Acetylserotonin O-methyltransferase explained

acetylserotonin O-methyltransferase
Ec Number:	2.1.1.4
Cas Number:	9029-77-0
Go Code:	0017096

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.^[1]

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.^{[2] [3]}

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.The structure of N- Acetylserotonin O-methyltransferase has been determined by X-ray diffraction.^[4]

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.

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). 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).

Amino acid sequences

Bos taurus (cattle) has 350 amino acids and the amino acid sequence is:

MCSQEGEGYSLLKEYANAFMVSQVLFAACELGVFELLAEALEPLDSAAVSSHLGSSPGDRAATEHLCVPEAAASRREGRKSCVCKHGARQHLPGERQPQVPAGHAAVRGQDRLRLLAPPGEAVREGRNQYLKAFGIPSEELFSAIYRSEDERLQFMQGLQDVWRLEGATVLAAFDLSPFPLICDLGGGSGALAKACVSLYPGCRAIVFDIPGVVQIAKRHFSASEDERISFHEGDFFKDALPEADLYILARVLHDWTDAKCSHLLQRVYRACRTGGGILVIESLLDTDGRGPLTTLLYSLNMLVQTEGRERTPGRSTARSVGPAASETCGDGGRGEPTMLSWPGNQACSV

For Homo sapiens (human) with 373 amino acids the sequence is:

MGSSEDQAYRLLNDYANGFMVSQVLFAACELGVFDLLAEAPGPLDVAAVAAGVRASAHGTELLLDICVSLKLLKVETRGGKAFYRNTELSSDYLTTVSPTSQCSMLKYMGRTSYRCWGHLADAVREGRNQYLETFGVPAEELFTAIYRSEGERLQFMQALQEVWSVNGRSVLTAFDLSVFPLMCDLGGTRIKLETIILSKLSQGQKTKHRVFSLIGGAGALAKECMSLYPGCKITVFDIPEVVWTAKQHFSFQEEEQIDFQEGDFFKDPLPEADLYILARVLHDWADGKCSHLLERIYHTCKPGGGILVIESLLDEDRRGPLLTQLYSLNMLVQTEGQERTPTHYHMLLSSAGFRDFQFKKTGAIYDAILARK

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.^[3]

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.^[5]

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.^[6] 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.

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.

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.^[7]

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.^[8]

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.^[9]

Developmental disorders

Subjects with autism were found to have significantly lower levels of melatonin and acetylserotonin O-methyltransferase (ASMT) than controls.^[10]

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.^[11]

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.^[12] 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.^[13]

See also

• Methyltransferase

Further reading

• Itoh MT, Hosaka T, Mimuro T . Gonadotropin-releasing hormone increases melatonin release in the pineal gland of the female rat in vitro. . Horm. Metab. Res. . 35 . 3 . 153–7 . 2003 . 12734775 . 10.1055/s-2003-39076 . 22082149 . etal.
• Ross MT, Grafham DV, Coffey AJ . The DNA sequence of the human X chromosome. . Nature . 434 . 7031 . 325–37 . 2005 . 15772651 . 2665286 . 10.1038/nature03440 . 2005Natur.434..325R . etal.
• Fukuda T, Akiyama N, Ikegami M . 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 . 2010 . 20418777 . 10.1097/NEN.0b013e3181db7d3c . etal. free .
• Donohue SJ, Roseboom PH, Illnerova H . Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA. . DNA Cell Biol. . 12 . 8 . 715–27 . 1993 . 8397829 . 10.1089/dna.1993.12.715 . etal.
• Toma C, Rossi M, Sousa I . Is ASMT a susceptibility gene for autism spectrum disorders? A replication study in European populations. . Mol. Psychiatry . 12 . 11 . 977–9 . 2007 . 17957233 . 10.1038/sj.mp.4002069 . 20794666 . etal.
• Gerhard DS, Wagner L, Feingold EA . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 528928 . 10.1101/gr.2596504 . etal.
• Jonsson L, Ljunggren E, Bremer A . Mutation screening of melatonin-related genes in patients with autism spectrum disorders. . BMC Med. Genom. . 3. 10 . 2010 . 20377855 . 3020629 . 10.1186/1755-8794-3-10 . etal . free .
• Holt R, Barnby G, Maestrini E . Linkage and candidate gene studies of autism spectrum disorders in European populations. . European Journal of Human Genetics . 18. 9. 1013–1019 . 2010 . 20442744 . 2987412 . 10.1038/ejhg.2010.69 . etal.
• Gałecki P, Szemraj J, Bartosz G, Bieńkiewicz M, Gałecka E, Florkowski A, Lewiński A, Karbownik-Lewińska M . Single-nucleotide polymorphisms and mRNA expression for melatonin synthesis rate-limiting enzyme in recurrent depressive disorder. . J. Pineal Res. . 48 . 4 . 311–7 . 2010 . 20433639 . 10.1111/j.1600-079X.2010.00754.x . 24963323 . 4.
• Yi H, Donohue SJ, Klein DC, McBride OW . Localization of the hydroxyindole-O-methyltransferase gene to the pseudoautosomal region: implications for mapping of psychiatric disorders. . Hum. Mol. Genet. . 2 . 2 . 127–31 . 1993 . 8098975 . 10.1093/hmg/2.2.127 .
• Sato T, Deguchi T, Ichikawa T . Localization of hydroxyindole O-methyltransferase-synthesizing cells in bovine epithalamus: immunocytochemistry and in-situ hybridization. . Cell Tissue Res. . 263 . 3 . 413–8 . 1991 . 1878930 . 10.1007/BF00327275 . 7189534 . etal.
• Strausberg RL, Feingold EA, Grouse LH . 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 . 2002 . 12477932 . 139241 . 10.1073/pnas.242603899 . 2002PNAS...9916899M . etal. free .
• Rodriguez IR, Mazuruk K, Schoen TJ, Chader GJ . Structural analysis of the human hydroxyindole-O-methyltransferase gene. Presence of two distinct promoters. . J. Biol. Chem. . 269 . 50 . 31969–77 . 1994 . 10.1016/S0021-9258(18)31790-3 . 7989373 . free .
• Stefulj J, Hörtner M, Ghosh M . Gene expression of the key enzymes of melatonin synthesis in extrapineal tissues of the rat. . J. Pineal Res. . 30 . 4 . 243–7 . 2001 . 11339514 . 10.1034/j.1600-079X.2001.300408.x . 5800718 . etal.
• Melke J, Goubran Botros H, Chaste P . Abnormal melatonin synthesis in autism spectrum disorders. . Mol. Psychiatry . 13 . 1 . 90–8 . 2008 . 17505466 . 2199264 . 10.1038/sj.mp.4002016 . etal.

Notes and References

1. Kanehisa M. . Goto S. . Hattori M. . Aoki-Kinoshita K.F. . Itoh M. . Kawashima S. . Katayama T. . Araki M. . Hirakawa M. . 2006 . From genomics to chemical genomics: new developments in KEGG . Nucleic Acids Res . 34 . 90001. D354–357 . 16381885 . 10.1093/nar/gkj102 . 1347464. etal. [See also comments in Thomson's website]
2. Donohue SJ, Roseboom PH, Illnerova H, Weller JL, Klein DC . Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA . DNA Cell Biol. . 12 . 8 . 715–27 . October 1993 . 8397829 . 10.1089/dna.1993.12.715.
3. Rodriguez IR, Mazuruk K, Schoen TJ, Chader GJ . Structural analysis of the human hydroxyindole-O-methyltransferase gene. Presence of two distinct promoters . J. Biol. Chem. . 269 . 50 . 31969–77 . December 1994 . 10.1016/S0021-9258(18)31790-3 . 7989373 . free .
4. Botros HG, Legrand P, Pagan C, Bondet V, Weber P, Ben-Abdallah M, Lemière N, Huguet G, Bellalou J, Maronde E, Beguin P, Haouz A, Shepard W, Bourgeron T . 6 . Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway . Journal of Pineal Research . 54 . 1 . 46–57 . January 2013 . 22775292 . 10.1111/j.1600-079x.2012.01020.x . 205836404 .
5. Pozo D, García-Mauriño S, Guerrero JM, Calvo JR . 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 . August 2004 . 15230868 . 10.1111/j.1600-079X.2004.00135.x . 22197004 .
6. 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 . MetaCyc: a multiorganism database of metabolic pathways and enzymes . Nucleic Acids Res. . 34 . Database issue . D511–6 . January 2006 . 16381923 . 1347490 . 10.1093/nar/gkj128 .
7. Maltsev N, Glass E, Sulakhe D, Rodriguez A, Syed MH, Bompada T, Zhang Y, D'Souza M . PUMA2--grid-based high-throughput analysis of genomes and metabolic pathways . Nucleic Acids Res. . 34 . Database issue . D369–72 . January 2006 . 16381888 . 1347457 . 10.1093/nar/gkj095 .
8. Fèvre-Montange M, Champier J, Szathmari A, Wierinckx A, Mottolese C, Guyotat J, Figarella-Branger D, Jouvet A, Lachuer J . Microarray analysis reveals differential gene expression patterns in tumors of the pineal region . J. Neuropathol. Exp. Neurol. . 65 . 7 . 675–84 . July 2006 . 16825954 . 10.1097/01.jnen.0000225907.90052.e3 . free .
9. Srinivasan V, Smits M, Spence W, Lowe AD, Kayumov L, Pandi-Perumal SR, Parry B, Cardinali DP . Melatonin in mood disorders . World J. Biol. Psychiatry . 7 . 3 . 138–51 . 2006 . 16861139 . 10.1080/15622970600571822 . 21794734 .
10. Web site: Genetic studies probe sleep hormone's role in autism. 13 November 2011.
11. Yi H, Donohue SJ, Klein DC, McBride OW . Localization of the hydroxyindole-O-methyltransferase gene to the pseudoautosomal region: implications for mapping of psychiatric disorders . Hum. Mol. Genet. . 2 . 2 . 127–31 . February 1993 . 8098975 . 10.1093/hmg/2.2.127 .
12. Djeridane Y, Touitou Y . Chronic diazepam administration differentially affects melatonin synthesis in rat pineal and Harderian glands . Psychopharmacology . 154 . 4 . 403–7 . April 2001 . 11349394 . 10.1007/s002130000631 . 22918068 .
13. Reiter RJ, Tan DX, Terron MP, Flores LJ, Czarnocki Z . Melatonin and its metabolites: new findings regarding their production and their radical scavenging actions . Acta Biochim. Pol. . 54 . 1 . 1–9 . 2007 . 17351668 . 10.18388/abp.2007_3264. free .