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Improved Management of Autism Spectrum Disorder (ASD) by Micronutrients
Published in Kedar N. Prasad, Micronutrients in Health and Disease, 2019
Many gene defects have been associated with ASD. They include common polygenic risk, de novo single nucleotide variants, and rare inherited variants, which confer heterogeneity and complexity of ASD.19 Copy variants in genes regulating synapse formation and intrasynaptic connections, and polymorphisms in genes encoding prosocial peptide system-oxytocin and vasopressin are associated with ASD.20 Polymorphisms in genes PON1, glutathione S-transferase (GSTM1 and GSTP1), delta aminolevulinic acid dehydratase, and the metal regulatory transcriptional factor 1 may increase the susceptibility to environmental toxins.5 Sleep disruption is commonly observed in children with ASD was associated with two melatonin pathway genes that showed decreased expression of acetylserotonin O-methyltransferase (ASMT) and cytochrome P450 1A2 (CYP1A2).21 Several clinical studies have revealed that supplementation with melatonin improved sleeping pattern, including longer sleep duration, less nighttime awakening, and quicker sleep onset in patients with ASD.22 In addition, improvements in sleeping pattern were noted when other sleep medication failed.
The Multi-Regulatory Properties of Melatonin in Plants
Published in Akula Ramakrishna, Victoria V. Roshchina, Neurotransmitters in Plants, 2018
Marino B. Arnao, Josefa Hernández-Ruiz
Chemically, melatonin (N-acetyl-5-methoxytryptamine) is an indolic compound derived from serotonin (5-hydroxytryptamine) (Figure 5.1). Both biogenic amines are synthesized from the amino acid tryptophan in an extensively studied biosynthetic pathway in both animals and plants (Reiter, 1991; Arnao and Hernández-Ruiz, 2006, 2014a, 2015a, 2015b; Tan et al., 2015; Back et al., 2016; Nawaz et al., 2016). In plants, tryptophan is converted into tryptamine by tryptophan decarboxylase (TDC) (Figure 5.1). Tryptamine is then converted into 5-hydroxytryptamine (commonly known as serotonin) by tryptamine 5-hydroxylase (T5H), an enzyme that has been only characterized in rice, and which possibly acts with a large number of substrates, although this has not been studied in depth (Kang et al., 2007; Fujiwara et al., 2010; Park et al., 2012, 2013b). The N-acetylation of serotonin is catalyzed by the enzyme serotonin N-acetyltransferase (SNAT) (Ferry et al., 2000; Byeon et al., 2015b, 2016). N-acetylserotonin is then methylated by acetylserotonin-O-methyltransferase (ASMT), a hydroxyindole-O-methyltransferase that generates melatonin. In plants, the methylation of N-acetylserotonin can also be made by a caffeic acid O-methyltransferase (COMT), an enzyme that can act on a broad diversity of substrates including caffeic acid and quercetin (Byeon et al., 2014a, 2015a; Lee et al., 2014b). Serotonin can also be transformed into 5-methoxytryptamine by ASMT (and by COMT), and then generate melatonin through the action of SNAT. Also, melatonin can be generated through the formation of N-acetyltryptamine, which is converted into N-acetylserotonin. Finally, serotonin can be formed from 5-hydroxytryptophan, after the action of tryptophan hydroxylase (TPH) and TDC, the latter step occurring mainly in animals but also in plants to a lesser extent.
The melatonin receptor 1B gene links circadian rhythms and type 2 diabetes mellitus: an evolutionary story
Published in Annals of Medicine, 2023
Hui Zhu, Zhi-jia Zhao, Hong-yi Liu, Jie Cai, Qin-kang Lu, Lin-dan Ji, Jin Xu
Synthesis of the pineal hormone melatonin is regulated by the SCN master clock and synchronized to the environmental light-dark cycle. Melatonin secretion generally occurs in darkness (at night) and peaks at 00:00 and 4:00 am. Importantly, nighttime melatonin production is blocked by light, especially blue light at wavelengths of 460–480 nm and intensities < 200 lux [43–45]. The biosynthetic precursor of melatonin is tryptophan, which is hydroxylated to 5-hydroxytryptophan and then decarboxylated to generate serotonin. Subsequently, serotonin is acetylated to N-acetylserotonin by arylalkylamine N-acetyltransferase (AANAT) and then converted to melatonin by acetylserotonin O-methyltransferase [16]. When the environmental photoperiodic information reaches intrinsic photosensitive retinal ganglion cells (ipRGCs), it is conveyed to the SCN by the retinal hypothalamic tract. Afterward, the signal is projected to the pineal gland through a neuronal signaling cascade that promotes or inhibits melatonin secretion in pinealocytes (Figure 1) [41,46,47].
Diurnal and circadian variations in indole contents in the goose pineal gland
Published in Chronobiology International, 2018
N. Ziółkowska, B. Lewczuk, M. Prusik
Indolamines such as serotonin and melatonin have multiple functions, including regulation of mood and appetite, and of circadian rhythms, such as the sleep–wake cycle (Jenkins et al. 2016; Simonneaux and Ribelayga 2003). These substances are synthesized in the pineal gland, and one of them, serotonin, is also widely produced in other parts of the brain and body tissues (Jenkins et al. 2016; Rawdon and Andrew 1994; Simonneaux and Ribelayga 2003). The precursor for synthesis of all pineal indolamines is tryptophan, which is hydroxylated in the mitochondria of pineal parenchymal cells to 5-hydroxytryptophan (5-HTRP) (Figure 1) (Simonneaux and Ribelayga 2003). 5-HTRP is decarboxylated by aromatic amino-acid decarboxylase (AADC) to serotonin. Serotonin is transformed into N-acetylserotonin (NAS) by arylalkylamine N-acetyltransferase (AA-NAT), and then NAS is methylated by N-acetylserotonin O-methyltransferase (ASMT) to form the main pineal hormone, melatonin. The transformation of serotonin to melatonin is not the only metabolic pathway involving serotonin. Some of this amine undergoes oxidative deamination to 5-hydroxyindole acetaldehyde (5-HIAL), an unstable compound, which is reduced to 5-hydroxytryptophol (5-HTOL) or dehydrogenated to 5-hydroxyindole acetic acid (5-HIAA). These 5-hydroxyindoles are then methylated to 5-methoxytryptophol (5-MTOL) and 5-methoxyindole acetic acid (5-MIAA), respectively. Another possible pathway of serotonin transformation is its direct methylation by ASMT to 5-methoxytryptamine (5-MTAM).
Mitochondrial dysfunction in age-related macular degeneration: melatonin as a potential treatment
Published in Expert Opinion on Therapeutic Targets, 2020
Saeed Mehrzadi, Karim Hemati, Russel J. Reiter, Azam Hosseinzadeh
Melatonin is synthesized from the amino acid L-tryptophan in four consecutive enzymatic steps. (I) L-tryptophan is hydroxylated by tryptophan hydroxylase to form 5-hydroxytryptophan. (II) 5-hydroxytryptophan is decarboxylated by l-aromatic amino acid decarboxylase to form 5-hydroxytryptamine (5-HT, also called serotonin). (III) arylalkylamine N-acetyltransferase/serotonin N-acetyltransferase (AANAT/SNAT) acetylates serotonin to form N-acetyl-5-hydroxytryptamine (N-acetylserotonin, AANAT). (IV) N-acetylserotonin is converted to melatonin (N‐acetyl‐5‐methoxytryptamine) by N‐acetylserotonin‐O‐methyltransferase (ASMT); AANAT is considered as the rate-limiting step in the biosynthesis of melatonin [24]. In addition to this classic melatonin synthetic pathway, new evidence indicates the existence of an alternative pathway for the biosynthesis of melatonin, in which melatonin is produced from N-acetylation of 5-methoxytryptamine generated from the O-methylation of serotonin. This alternative pathway may be prominent in certain organisms and under some conditions [25]. Once produced, melatonin is immediately released into the blood or into the cerebrospinal fluid [26]. Melatonin functions may be mediated through receptor-dependent or receptor-independent mechanisms. The receptor-independent actions of melatonin relate to melatonin’s ability to scavenge free radicals and receptor-dependent actions result from binding to cytosolic molecules, e.g., calmodulin and to membrane receptors including MT1 and MT2 receptors or nuclear receptors including RAR-related orphan receptors (RORs) and the retinoid Z receptors (RZRs) [27].