Vmax, 528 pmol/min/mg protein). These data suggest that serotonin can be converted into either N-acetylserotonin by SNAT or into 5-MT by COMT, after which it is metabolized into melatonin by COMT or SNAT, respectively. To support this hypothesis, serotonin was incubated in the presence of both AtSNAT and AtCOMT enzymes. In addition to melatonin production, the production of major intermediates depended on incubation temperatures; N-acetylserotonin was predominantly produced at high temperatures (45°C), while low temperatures (37°C) favored the production of 5-MT. Our results provide biochemical evidence for the presence of a serotonin O-methylation pathway in plant melatonin biosynthesis. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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- View/download PDF
31. Melatonin and its metabolites ameliorate ultraviolet B-induced damage in human epidermal keratinocytes.
- Author
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Janjetovic, Zorica, Nahmias, Zachary P., Hanna, Sherie, Jarrett, Stuart G., Kim, Tae‐Kang, Reiter, Russel J., and Slominski, Adrzej T.
- Subjects
- *
MELATONIN , *METABOLITES , *PHYSIOLOGICAL effects of ultraviolet radiation , *KERATINOCYTES , *HYDROGEN peroxide , *GLUTATHIONE , *CELL proliferation - Abstract
We investigated the protective effects of melatonin and its metabolites: 6-hydroxymelatonin (6-OHM), N1-acetyl- N2-formyl-5-methoxykynuramine (AFMK), N-acetylserotonin (NAS), and 5-methoxytryptamine (5-MT) in human keratinocytes against a range of doses (25, 50, and 75 mJ/cm2) of ultraviolet B (UVB) radiation. There was significant reduction in the generation of reactive oxygen species (50-60%) when UVB-exposed keratinocytes were treated with melatonin or its derivatives. Similarly, melatonin and its metabolites reduced the nitrite and hydrogen peroxide levels that were induced by UVB as early as 30 min after the exposure. Moreover, melatonin and its metabolites enhanced levels of reduced glutathione in keratinocytes within 1 hr after UVB exposure in comparison with control cells. Using proliferation assay, we observed a dose-dependent increase in viability of UVB-irradiated keratinocytes that were treated with melatonin or its derivatives after 48 hr. Using the dot-blot technique and immunofluorescent staining we also observed that melatonin and its metabolites enhanced the DNA repair capacity of UVB-induced pyrimidine photoproducts (6-4)or cyclobutane pyrimidine dimers generation in human keratinocytes. Additional evidence for induction of DNA repair in cells exposed to UVB and treated with the indole compounds was shown using the Comet assay. Finally, melatonin and its metabolites further enhanced expression of p53 phosphorylated at Ser-15 but not at Ser-46 or its nonphosphorylated form. In conclusion, melatonin, its precursor NAS, and its metabolites 6-OHM, AFMK, 5-MT, which are endogenously produced in keratinocytes, protect these cells against UVB-induced oxidative stress and DNA damage. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
32. Role of peripheral 5-HT5A receptors in 5-HT-induced cardiac sympatho-inhibition in type 1 diabetic rats
- Author
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Mónica García-Domingo, Asunción Morán, Carlos M. Villalón, Oswaldo Hernández-Abreu, José Carretero, and José Ángel García-Pedraza
- Subjects
Male ,Sympathetic Nervous System ,Molecular biology ,Pyridines ,Receptor expression ,lcsh:Medicine ,Stimulation ,030204 cardiovascular system & hematology ,Norepinephrine ,chemistry.chemical_compound ,0302 clinical medicine ,lcsh:Science ,Receptor ,Multidisciplinary ,Immunohistochemistry ,medicine.anatomical_structure ,Receptor, Serotonin, 5-HT1D ,Receptor, Serotonin, 5-HT1B ,Agonist ,Serotonin ,medicine.medical_specialty ,Indorenate ,medicine.drug_class ,Carbazoles ,Electric Stimulation Therapy ,Article ,Diabetes Mellitus, Experimental ,5-Methoxytryptamine ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Pyrroles ,Chromans ,Rats, Wistar ,5-HT receptor ,business.industry ,lcsh:R ,Biphenyl Compounds ,Cardiovascular biology ,Rats ,Fluorobenzenes ,Diabetes Mellitus, Type 1 ,Endocrinology ,chemistry ,Receptors, Serotonin ,Stellate ganglion ,lcsh:Q ,business ,030217 neurology & neurosurgery - Abstract
5-HT inhibits cardiac sympathetic neurotransmission in normoglycaemic rats, via 5-HT1B, 5-HT1D and 5-HT5A receptor activation. Since type 1 diabetes impairs the cardiac sympathetic innervation leading to cardiopathies, this study aimed to investigate whether the serotonergic influence on cardiac noradrenergic control is altered in type 1 diabetic rats. Diabetes was induced in male Wistar rats by streptozotocin (50 mg/kg, i.p.). Four weeks later, the rats were anaesthetized, pithed and prepared for producing tachycardic responses by electrical preganglionic stimulation (C7-T1) of the cardioaccelerator sympathetic outflow or i.v. noradrenaline bolus injections. Immunohistochemistry was performed to study 5-HT1B, 5-HT1D and 5-HT5A receptor expression in the stellate ganglion from normoglycaemic and diabetic rats. In the diabetic group, i) i.v. continuous infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT1/5A agonist 5-carboxamidotryptamine (without modifying noradrenaline-induced tachycardia), but not by the agonists indorenate (5-HT1A), CP 93,129 (5-HT1B), PNU 142633 (5-HT1D), or LY344864 (5-HT1F); ii) SB 699551 (5-HT5A antagonist; i.v.) completely reversed 5-CT-induced cardiac sympatho-inhibition; and iii) 5-HT5A receptors were more expressed in the stellate ganglion compared to normoglycaemic rats. These results show the prominent role of the peripheral 5-HT5A receptors prejunctionally inhibiting the cardiac sympathetic drive in type 1 diabetic rats.
- Published
- 2020
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33. BEHAVIORAL FEATURES OF WISTAR RATS IN A MODEL OF HYPERSEROTONEMIA INDUCED BY CHRONIC ADMINISTRATION OF 5-METHOXYTRYPTAMINE
- Author
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Polina Shlapakova, Vasilina Gedzun, and V. A. Dubynin
- Subjects
chemistry.chemical_compound ,chemistry ,business.industry ,5-Methoxytryptamine ,Medicine ,Pharmacology ,business - Published
- 2020
- Full Text
- View/download PDF
34. Metabotropic 5-HT receptor-mediated effects in the human submucous plexus.
- Author
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Annaházi A, Berger TE, Demir IE, Zeller F, Müller M, Anneser M, Skerra A, Michel K, and Schemann M
- Subjects
- 5-Hydroxytryptophan, 5-Methoxytryptamine, Amides, Humans, Receptors, Serotonin physiology, Serotonin pharmacology, Submucous Plexus
- Abstract
Background: Serotonin (5-HT) is an important mediator in the gastrointestinal tract, acting on different neuronal 5-HT receptors. The ionotropic 5-HT
3 receptor mediates immediate but transient spike discharge in human enteric neurons. We studied the role of the metabotropic 5-HT1P , 5-HT4 , and 5-HT7 receptors to activate human submucous neurons., Methods: Neuroimaging using the voltage sensitive dye Di-8-ANEPPS was performed in submucous plexus preparations from human surgical specimens of the small and large intestine. We synthesized a new, stable 5-HT1P agonist, 5-benzyloxyhydrazonoindalpine (5-BOHIP)., Key Results: 5-HT evoked a fast and late-onset spike discharge in enteric neurons. The fast component was blocked by the 5-HT3 receptor antagonist cilansetron, while the remaining sustained response was significantly reduced by the 5-HT1P receptor antagonist 5-hydroxytryptophanyl-5-hydroxytryptophan amide (5-HTP-DP). The newly synthesized 5-HT1P agonist 5-BOHIP induced a slowly developing, long-lasting activation of submucous neurons, which was blocked by 5-HTP-DP. We could not demonstrate any 5-HT7 receptor-induced spike discharge based on the lack of response to 5-carboxamidotryptamine. Similarly, the 5-HT4 agonists 5-methoxytryptamine and prucalopride evoked no immediate or late-onset spike discharge., Conclusions & Inferences: Our work demonstrated for the first time the presence of functional 5-HT1P receptors on human submucous neurons. Furthermore, we found no evidence for a role of 5-HT4 or 5-HT7 receptors in the postsynaptic activation of human submucous neurons by 5-HT., (© 2022 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)- Published
- 2022
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35. Treatment of Platelet Deficiency in a Cohort of Patients by a Combination of Melatonin and 5-Methoxytryptamine
- Author
-
Carlo Pastore
- Subjects
medicine.medical_specialty ,business.industry ,General Engineering ,Melatonin ,chemistry.chemical_compound ,Endocrinology ,chemistry ,5-Methoxytryptamine ,Internal medicine ,Cohort ,medicine ,Platelet ,business ,medicine.drug - Published
- 2021
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- View/download PDF
36. Metabolism of melatonin and biological activity of intermediates of melatoninergic pathway in human skin cells.
- Author
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Tae-Kang Kim, Kleszczyński, Konrad, Janjetovic, Zorica, Sweatman, Trevor, Zongtao Lin, Wei Li, Reiter, Russel J., Fischer, Tobias W., and Slominski, Andrzej T.
- Subjects
- *
KERATINOCYTES , *MELATONIN , *MELANOCYTES , *LIQUID chromatography , *MASS spectrometry - Abstract
Indolic and kynuric pathways of skin melatonin metabolism were monitored by liquid chromatography mass spectrometry in human keratinocytes, melanocytes, dermal fibroblasts, and melanoma cells. Production of 6-hydroxymelatonin [6(OH)M], N¹-acetyl-N²-formyl-5-methoxykynuramine (AFMK) and 5-methoxytryptamine (5-MT) was detected in a cell type-dependent fashion. The major metabolites, 6(OH)M and AFMK, were produced in all cells. Thus, in immortalized epidermal (HaCaT) keratinocytes, 6(OH)M was the major product with Vmax = 63.7 ng/106 cells and Km = 10.2 µM, with lower production of AFMK and 5-MT. Melanocytes, keratinocytes, and fibroblasts transformed melatonin primarily into 6(OH)M and AFMK. In melanoma cells, 6(OH)M and AFMK were produced endogenously, a process accelerated by exogenous melatonin in the case of AFMK. In addition, N-acetylserotonin was endogenously produced by normal and malignant melanocytes. Metabolites showed selective antiproliferative effects on human primary epidermal keratinocytes in vitro. In ex vivo human skin, both melatonin and AFMK-stimulated expression of involucrin and keratins-10 and keratins-14 in the epidermis, indicating their stimulatory role in building and maintaining the epidermal barrier. In summary, the metabolism of melatonin and its endogenous production is cell type-dependent and expressed in all three main cell populations of human skin. Furthermore, melatonin and its metabolite AFMK stimulate differentiation in human epidermis, indicating their key role in building the skin barrier. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
37. Functions and prospects of melatonin in plant growth, yield, and quality.
- Author
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Wang K, Xing Q, Ahammed GJ, and Zhou J
- Subjects
- 5-Methoxytryptamine, Animals, Crops, Agricultural metabolism, Free Radicals, Plant Physiological Phenomena, Melatonin metabolism
- Abstract
Melatonin (N-acetyl-5-methoxytryptamine) is an indole molecule widely found in animals and plants. It is well known that melatonin improves plant resistance to various biotic and abiotic stresses due to its potent free radical scavenging ability while being able to modulate plant signaling and response pathways through mostly unknown mechanisms. In recent years, an increasing number of studies have shown that melatonin plays a crucial role in improving crop quality and yield by participating in the regulation of various aspects of plant growth and development. Here, we review the effects of melatonin on plant vegetative growth and reproductive development, and systematically summarize its molecular regulatory network. Moreover, the effective concentrations of exogenously applied melatonin in different crops or at different growth stages of the same crop are analysed. In addition, we compare endogenous phytomelatonin concentrations in various crops and different organs, and evaluate a potential function of phytomelatonin in plant circadian rhythms. The prospects of different approaches in regulating crop yield and quality through exogenous application of appropriate concentrations of melatonin, endogenous modification of phytomelatonin metabolism-related genes, and the use of nanomaterials and other technologies to improve melatonin utilization efficiency are also discussed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
38. Changes in the Metabolic Profile of Melatonin Synthesis-Related Indoles during Post-Embryonic Development of the Turkey Pineal Organ.
- Author
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Martyniuk K, Hanuszewska-Dominiak M, and Lewczuk B
- Subjects
- 5-Hydroxytryptophan, 5-Methoxytryptamine, Circadian Rhythm, Embryonic Development, Hydroxyindoleacetic Acid metabolism, Indoles metabolism, Metabolome, Serotonin analogs & derivatives, Serotonin metabolism, Tryptophan metabolism, Melatonin metabolism, Pineal Gland metabolism
- Abstract
Research on age-dependent changes in pineal activity has been limited almost exclusively to melatonin (MLT). This study determined, for the first time, the alterations occurring in the metabolic profile of MLT synthesis-related indoles during the post-embryonic development period in birds. Turkeys reared under a 12 h light/dark cycle were euthanized at 2 h intervals for 24 h at the ages of 2, 7, 14, and 28 days and 10, 20, 30, and 45 weeks. The results showed prominent changes in the metabolic profile of indoles during development and could be distinguished in four stages. The first stage, from hatching to the age of 2 weeks, was characterized by a decrease in the 5-hydroxytryptophan concentration and an increase in the concentrations of serotonin (5-HT), MLT, 5-methoxyindoleacetic acid, and 5-methoxytryptamine (5-MTAM). During the second stage, around the age of 1 month, the concentrations of N-acetylserotonin (NAS) and MLT reached a maximum. The synthesis and degradation of 5-HT were also the highest. The third stage, around the age of 10 weeks, was characterized by decreased levels of 5-HT (approximately 50%) and 5-hydroxyindoleacetic acid and a high level of 5-MTAM. The last stage, covering the age of 20 to 45 weeks, was characterized by a large decrease in the synthesis, content, and degradation of 5-HT. Despite these changes, there were no prominent differences in the nocturnal levels of NAS and MLT between the third and fourth stages. The concentrations of all tryptophan derivatives showed daily fluctuations until the age of 45 weeks.
- Published
- 2022
- Full Text
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39. The antioxidant behaviour of melatonin and structural analogues during lipid peroxidation depends not only on their functional groups but also on the assay system
- Author
-
Fagali, Natalia and Catalá, Angel
- Subjects
- *
ANTIOXIDANTS , *LIPID peroxidation (Biology) , *MELATONIN , *BIOLOGICAL assay , *INDOLE compounds , *UNSATURATED fatty acids , *CHLOROFORM - Abstract
Abstract: There is no general agreement yet on the antioxidant effect of pineal indoles against lipid peroxidation. Accordingly, the main goal of the present work was to study the antioxidant activity of melatonin (MLT), N-acetylserotonin (NAS), 5-HO-tryptophan (5HO-TRP) and 5-methoxytryptamine (5MTP) in two different lipid systems with high content of polyunsaturated fatty acids (PUFAs): triglycerides (rich in 20:5 n-3, 22:6 n-3) dissolved in chloroform and sonicated liposomes made of retinal lipids (rich in 22:6 n-3). In the triglyceride–chloroform-system the peroxidation reaction was initiated by cumene hydroperoxide (CHP) whereas liposomes were peroxidized with Fe 2+ . The techniques employed at the present work were: (1) TBARS production, (2) DPPH assay, (3) determination of conjugated dienes production and (4) analysis of fatty acid profile by GC–MS. Butylated hydroxytoluene (BHT) was employed as a reference because of its well known antioxidant capacity. Our results showed that MLT and 5MTP were unable to protect PUFAs against lipid peroxidation in both systems, whereas NAS and 5HO-TRP were better antioxidants that BHT in the triglyceride-system but ineffective in the liposome-system. We conclude that the antioxidant behaviour of pineal indoles depends not only on their functional groups but also on the assay system and could be explained by the polar paradox theory. [Copyright &y& Elsevier]
- Published
- 2012
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- View/download PDF
40. Melatonin, hormone of darkness and more – occurrence, control mechanisms, actions and bioactive metabolites.
- Author
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Hardeland, R.
- Subjects
- *
MELATONIN , *NITRIC oxide , *HORMONES , *PINEAL gland secretions , *TRYPTAMINE - Abstract
In its role as a pineal hormone, melatonin is a pleiotropic, nocturnally peaking and systemically acting chronobiotic. These effects are largely explained by actions via G protein-coupled membrane receptors found in the suprachiasmatic nucleus, but also in numerous other sites. Nuclear (ROR/RZR), cytoplasmic (quinone reductase-2, calmodulin, calreticulin) and mitochondrial binding sites and radical-scavenging properties contribute to the actions of melatonin. Regulation of pineal melatonin biosynthesis is largely explained by control mechanisms acting on arylalkylamine N-acetyltransferase, at the levels of gene expression and/or enzyme stability influenced by phosphorylation and interaction with 14-3-3 proteins. Melatonin is not only a hormone but is also synthesized in numerous extrapineal sites, in which it sometimes attains much higher quantities than in the pineal and the circulation. It is also present in many taxonomically distant groups of organisms, including bacteria, fungi, and plants. Moreover, melatonin is a source of bioactive metabolites, such as 5-methoxytryptamine, N 1-acetyl- N 2-formyl-5-methoxykynuramine and N 1-acetyl-5-methoxykynuramine. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
41. CYP2D6 and DRD2 genes differentially impact pharmacodynamic sensitivity and time course of prolactin response to perphenazine.
- Author
-
Aklillu, Eleni, Kalow, Werner, Endrenyi, Laszlo, Harper, Patricia, Miura, Jun, and Ozdemir, Vural
- Abstract
We observed that CYP2D6 contributes to pharmacodynamic tissue sensitivity to perphenazine as measured by the areas under the curve (AUCs) expressed as a ratio (prolactin-AUC0-6/perphenazine-AUC0-6) in Chinese Canadians [Pharmacogenetics and Genomics 2007; 17:339-347]. As genetic heterogeneity in drug targets can influence drug response, we sought to further evaluate the contribution of CYP2D6 to pharmacodynamic sensitivity in our previous study sample in tandem with DRD2, the primary molecular target for perphenazine.Genotyping for DRD2 Taq1A, -141C ins/del and Ser311Cys functional polymorphisms was performed using PCR-restriction-fragment length polymorphism methods.After controlling for DRD2 polymorphisms, CYP2D6 was a significant predictor of pituitary pharmacodynamic tissue sensitivity to perphenazine (P=0.024; power=80.4%). Taq1A polymorphism significantly influenced the time course of prolactin response (P=0.039; power=70%). A1/A1 genotype displayed a higher prolactin elevation 2 h after perphenazine administration (P=0.02). Patients with -141C ins/ins genotype showed a strong trend toward a 38% larger prolactin AUC compared with the -141C ins/del genotypic group (P=0.07).CYP2D6 seems to be an independent contributor to pituitary pharmacodynamic tissue sensitivity to perphenazine after accounting for DRD2 functional polymorphisms. The A1 allele of the Taq1A polymorphism was previously shown to decrease D2 receptor density in vitro and in neuroimaging studies in vivo. At a given antipsychotic dose, individuals with A1 allele might thus achieve a higher DRD2 antipsychotic occupancy, which is consistent with an increased prolactin elevation in the A1/A1 genotype in this study. These findings provide a basis for further studies on the endogenous substrates of CYP2D6 and the rational selection of candidate genes for long-term consequences of antipsychotic-induced hyperprolactinemia (e.g. susceptibility to breast and prostate cancers). [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
42. The effect of melatonin and structural analogues on the lipid peroxidation of triglycerides enriched in ω-3 polyunsaturated fatty acids
- Author
-
Fagali, Natalia and Catalá, Angel
- Subjects
- *
MELATONIN , *UNSATURATED fatty acids , *PEROXIDATION , *TRIGLYCERIDES - Abstract
Abstract: The lipid peroxidation of triglycerides enriched in polyunsaturated fatty acids was investigated by photoemission techniques and the TBARS assay. Butylated hydroxytoluene, 5-OH-tryptophan and N-acetylserotonin inhibited light emission and TBARS formation in a concentration dependent manner. However, it was enhanced in the presence of melatonin and 5-methoxytryptamine and was dependent on its concentration. The total relative luminic units were found to be lower in those systems incubated in the presence of butylated hydroxytoluene, N-acetylserotonin or 5-OH-tryptophan; this decreased proportionally to the concentration of the compound tested. The order of inhibition was 5-OH-tryptophan> N-acetylserotonin>butylated hydroxytoluene with the following IC50 values: 0.65, 6.5 and 9.0 mM respectively. The free-radical scavenging activity of the indole derivatives was also analyzed by the DPPH method, and the results indicate that 5-OH-tryptophan, and N-acetylserotonin exhibited a dose-dependent free-radical scavenging ability at all of the tested concentrations. Thus, at 10 μM concentration a decrease of 84.71% and 73.50% of initial DPPH was observed, compared to 51.00% of BHT. Melatonin and 5-methoxytriptamine decreased the initial concentration of DPPH only 1.85% and 5.0%, respectively. The possible formation of N 1-acetyl-N 2 formyl-5-methoxykynuramine (AFMK) during lipid peroxidation of triglycerides enriched in PUFAs with cumene hydroperoxide in the presence of melatonin was also analyzed. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
43. CYP2D6 genotype in relation to perphenazine concentration and pituitary pharmacodynamic tissue sensitivity in Asians: CYP2D6-serotonin-dopamine crosstalk revisited.
- Author
-
Ozdemir, Vural, Bertilsson, Leif, Miura, Jun, Carpenter, Erin, Reist, Christopher, Harper, Patricia, Widén, Jolanta, Svensson, Jan-Olof, Albers, Lawrence J., Kennedy, James L., Endrenyi, Laszlo, and Kalow, Werner
- Abstract
Hyperprolactinemia is a common side effect of first-generation antipsychotics mediated by antagonism of dopaminergic neurotransmission in the pituitary. Most first-generation antipsychotics are metabolized by CYP2D6 in the liver. Further, CYP2D6 is expressed in the human brain as a 5-methoxyindolethylamine O-demethylase potentially contributing to regeneration of serotonin from 5-methoxytryptamine. As dopaminergic neurotransmission is subject to regulation by serotonin, CYP2D6 may exert a nuanced (serotonergic) influence on dopaminergic tone in the pituitary. CYP2D6∗10 is an allele associated with reduced enzyme function and occurs in high frequency (about 50%) in Asians. We prospectively evaluated significance of CYP2D6 genetic variation for prolactin response to perphenazine (a model first-generation antipsychotic) in Asians.A single oral dose of perphenazine (0.1 mg/kg) or placebo was administered to 22 medication-free nonsmoker healthy male Chinese-Canadian volunteers, following a double-blind within-subject randomized design. Blood samples were drawn at baseline and 2, 3, 4, 5 and 6 h after drug administration.In volunteers with CYP2D6∗10/CYP2D6∗10 genotype, the mean area under curve (AUC0-6) for perphenazine concentration was 2.9-fold higher than those who carry the CYP2D6∗1 allele (P<0.01). Notably, volunteers homozygous for CYP2D6∗10 exhibited a significant reduction (66%) in mean pharmacodynamic tissue sensitivity as measured by the (prolactin-AUC0-6/perphenazine-AUC0-6) ratio (P=0.02).CYP2D6 genotype is a significant contributor to perphenazine concentration in Chinese-Canadians. Importantly, prolactin response, when normalized per unit perphenazine concentration, appears to be blunted in volunteers homozygous for CYP2D6∗10. We suggest that CYP2D6 genetic variation may potentially influence pharmacodynamic tissue sensitivity in the pituitary, presumably through disposition of an endogenous substrate (e.g. 5-methoxytryptamine). [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
44. Could endogenous substrates of drug-metabolizing enzymes influence constitutive physiology and drug target responsiveness?
- Author
-
Ozdemir, Vural, Gunes, Arzu, Dahl, Marja-Liisa, Scordo, M. Gabriella, Williams-Jones, Bryn, and Someya, Toshiyuki
- Subjects
PHARMACOKINETICS ,BIOINFORMATICS ,DRUG metabolism ,PHARMACOGENOMICS ,CYTOCHROME P-450 ,DOPAMINE ,SEROTONIN - Abstract
Integration of genomic data from pharmacokinetic pathways and drug targets is an emerging trend in bioinformatics, but is there a clear separation of pharmacokinetic pathways and drug targets? Should we also consider the potential interactions of endogenous substrates of drug-metabolizing enzymes with receptors and other molecular drug targets as we combine pharmacogenomic datasets? We discuss these overarching questions through a specific pharmacogenomic case study of the cytochrome P450 (CYP)2D6, serotonin and dopamine triad. Importantly, CYP2D6 may contribute to the regeneration of serotonin from 5-methoxytryptamine by virtue of its catalytic function as a 5-methoxyindolethylamine O-demethylase. Furthermore, serotonergic neurons provide a regulatory feedback on dopaminergic neurotransmission. Hence, we hypothesize that independent of its role as a pharmacokinetic gene, CYP2D6 may nuance the regulation of serotonergic and dopaminergic neurophysiology. Additionally, we reflect upon the contribution of hyperspecialization in biomedicine to the present disconnect between research on pharmacokinetics and drug targets, and the potential for remedying this important gap through informed dialogue among clinical pharmacologists, human geneticists, bioethicists and applied social scientists. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
45. Proposal of 5-methoxy- N -methyl- N -isopropyltryptamine consumption biomarkers through identification of in vivo metabolites from mice
- Author
-
David Fabregat-Safont, Manuela Barneo-Muñoz, Félix Hernández, F. Martinez-Garcia, María Ibáñez, Juan V. Sancho, Generalitat Valenciana (Group of Excellence Prometeo II 2014/023), Ministerio de Economía y Competitividad (Project: CTQ2015-65603-P), NPS-Euronet (HOME/2014/JDRUG/AG/DRUG/7086), co-funded by the European Commission, David Fabregat-Safont acknowledges Ministerio de Educación, Cultura y Deporte for his predoctoral grant (Grant FPU15/2033), and Manuela Barneo-Muñoz and Ferran Martinez-Garcia Generalitat Valenciana (Group of Excellence PROMETEO2016/076) and University Jaume I (UJI-B2016-45)
- Subjects
Male ,Tryptamine ,Cathinone ,Metabolite ,Urine ,Pharmacology ,01 natural sciences ,Biochemistry ,Mass Spectrometry ,Analytical Chemistry ,5-Methoxytryptamine ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Tryptamines In vivo studies ,0302 clinical medicine ,metabolite identification ,Pharmacokinetics ,Synthetic cannabinoids ,medicine ,Animals ,030216 legal & forensic medicine ,Chromatography, High Pressure Liquid ,Chromatography ,5-MeO-MiPT ,Illicit Drugs ,010401 analytical chemistry ,Organic Chemistry ,General Medicine ,0104 chemical sciences ,Tryptamines ,Europe ,chemistry ,high resolution mass spectrometry ,new psychoactive substances ,Psilocin ,Biomarkers ,medicine.drug - Abstract
New psychoactive substances (NPS) are a new breed of synthetically produced substances designed to mimic the effects of traditional illegal drugs. Synthetic cannabinoids and synthetic cathinones are the two most common groups, which try to mimic the effects of the natural compounds 9Δ-tetrahydrocannabinol and cathinone, respectively. Similarly, synthetic tryptamines are designer compounds which are based on the compounds psilocin, N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine found in some mushrooms. One of the most important tryptamine compounds found in seizures is 5-methoxy-N,N-diisopropyltryptamine, which has been placed as controlled substance in USA and some European countries. The control of this compound has promoted the rising of another tryptamine, the 5-methoxy-N-methyl-N-isopropyltryptamine, which at the time of writing this article has not been banned yet. So, it is undeniable that this new substance should be monitored. 5-methoxy-N-methyl-N-isopropyltryptamine has been reported by the Spanish Early Warning System and detected in our laboratory in two pill samples purchased in a local smart shop. This has promoted the need of stablishing consumption markers for this compound in consumers’ urine. In the present work, the metabolism and pharmacokinetic of 5-methoxy-N-methyl-N-isopropyltryptamine has been studied by an in vivo approach, using adult male mice of the inbred strain C57BLJ/6. The use of ultra-high performance liquid chromatography coupled to high resolution mass spectrometry allowed the identification of four metabolites. After the pharmacokinetic study in serum and urine, the O-demethylated metabolite and the non-metabolised parent compound are proposed as consumption markers in hydrolysed urine. Data reported in this work will help hospitals and forensic laboratories to monitor the consumption and potential intoxication cases related to this tryptamine.
- Published
- 2017
- Full Text
- View/download PDF
46. Proton and Carbon‐13 NMR Studies of Some Tryptamines, Precursors, and Derivatives: Ab Initio Calculations for Optimized Structures.
- Author
-
Rothchild, Robert
- Subjects
- *
HALLUCINOGENIC drugs , *PSYCHIATRIC drugs , *TRYPTAMINE , *BIOGENIC amines , *SPECTRUM analysis - Abstract
Proton and carbon‐13 NMR data are presented for 5‐methoxytryptamine, 1; 6‐methoxytryptamine, 2; N,N ‐diisopropyl‐5‐methoxytryptamine, 3, (5‐MeO‐DIPT); and N,N ‐diisopropyl‐5‐methoxyindole‐3‐glyoxylamide, 4, at 300 MHz ( 1 H) and 75 MHz ( 13 C) in CDCl 3 at ambient temperature. Compound 3, considered a potential hallucinogen, had been placed into Schedule I of the Controlled Substances Act, effective April 4, 2003, by the U.S. Drug Enforcement Administration. Compound 4 can serve as a possible precursor to 3. We believe that these are the first proton NMR assignments obtained at medium field (7 tesla) using selective homodecoupling and two‐dimensional homonuclear chemical shift correlation spectra (using one or more of the COSY45, COSY90, and COSYLR experiments) for rigorous aryl proton assignments in this group of compounds. Significant observed differences in the proton and carbon‐13 NMR spectra should allow facile distinction of the 5‐methoxy series, 1 and 3, from the 6‐methoxy series, 2. Energy minimizations to obtain optimized structures for each compound were performed at the Hartree–Fock level with the 6‐31G* basis set, and the resulting geometries are discussed. The presented geometry calculations appear to be the most accurate reported to date for 1 based on the basis set employed, and the first HF/6‐31G* structures for compounds 2, 3, or 4. Appreciable geometry differences in 3 and 4 for the pendant sidechain containing the N[CH(CH 3 ) 2 ] 2 moiety are noteworthy. Proximity of the carbonyl oxygens in 4 to H2 and H4 is suggested as a possible contributing factor in the deshielding of these protons in the NMR spectrum. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
47. Fourier transform infrared spectra and molecular structure of 5-methoxytryptamine, N-acetyl-5-methoxytryptamine and N-phenylsulfonamide-5-methoxytryptamine
- Author
-
Bayari, S. and Ide, S.
- Subjects
- *
ANTIOXIDANTS , *POISONS , *INFRARED spectra , *X-ray diffraction - Abstract
5-Methoxytryptamine (5-MT) is a potent antioxidant and has radioprotective action. N-acetyl-5-methoxytryptamine (melatonin, NA-5-MT) is a free radical scavenger and antioxidant, which protects against oxidative damage due to a variety of toxicants. The infrared spectra of 5-MT, NA-5-MT and new synthesized N-phenylsulfonamide-5-methoxytryptamine (PS-5-MT) were investigated in the region between 4000 and 400 cm−1. Vibrational assignments of the molecules have been made for fundamental modes on the basis of the group vibrational concept, infrared intensity and comparison with the assignments for related molecules. X-ray powder diffraction patterns of molecules were also recorded. In order to optimize the geometries of the molecules, molecular mechanic calculations (MM3) were performed. Conformational analysis of 5-MT, NA-5-MT and PS-5-MT was also established by the using PM3 method. [Copyright &y& Elsevier]
- Published
- 2003
- Full Text
- View/download PDF
48. Determination of 5-MeO-DIPT in Human Urine Using Gas Chromatography Coupled with High-Resolution Orbitrap Mass Spectrometry
- Author
-
Hui Yan, Yunli Zhao, Xiuying Yan, Zhiguo Yu, and Ping Xiang
- Subjects
Serotonin ,Resolution (mass spectrometry) ,Health, Toxicology and Mutagenesis ,Ethyl acetate ,Urine ,Toxicology ,Orbitrap ,Mass spectrometry ,01 natural sciences ,Gas Chromatography-Mass Spectrometry ,Mass Spectrometry ,Analytical Chemistry ,law.invention ,Designer Drugs ,5-Methoxytryptamine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,law ,Environmental Chemistry ,Humans ,030216 legal & forensic medicine ,Detection limit ,Chemical Health and Safety ,Chromatography ,Chemistry ,010401 analytical chemistry ,0104 chemical sciences ,Substance Abuse Detection ,Gas chromatography ,Gas chromatography–mass spectrometry - Abstract
5-Methoxy-N,N-Diisopropyltryptamine (5-MeO-DIPT) is a designer hallucinogen derived from tryptamine and its use has been banned by many countries. In this study, a qualitative and quantitative method was developed for determining 5-MeO-DIPT in urine by gas chromatography high-resolution mass spectrometry. 5-hydroxy-N,N-diisopropyltryptamine (5-OH-DIPT) and 5-methoxy-N-isopropyltryptamine (5-MeO-IPT) were identified as 5-MeO-DIPT metabolites in abusers’ urine. 5-MeO-DIPT was extracted from urine by liquid–liquid extraction with ethyl acetate under alkaline conditions. The extract was analyzed by GC-Orbitrap-MS in full scan mode with a resolution of 60,000 full width at half maxima (FWHM). The linear range of this method was 2–300 ng/mL with r > 0.99, and the limit of detection was 1 ng/mL. The accuracy and precision were 93–108.7% and 3.1–10.3%, respectively. This method is simple and sensitive. It has been successfully used to detect 5-MeO-DIPT in drug abusers’ urine, which showed that the concentrations of 5-MeO-DIPT were between 1 and 2.8 ng/mL. 5-OH-DIPT and 5-MeO-IPT, two urinary major metabolites of 5-MeO-DIPT, were identified in urine samples from 5-MeO-DIPT users. Furthermore, the stability of 5-MeO-DIPT in human urine was investigated. It was discovered that the concentration of 5-MeO-DIPT in urine decreased by 22.8, 33.2 and 38.2% after samples were stored for 24 h at 25°C, 5 days at 4°C and 7 days at 4°C, respectively. And 5-MeO-DIPT in urine were stable after they were stored for 30 days at −20°C. Therefore, it is recommended that urine should be stored under freezing conditions before performing 5-MeO-DIPT analysis.
- Published
- 2019
49. Alternative Ligands at Melatonin Receptors.
- Author
-
Legros C, Yous S, and Boutin JA
- Subjects
- 5-Methoxytryptamine, Animals, Ligands, Mammals metabolism, Receptors, Melatonin, Iodine Radioisotopes, Melatonin pharmacology
- Abstract
Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone that possesses a wide range of biological effects. Most of the main recognized effects of this hormone in mammals are due to its interaction with two G protein-coupled receptors, MT1 and MT2. Ligand-binding studies have been based on the use of its radioligand analog, 2[125I]-iodomelatonin, a super agonist discovered in the early 1990s. This compound has been used in most of the binding studies reported in the literature. Nevertheless, more recently other possibilities arose. This chapter is a brief summary of those alternative radioligands and of their benefits one can find in using them., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
- Full Text
- View/download PDF
50. Cloning, Expression, Purification, Crystallization, and X-Ray Structural Determination of the Human NQO2 in Complex with Melatonin.
- Author
-
Calamini B, Ferry G, and Boutin JA
- Subjects
- 5-Methoxytryptamine, Animals, Antioxidants, Cloning, Molecular, Crystallization, Humans, Ligands, Mammals metabolism, Receptors, Melatonin metabolism, X-Rays, Melatonin metabolism, Quinone Reductases genetics, Quinone Reductases metabolism
- Abstract
Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone which possesses a wide range of biological effects. The effects mediated by melatonin are in part attributed to the antioxidant properties of the molecule, which may act as scavenger of free radicals, and also to the binding of melatonin to its protein targets. For a long time, melatonin had been described as a ligand of a putative "receptor" present in the mammalian brain. Several studies were thus carried out with the goal of clarifying the nature of this melatonin "receptor," which led to the discovery of MT3 as the third melatonin binding site. This binding site was confirmed independently by several groups, and it was eventually demonstrated that MT3 was the enzyme quinone reductase 2 (NQO2). Among the different approaches used to validate that MT3 was indeed NQO2, the co-crystallization of NQO2 with melatonin was key in demonstrating the exact binding site and mode of melatonin to the enzyme and led to a clear understanding of the residues important for protein binding and inhibition. In this chapter, we described the details for the cloning, expression, and purification of the human enzyme NQO2. We also describe a detailed protocol for the crystallization of melatonin with this protein., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
- Full Text
- View/download PDF
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