Recent studies foundmessenger RNA (mRNA) transcripts of the HOIMT gene inB lymphocytes,T helper lymphocytes,cytoxic T lymphocytes, andnatural killer lymphocytes in humans. This finding, in conjunction with research on alternative splicing of the HOIMThnRNA, suggests thatHydroxyindole O-methyltransferase (synonym forN- 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.[7]
N-Acetylserotonin O-methyltransferase is an enzyme that is coded for by genes located on thepseudoautosomal region of the X and Y chromosome, and is most abundantly found in thepineal gland andretina of humans.[8]
The human HOIMT gene is approximately 35 kb in length and contains 9-10exons. The gene can bealternatively spliced to form at least three possibleisoforms, 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.[9]
N-Acetylserotonin O-methyltransferase (ASMT) adopts the canonical SAM-dependent methyltransferase architecture in itsC-terminal catalytic domain, where a seven-strandedβ-sheet flanked byα-helices forms the S-adenosyl-L-methionine (SAM) binding pocket and catalytic site characteristic of class I (Rossmann-like) methyltransferases. ASMT functions as ahomodimer, with the predominantly helicalN-terminal domains of two monomers intertwining to stabilize the quaternary structure and contribute to proper active-site geometry. In the human X-ray structure, the substrate-binding pocket positions the 5-hydroxy group of N-acetylserotonin fornucleophilic attack on the SAM-derived methyl group, while conserved residues coordinate SAM or S-adenosyl-L-homocysteine (SAH) and interact with the indole ring to enforce regioselective O-methyl transfer.[11]
The structure ofN- Acetylserotonin O-methyltransferase has been determined byX-ray diffraction.[12]
N-Acetylserotonin O-methyltransferase can be classified under three types of enzyme functional groups:transferases, one-carbon group transferrers, andmethyltransferases.[6]
It catalyzes two reactions in thetryptophan metabolism pathway, and both can be traced back toserotonin. Serotonin has many fates in this pathway, andN- 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.
In one metabolic pathway fromtryptophan,N-Acetylserotonin O-methyltransferase catalyzes two separate reactions.The first is the reaction of N-acetylserotonin to melatonin. S-adenosyl-L-methionine (SAM) is used as the source of themethyl group and is converted to S-adenosyl-L-homocysteine (SAH).[6][13]
The second reaction catalyzed by the enzyme is later in the pathway, afterserotonin has been metabolised to 5-hydroxyindoleacetic acid. This is further converted to 5-methoxyindoleacetate, with the same SAMcofactor.[6][14]
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.[15]
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, ormajor 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 ofhydroxyindole-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.[16]
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.[19]
HIOMT as the limiting reagent in the melatonin biosynthetic pathway
There has been some controversy over the regulatory power ofhydroxyindole-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.[20] 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.[21]
^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".Journal of Pineal Research.37 (1):48–54.doi:10.1111/j.1600-079X.2004.00135.x.PMID15230868.S2CID22197004.
^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 and Cell Biology.12 (8):715–727.doi:10.1089/dna.1993.12.715.PMID8397829.
^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.PMID22775292.S2CID205836404.
^Srinivasan V, Smits M, Spence W, Lowe AD, Kayumov L, Pandi-Perumal SR, et al. (2006). "Melatonin in mood disorders".The World Journal of Biological Psychiatry.7 (3):138–151.doi:10.1080/15622970600571822.PMID16861139.S2CID21794734.
^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".Human Molecular Genetics.2 (2):127–131.doi:10.1093/hmg/2.2.127.PMID8098975.
^Djeridane Y, Touitou Y (April 2001). "Chronic diazepam administration differentially affects melatonin synthesis in rat pineal and Harderian glands".Psychopharmacology.154 (4):403–407.doi:10.1007/s002130000631.PMID11349394.S2CID22918068.
Itoh MT, Hosaka T, Mimuro T, Hamada N, Ishizuka B (March 2003). "Gonadotropin-releasing hormone increases melatonin release in the pineal gland of the female rat in vitro".Hormone and Metabolic Research = Hormon- Und Stoffwechselforschung = Hormones Et Metabolisme.35 (3):153–157.doi:10.1055/s-2003-39076.PMID12734775.S2CID22082149.
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 and Cell Biology.12 (8):715–727.doi:10.1089/dna.1993.12.715.PMID8397829.
Toma C, Rossi M, Sousa I, Blasi F, Bacchelli E, Alen R, et al. (November 2007). "Is ASMT a susceptibility gene for autism spectrum disorders? A replication study in European populations".Molecular Psychiatry.12 (11):977–979.doi:10.1038/sj.mp.4002069.PMID17957233.S2CID20794666.
Gałecki P, Szemraj J, Bartosz G, Bieńkiewicz M, Gałecka E, Florkowski A, et al. (May 2010). "Single-nucleotide polymorphisms and mRNA expression for melatonin synthesis rate-limiting enzyme in recurrent depressive disorder".Journal of Pineal Research.48 (4):311–317.doi:10.1111/j.1600-079X.2010.00754.x.PMID20433639.S2CID24963323.
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".Human Molecular Genetics.2 (2):127–131.doi:10.1093/hmg/2.2.127.PMID8098975.
Sato T, Deguchi T, Ichikawa T, Fujieda H, Wake K (March 1991). "Localization of hydroxyindole O-methyltransferase-synthesizing cells in bovine epithalamus: immunocytochemistry and in-situ hybridization".Cell and Tissue Research.263 (3):413–418.doi:10.1007/BF00327275.PMID1878930.S2CID7189534.
Stefulj J, Hörtner M, Ghosh M, Schauenstein K, Rinner I, Wölfler A, et al. (May 2001). "Gene expression of the key enzymes of melatonin synthesis in extrapineal tissues of the rat".Journal of Pineal Research.30 (4):243–247.doi:10.1034/j.1600-079X.2001.300408.x.PMID11339514.S2CID5800718.
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