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'''N-Acetylserotonin O-methyltransferase''' is an enzyme that 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. [1]
Structure and Gene Location
''N- Acetylserotonin O-methyltransferase'' is an enzyme that is coded for by genes located on the PAR region of the X and Y chromosome, and is most abundantly found in the pineal gland and retina of humans. [2]
Although the exact structure of ''N- Acetylserotonin O-methyltransferase'' has yet to be determined by X-Ray diffraction, the crystal structure of the Maf domain of human ''N- Acetylserotonin O-methyltransferase''-like protein has been found. [3]
Class of Enzyme and Function
''N- Acetylserotonin O-methyltransferase'' can be classified under three types of enzyme functional groups: transferases, one-carbon group transferers, and methyltransferases. [4] 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. Figure 1 is a clear picture of where ''N- Acetylserotonin O-methyltransferase'' is used during tryptophan metabolism (see two locations of enzyme number 2.1.1.4) [5]
'Figure 1'.
Synonyms
Synonyms of ''N- Acetylserotonin O-methyltransferase'' are ''Hydroxyindole O-methyltransferase'' (HIOMT), ''Acetylserotonin O-methyltransferase'' (ASMT), ''Acetylserotonin N-methyltransferase'', ''Acetylserotonin methyltransferase'' (Y chromosome).[5] 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). [5]
Amino Acid Sequences
[8]
'''Bos taurus''' (350 Amino Acids)
MCSQEGEGYSLLKEYANAFMVSQVLFAACELGVFELLAEALEPLDSAAVSSHLGSSPGD
RAATEHLCVPEAAASRREGRKSCVCKHGARQHLPGERQPQVPAGHAAVRGQDRLRLLAP
PGEAVREGRNQYLKAFGIPSEELFSAIYRSEDERLQFMQGLQDVWRLEGATVLAAFDLS
PFPLICDLGGGSGALAKACVSLYPGCRAIVFDIPGVVQIAKRHFSASEDERISFHEGDF
FKDALPEADLYILARVLHDWTDAKCSHLLQRVYRACRTGGGILVIESLLDTDGRGPLTT
LLYSLNMLVQTEGRERTPGRSTARSVGPAASETCGDGGRGEPTMLSWPGNQACSV
'''Homo sapiens''' (373 Amino Acids)
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. [9]
Expression in immune cells
Recent studies found 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 endoctrine and nervous system functions. In other words, the gene may be expressed in various isoforms in different cells of the body. [10]
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. [11]
'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. [5]
'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. [5]
'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. [14]
'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. [15]
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 (eg 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 HOIMT could provide valuable insight on the nature and onset of these impairing disorders. [16]
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 the this gene in genetic disorders. [17]
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.[18] 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. [19]
References
1. Kanehisa, M., Goto, S., Hattori, M., Aoki-Kinoshita, K.F., Itoh, M., Kawashima, S., Katayama, T., Araki, M., and Hirakawa, M.; From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res. 34, D354-357 (2006). [pubmed] [pdf] [See also comments in Thomson's website]
2. Online Mendelian Inheritance in Man, OMIM (TM). Johns Hopkins University, Baltimore, MD. MIM Number: {300015}: {11/19/1998}: . World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/
3. PDB ID: 2P5X
Min, J., Wu, H., Dombrovski, L., Loppanu, P., Weigelt, J., Sundstrom, M., Arrowsmith, C.H., Edwards, A.M., Bochkarve, A., Plotnikov, A.M., Crystal Structure of Maf Domain of Human N- Acetylseratonin O-methyltransferase
Structural Genomics Consotrium (SGC) (2007)
URL: http://www.rcsb.org/pdb/explore.do?structureId=2P5X
4. Kanehisa, M., KEGG. (2006)
5. Kanehisa, M., KEGG. (2006)
6. Kanehisa, M., KEGG. (2006)
7. Kanehisa, M., KEGG. (2006)
8. Kanehisa, M., KEGG. (2006)
9. Rodriguez, I.R. et. al. Structural analysis of the human hydroxyindole-O-methyltransferase gene. Journal of biological chemistry. 1994 Dec 16; 269(50):31969-77. URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=search&Dopt=b&term=7989373
10. Pozo, D., Garcia-Maurino, S., Guerrero, J.M., Calvo, J.R. Journal of Pineal Research. 2004 Aug;37(1):48-54. URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=search&Dopt=b&term=15230868
11. Ron Caspi, Hartmut Foerster, Carol A. Fulcher, Rebecca Hopkinson, John Ingraham, Pallavi Kaipa, Markus Krummenacker, Suzanne Paley, John Pick, Seung Y. Rhee, Christophe Tissier, Peifen Zhang and Peter D. Karp. “MetaCyc: a multiorganism database of metabolic pathways and enzymes.” Nucleic Acids Research Oct. 2005: Vol 34- SRI International, 333 Ravenswood, Menlo Park, CA 94025, USA, Department of Plant biology, Carnegie Institution, 260 Panama Street, Stanford, CA 94305, USA and 2Section of Microbiology, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA. Accessed 25 Apr. 2007
URL: http://www.ai.sri.com/pkarp/pubs/06metacyc.pdf
12. Kanehisa, M., KEGG. (2006)
13. Kanehisa, M., KEGG. (2006)
14. PUMA2--grid-based high-throughput analysis of genomes and metabolic pathways. Maltsev N, Glass E, Sulakhe D, Rodriguez A, Syed MH, Bompada T, Zhang Y, D'Souza M. Nucleic Acids Res. 2006 Jan 1;34(Database issue):D369-72.
URL: http://compbio.mcs.anl.gov/puma2/cgi-bin/pathway.cgi?tax_id=&user=&key=&header=puma2&pw=SRTMEL.ANA
15. Fevre Montagne, M. et. al. Microarray analysis reveals differential gene expression patterns in tumors of the pineal region. Journal of neuropathology and experimental neurology. 2006 Jul;65(7):675-84. URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=search&Dopt=b&term=16825954
16. Venkataramanujan, S. et. al. Melatonin in Mood Disorders. World Journal of Biological Psychiatry. 2006 Aug:7(3):138-151. URL: http://www.informaworld.com/smpp/content~content=a749302090~db=all
17. Huafang, Y. et. al. Localization of the hydroxyindole-O-methyltransferase gene to the pseudoautosomal region: implications for mapping of psychiatric disorders. Human Molecular Genetics. 1993:2(2):127-131. URL: http://hmg.oxfordjournals.org/cgi/content/abstract/2/2/127http://hmg.oxfordjournals.org/cgi/content/abstract/2/2/127
18. Djeridane, Y., and Touitou, Y. Chronic diazepam administration differentially affects melatonin synthesis in rat pineal and Harderian glands. Psychopharmacology. 2001 April:154(4):1432-2072. URL: http://www.springerlink.com/content/5gd87g0bpyjth15h/
19. Reiter, R.J., Tan, D., Terron, M.P., Flores, L.J. Melatonin and its metabolites: new findings regarding their production and their radical scavenging actions. Acta Biochemica Polonica. 2007 March:54(1):1-9.
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