Acetylserotonin O-methyltransferase
acetylserotonin O-methyltransferase | |||||||||
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Identifiers | |||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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ASMT | |||
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Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process | |||
Sources:Amigo / QuickGO |
Ensembl |
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UniProt |
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RefSeq (mRNA) |
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RefSeq (protein) |
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Location (UCSC) | Chr X: 1.62 – 1.64 Mb | n/a | |||||||
PubMed search | [2] | n/a |
View/Edit Human |
N-Acetylserotonin O-methyltransferase, also known as ASMT, is an
In humans the ASMT enzyme is encoded by the
Structure and gene location
N-Acetylserotonin O-methyltransferase is an enzyme that is coded for by genes located on the pseudoautosomal region of the X and Y chromosome, and is most abundantly found in the pineal gland and retina of humans.[6] The structure of N- Acetylserotonin O-methyltransferase has been determined by
Class of enzyme and function
N-Acetylserotonin O-methyltransferase can be classified under three types of enzyme functional groups: transferases, one-carbon group transferrers, and methyltransferases.[8]
It catalyzes two reactions in the tryptophan metabolism pathway, and both can be traced back to serotonin. Serotonin has many fates in this pathway, and N- Acetylserotonin O-methyltransferase catalyzes reactions in two of these fates. The enzyme has been studied most for its catalysis of the final step of the pathway from serotonin to melatonin, but it also catalyzes one of the reactions in the many step process of serotonin → 5-Methoxy-indolacetate.
Synonyms
Synonyms of N- Acetylserotonin O-methyltransferase are Hydroxyindole O-methyltransferase (HIOMT), Acetylserotonin O-methyltransferase (ASMT), Acetylserotonin N-methyltransferase, Acetylserotonin methyltransferase (Y chromosome).[8] The most commonly used synonym is Hydroxyindole O-methyltransferase (HIOMT).
Organisms
N- Acetylserotonin O-methyltransferase is found in both prokaryotes and eukaryotes. It is found in the bacteria Rhodopirellula baltica and Chromobacterium violaceum. It is also found in the following eukaryotes: Gallus gallus (chicken), Bos taurus (cow), Homo sapiens (human), Macaca mulatta (rhesus monkey), and Rattus norvegicus (rat).[8]
Amino acid sequences
Bos taurus (cattle) has 350
MCSQEGEGYSLLKEYANAFMVSQVLFAACELGVFELLAEALEPLDSAAVSSHLGSSPGD RAATEHLCVPEAAASRREGRKSCVCKHGARQHLPGERQPQVPAGHAAVRGQDRLRLLAP PGEAVREGRNQYLKAFGIPSEELFSAIYRSEDERLQFMQGLQDVWRLEGATVLAAFDLS PFPLICDLGGGSGALAKACVSLYPGCRAIVFDIPGVVQIAKRHFSASEDERISFHEGDF FKDALPEADLYILARVLHDWTDAKCSHLLQRVYRACRTGGGILVIESLLDTDGRGPLTT LLYSLNMLVQTEGRERTPGRSTARSVGPAASETCGDGGRGEPTMLSWPGNQACSV
For Homo sapiens (human) with 373 amino acids[8] the sequence is:
MGSSEDQAYRLLNDYANGFMVSQVLFAACELGVFDLLAEAPGPLDVAAVAAGVRASAHG TELLLDICVSLKLLKVETRGGKAFYRNTELSSDYLTTVSPTSQCSMLKYMGRTSYRCWG HLADAVREGRNQYLETFGVPAEELFTAIYRSEGERLQFMQALQEVWSVNGRSVLTAFDL SVFPLMCDLGGTRIKLETIILSKLSQGQKTKHRVFSLIGGAGALAKECMSLYPGCKITV FDIPEVVWTAKQHFSFQEEEQIDFQEGDFFKDPLPEADLYILARVLHDWADGKCSHLLE RIYHTCKPGGGILVIESLLDEDRRGPLLTQLYSLNMLVQTEGQERTPTHYHMLLSSAGF RDFQFKKTGAIYDAILARK
Alternative splicing
The human HOIMT gene is approximately 35 kb in length and contains 9-10
Expression in immune cells
Recent studies found
Reactions catalyzed
In the tryptophan metabolism pathway, N- Acetylserotonin O-methyltransferase catalyzes two separate reactions. The first reaction shown (Figure 2) is the reaction of N-acetyl-serotonin to N-acetyl-5-methoxy-tryptamine. S-adenosyl-L-methionine is used as a substrate and is converted to S-adenosyl-L-homocysteine.[10] Figure 2: Reaction catalyzed by N- Acetylserotonin O-methyltransferase
Figure 3 is the same reaction as above, but the figure provides a clearer picture of how the reactant proceeds to product using N-Acetylserotonin O-methyltransferase in addition to the substrate.[8]
Figure 3: Role of N- Acetylserotonin O-methyltransferase
The second reaction (Figure 4) catalyzed by N-Acetylserotonin O-methyltransferase in the tryptophan metabolism pathway is: S-Adenosyl-L-methionine + 5-Hydroxyindoleacetate ↔ S-Adenosyl-L-homocysteine + 5-Methoxyindoleacetate.[8]
Figure 4: Second reaction catalyzed by N- Acetylserotonin O-methyltransferase
Figure 5 is a more general scheme of the reaction pathway from serotonin to melatonin. The number 2.1.1.4 refers to the Enzyme Commission Number (EC Number) for N- Acetylserotonin O-methyltransferase. These two steps are embedded in the highly involved tryptophan metabolism pathway.[11]
Figure 5: Pathway serotonin → melatonin
Clinical implications
Tumors
There is evidence of high HIOMT gene expression in pineal parenchymal tumors (PPTs). This finding has led to the study of varying gene expression as a diagnostic marker for such tumors. Abnormally high levels of HIOMT in these glands could serve as an indication of the existence of PPTs in the brain.[12]
Psychiatric disorders
Melatonin levels are used as a trait marker for mood disorders, meaning that abnormal levels of melatonin can be used in conjunction with other diagnostic criteria to determine whether a mood disorder (e.g. Seasonal affective disorder, bipolar disorder, or major depressive disorder) exists. Melatonin levels can also be used as a state marker, contributing to conclusions on the severity of a patient's illness at a given point in time. Because studies have shown a direct correlation between the amount of hydroxyindole-O-methyltransferase in the pineal gland and the melatonin level, additional knowledge of HIOMT could provide valuable insight on the nature and onset of these impairing disorders.[13]
Developmental disorders
Subjects with
Linkage analysis
High frequency polymorphism exists on the PAR region of the sex chromosomes, where the HIOMT gene is located. Linkage analysis of a diseased locus with high frequency polymorphism of this region could lead to vital information about the role of this gene in genetic disorders.[15]
Additional research
HIOMT as the limiting reagent in the melatonin biosynthetic pathway
There has been some controversy over the regulatory power of hydroxyindole-O-methyltransferase in the production of melatonin. In 2001, it was argued that another enzyme in the pathway, N-acetyl transferase (NAT) was the limiting reagent in the production of melatonin.[16] Recent findings, however, have suggested that HIOMT, not NAT, is the limiting reagent, and a direct correlation between HIOMT expression and melatonin levels has been shown to exist.[17]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000196433 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 16381885. [See also comments in Thomson's website]
- PMID 8397829.
- ^ PMID 7989373.
- ^ Online Mendelian Inheritance in Man (OMIM): x-chromosomal ASMT - 300015
- S2CID 205836404.
- ^ a b c d e f g Enzyme 2.1.1.4 at KEGG Pathway Database.
- S2CID 22197004.
- PMID 16381923.
- PMID 16381888.
- PMID 16825954.
- S2CID 21794734.
- ^ "Genetic studies probe sleep hormone's role in autism". 13 November 2011.
- PMID 8098975.
- S2CID 22918068.
- PMID 17351668.
Further reading
- Itoh MT, Hosaka T, Mimuro T, et al. (2003). "Gonadotropin-releasing hormone increases melatonin release in the pineal gland of the female rat in vitro". Horm. Metab. Res. 35 (3): 153–7. S2CID 22082149.
- Ross MT, Grafham DV, Coffey AJ, et al. (2005). "The DNA sequence of the human X chromosome". Nature. 434 (7031): 325–37. PMID 15772651.
- Fukuda T, Akiyama N, Ikegami M, et al. (2010). "Expression of hydroxyindole-O-methyltransferase enzyme in the human central nervous system and in pineal parenchymal cell tumors". J. Neuropathol. Exp. Neurol. 69 (5): 498–510. PMID 20418777.
- Donohue SJ, Roseboom PH, Illnerova H, et al. (1993). "Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA". DNA Cell Biol. 12 (8): 715–27. PMID 8397829.
- Toma C, Rossi M, Sousa I, et al. (2007). "Is ASMT a susceptibility gene for autism spectrum disorders? A replication study in European populations". Mol. Psychiatry. 12 (11): 977–9. S2CID 20794666.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. PMID 15489334.
- Jonsson L, Ljunggren E, Bremer A, et al. (2010). "Mutation screening of melatonin-related genes in patients with autism spectrum disorders". BMC Med. Genom. 3: 10. PMID 20377855.
- Holt R, Barnby G, Maestrini E, et al. (2010). "Linkage and candidate gene studies of autism spectrum disorders in European populations". European Journal of Human Genetics. 18 (9): 1013–1019. PMID 20442744.
- Gałecki P, Szemraj J, Bartosz G, Bieńkiewicz M, et al. (2010). "Single-nucleotide polymorphisms and mRNA expression for melatonin synthesis rate-limiting enzyme in recurrent depressive disorder". J. Pineal Res. 48 (4): 311–7. S2CID 24963323.
- Yi H, Donohue SJ, Klein DC, McBride OW (1993). "Localization of the hydroxyindole-O-methyltransferase gene to the pseudoautosomal region: implications for mapping of psychiatric disorders". Hum. Mol. Genet. 2 (2): 127–31. PMID 8098975.
- Sato T, Deguchi T, Ichikawa T, et al. (1991). "Localization of hydroxyindole O-methyltransferase-synthesizing cells in bovine epithalamus: immunocytochemistry and in-situ hybridization". Cell Tissue Res. 263 (3): 413–8. S2CID 7189534.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2002). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. PMID 12477932.
- Rodriguez IR, Mazuruk K, Schoen TJ, Chader GJ (1994). "Structural analysis of the human hydroxyindole-O-methyltransferase gene. Presence of two distinct promoters". J. Biol. Chem. 269 (50): 31969–77. PMID 7989373.
- Stefulj J, Hörtner M, Ghosh M, et al. (2001). "Gene expression of the key enzymes of melatonin synthesis in extrapineal tissues of the rat". J. Pineal Res. 30 (4): 243–7. S2CID 5800718.
- Melke J, Goubran Botros H, Chaste P, et al. (2008). "Abnormal melatonin synthesis in autism spectrum disorders". Mol. Psychiatry. 13 (1): 90–8. PMID 17505466.
External links
- Acetylserotonin+N-Methyltransferase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- ASMTL+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Human ASMT genome location and ASMT gene details page in the UCSC Genome Browser.