Acetylserotonin O-methyltransferase

N-Acetylserotonin O-methyltransferase, also known as ASMT, is an enzyme which catalyzes the final reaction in melatonin biosynthesis: converting Normelatonin to melatonin. This reaction is embedded in the more general tryptophan metabolism pathway. The enzyme also catalyzes a second reaction in tryptophan metabolism: the conversion of 5-hydroxy-indoleacetate to 5-methoxy-indoleacetate. The other enzyme which catalyzes this reaction is n-acetylserotonin-o-methyltransferase-like-protein.^[3]

acetylserotonin O-methyltransferase
Identifiers
EC no.	2.1.1.4
CAS no.	9029-77-0
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

ASMT
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 4A6D, 4A6E
Identifiers
Aliases	ASMT, ASMTY, HIOMT, HIOMTY, acetylserotonin O-methyltransferase
External IDs	OMIM: 402500, 300015 HomoloGene: 48261 GeneCards: ASMT
Gene location (Human) Chr. X chromosome (human)^[1] Band X;Y Start 1,615,059 bp^[1] End 1,643,081 bp^[1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in anterior pituitary oocyte bone marrow sural nerve canal of the cervix left uterine tube right adrenal gland left adrenal gland gastric mucosa blood n/a More reference expression data BioGPS n/a
Gene ontology Molecular function methyltransferase activity transferase activity protein homodimerization activity O-methyltransferase activity acetylserotonin O-methyltransferase activity identical protein binding S-methyltransferase activity S-adenosylmethionine-dependent methyltransferase activity Cellular component cytosol Biological process melatonin biosynthetic process methylation protein biosynthesis indolalkylamine biosynthetic process aromatic compound biosynthetic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 438 n/a Ensembl ENSG00000196433 n/a UniProt P46597 n/a RefSeq (mRNA) NM_004043 NM_001171038 NM_001171039 n/a RefSeq (protein) NP_001164509 NP_001164510 NP_004034 n/a Location (UCSC) Chr X: 1.62 – 1.64 Mb n/a PubMed search ^[2] n/a
Wikidata
View/Edit Human

In humans the ASMT enzyme is encoded by the pseudoautosomal ASMT gene. A copy exists near the endcaps of the short arms of both the X chromosome and the Y chromosome.^[4][5]

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 X-ray diffraction.^[7]

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 amino acids^[8] and the amino acid sequence is:

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 exons. The gene can be alternatively spliced to form at least three possible isoforms, although each of these isoforms has the same role in the biosynthesis of melatonin. It has also been found that the gene contains multiple promoter regions, an indication that multiple mechanisms of regulation exist.^[5]

Expression in immune cells

Recent studies found messenger RNA (mRNA) transcripts of the HOIMT gene in B lymphocytes, T helper lymphocytes, cytoxic T lymphocytes, and natural killer lymphocytes in humans. This finding, in conjunction with research on alternative splicing of the HOIMT hnRNA, suggests that Hydroxyindole O-methyltransferase (synonym for N- Acetylserotonin O-methyltransferase) plays a role in the human immune system, in addition to its endocrine and nervous system functions. In other words, the gene may be expressed in various isoforms in different cells of the body.^[9]

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 autism were found to have significantly lower levels of melatonin and acetylserotonin O-methyltransferase (ASMT) than controls.^[14]

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

• Methyltransferase

References

1. GRCh38: Ensembl release 89: ENSG00000196433 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. Kanehisa M.; Goto S.; Hattori M.; Aoki-Kinoshita K.F.; Itoh M.; Kawashima S.; Katayama T.; Araki M.; Hirakawa M.; et al. (2006). "From genomics to chemical genomics: new developments in KEGG". Nucleic Acids Res. 34 (90001): D354–357. doi:10.1093/nar/gkj102. PMC 1347464. PMID 16381885. [See also comments in Thomson's website]
4. Donohue SJ, Roseboom PH, Illnerova H, Weller JL, Klein DC (October 1993). "Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA". DNA Cell Biol. 12 (8): 715–27. doi:10.1089/dna.1993.12.715. PMID 8397829.
5. Rodriguez IR, Mazuruk K, Schoen TJ, Chader GJ (December 1994). "Structural analysis of the human hydroxyindole-O-methyltransferase gene. Presence of two distinct promoters". J. Biol. Chem. 269 (50): 31969–77. doi:10.1016/S0021-9258(18)31790-3. PMID 7989373.
6. Online Mendelian Inheritance in Man (OMIM): x-chromosomal ASMT - 300015
7. Botros HG, Legrand P, Pagan C, Bondet V, Weber P, Ben-Abdallah M, et al. (January 2013). "Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway". Journal of Pineal Research. 54 (1): 46–57. doi:10.1111/j.1600-079x.2012.01020.x. PMID 22775292. S2CID 205836404.
8. Enzyme 2.1.1.4 at KEGG Pathway Database.
9. Pozo D, García-Mauriño S, Guerrero JM, Calvo JR (August 2004). "mRNA expression of nuclear receptor RZR/RORalpha, melatonin membrane receptor MT, and hydroxindole-O-methyltransferase in different populations of human immune cells". J. Pineal Res. 37 (1): 48–54. doi:10.1111/j.1600-079X.2004.00135.x. PMID 15230868. S2CID 22197004.
10. Caspi R, Foerster H, Fulcher CA, Hopkinson R, Ingraham J, Kaipa P, Krummenacker M, Paley S, Pick J, Rhee SY, Tissier C, Zhang P, Karp PD (January 2006). "MetaCyc: a multiorganism database of metabolic pathways and enzymes" (PDF). Nucleic Acids Res. 34 (Database issue): D511–6. doi:10.1093/nar/gkj128. PMC 1347490. PMID 16381923.
11. Maltsev N, Glass E, Sulakhe D, Rodriguez A, Syed MH, Bompada T, Zhang Y, D'Souza M (January 2006). "PUMA2--grid-based high-throughput analysis of genomes and metabolic pathways". Nucleic Acids Res. 34 (Database issue): D369–72. doi:10.1093/nar/gkj095. PMC 1347457. PMID 16381888.
12. Fèvre-Montange M, Champier J, Szathmari A, Wierinckx A, Mottolese C, Guyotat J, Figarella-Branger D, Jouvet A, Lachuer J (July 2006). "Microarray analysis reveals differential gene expression patterns in tumors of the pineal region". J. Neuropathol. Exp. Neurol. 65 (7): 675–84. doi:10.1097/01.jnen.0000225907.90052.e3. PMID 16825954.
13. Srinivasan V, Smits M, Spence W, Lowe AD, Kayumov L, Pandi-Perumal SR, Parry B, Cardinali DP (2006). "Melatonin in mood disorders". World J. Biol. Psychiatry. 7 (3): 138–51. doi:10.1080/15622970600571822. PMID 16861139. S2CID 21794734.
14. "Genetic studies probe sleep hormone's role in autism". 13 November 2011.
15. Yi H, Donohue SJ, Klein DC, McBride OW (February 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. doi:10.1093/hmg/2.2.127. PMID 8098975.
16. Djeridane Y, Touitou Y (April 2001). "Chronic diazepam administration differentially affects melatonin synthesis in rat pineal and Harderian glands". Psychopharmacology. 154 (4): 403–7. doi:10.1007/s002130000631. PMID 11349394. S2CID 22918068.
17. Reiter RJ, Tan DX, Terron MP, Flores LJ, Czarnocki Z (2007). "Melatonin and its metabolites: new findings regarding their production and their radical scavenging actions" (PDF). Acta Biochim. Pol. 54 (1): 1–9. doi:10.18388/abp.2007_3264. 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. doi:10.1055/s-2003-39076. PMID 12734775. S2CID 22082149.
• Ross MT, Grafham DV, Coffey AJ, et al. (2005). "The DNA sequence of the human X chromosome". Nature. 434 (7031): 325–37. Bibcode:2005Natur.434..325R. doi:10.1038/nature03440. PMC 2665286. 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. doi:10.1097/NEN.0b013e3181db7d3c. 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. doi:10.1089/dna.1993.12.715. 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. doi:10.1038/sj.mp.4002069. PMID 17957233. 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. doi:10.1101/gr.2596504. PMC 528928. 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. doi:10.1186/1755-8794-3-10. PMC 3020629. 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. doi:10.1038/ejhg.2010.69. PMC 2987412. 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. doi:10.1111/j.1600-079X.2010.00754.x. PMID 20433639. 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. doi:10.1093/hmg/2.2.127. 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. doi:10.1007/BF00327275. PMID 1878930. 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. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. 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. doi:10.1016/S0021-9258(18)31790-3. 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. doi:10.1034/j.1600-079X.2001.300408.x. PMID 11339514. 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. doi:10.1038/sj.mp.4002016. PMC 2199264. 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.