“Acetylserotonin O-methyltransferase”的意思、由来-开放百科全书

In humans the ASMT enzyme is encoded by the ASMT gene. There are two identical copies, one of which resides on the X chromosome and the other on the Y chromosome.^[2]^[3]

Structure and Gene Location

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.^[5]

Class of Enzyme and Function

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).^[6] The most commonly used synonym is Hydroxyindole O-methyltransferase (HIOMT).

Organisms

Amino Acid Sequences

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.^[7]

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.^[8]

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.^[6]

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.^[6]

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.^[9]

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.^[10]

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.^[11]

Developmental disorders

Subjects with autism were found to have significantly lower levels of melatonin and Acetylserotonin O-methyltransferase (ASMT) than controls.^[12]

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.^[13]

Additional research

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.^[14] 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.^[15]

See also

References

1. ^{{cite journal |author1=Kanehisa M. |author2=Goto S. |author3=Hattori M. |author4=Aoki-Kinoshita K.F. |author5=Itoh M. |author6=Kawashima S. |author7=Katayama T. |author8=Araki M. |author9=Hirakawa M. | year = 2006 | title = From genomics to chemical genomics: new developments in KEGG | url = | journal = Nucleic Acids Res | volume = 34 | issue = | pages = D354–357 | pmid = 16381885 | doi=10.1093/nar/gkj102 | pmc=1347464|display-authors=etal}} [See also comments in Thomson's website]
2. ^{{cite journal |vauthors=Donohue SJ, Roseboom PH, Illnerova H, Weller JL, Klein DC | title = Human hydroxyindole-O-methyltransferase: presence of LINE-1 fragment in a cDNA clone and pineal mRNA | journal = DNA Cell Biol. | volume = 12 | issue = 8 |pages = 715–27 |date=October 1993 | pmid = 8397829 | doi = 10.1089/dna.1993.12.715| url = | issn = }}
3. ^¹{{cite journal |vauthors=Rodriguez IR, Mazuruk K, Schoen TJ, Chader GJ | title = Structural analysis of the human hydroxyindole-O-methyltransferase gene. Presence of two distinct promoters | journal = J. Biol. Chem. | volume = 269 | issue = 50 | pages = 31969–77 |date=December 1994 | pmid = 7989373 | doi = | url = http://www.jbc.org/cgi/content/abstract/269/50/31969 | issn = }}
4. ^{{OMIM|300015|x-chromosomal ASMT}}
5. ^{{PDB|2P5X}}; Min J, Wu H, Dombrovski L, Loppanu P, Weigelt J, Sundstrom M, Arrowsmith CH, Edwards AM, Bochkarve A, Plotnikov AM, Crystal Structure of Maf Domain of Human N- Acetylseratonin O-methyltransferase, Structural Genomics Consotrium (SGC) (2007)
6. ^¹²³⁴⁵⁶{{KEGG enzyme|2.1.1.4}}
7. ^{{cite journal |vauthors=Pozo D, García-Mauriño S, Guerrero JM, Calvo JR | title = mRNA expression of nuclear receptor RZR/RORalpha, melatonin membrane receptor MT, and hydroxindole-O-methyltransferase in different populations of human immune cells | journal = J. Pineal Res. | volume = 37 | issue = 1 | pages = 48–54 |date=August 2004 | pmid = 15230868 | doi = 10.1111/j.1600-079X.2004.00135.x | url = | issn = }}
8. ^{{cite journal |vauthors=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 | title = MetaCyc: a multiorganism database of metabolic pathways and enzymes | journal = Nucleic Acids Res. | volume = 34 | issue = Database issue | pages = D511–6 |date=January 2006 | pmid = 16381923 | pmc = 1347490 | doi = 10.1093/nar/gkj128 | url = http://www.ai.sri.com/pkarp/pubs/06metacyc.pdf | issn = }}
9. ^{{cite journal |vauthors=Maltsev N, Glass E, Sulakhe D, Rodriguez A, Syed MH, Bompada T, Zhang Y, D'Souza M | title = PUMA2--grid-based high-throughput analysis of genomes and metabolic pathways | journal = Nucleic Acids Res. | volume = 34 | issue = Database issue | pages = D369–72 |date=January 2006 | pmid = 16381888 | pmc = 1347457 | doi = 10.1093/nar/gkj095 | url = | issn = }}
10. ^{{cite journal |vauthors=Fèvre-Montange M, Champier J, Szathmari A, Wierinckx A, Mottolese C, Guyotat J, Figarella-Branger D, Jouvet A, Lachuer J | title = Microarray analysis reveals differential gene expression patterns in tumors of the pineal region | journal = J. Neuropathol. Exp. Neurol. | volume = 65 | issue = 7 | pages = 675–84 |date=July 2006 | pmid = 16825954 | doi = 10.1097/01.jnen.0000225907.90052.e3 | url = | issn = }}
11. ^{{cite journal | vauthors=Srinivasan V, Smits M, Spence W, Lowe AD, Kayumov L, Pandi-Perumal SR, Parry B, Cardinali DP | title = Melatonin in mood disorders | journal = World J. Biol. Psychiatry | volume = 7 | issue = 3 | pages = 138–51 | year = 2006 | pmid = 16861139 | doi = 10.1080/15622970600571822 | url = | issn = }}
12. ^http://sfari.org/news-and-opinion/conference-news/2011/society-for-neuroscience-2011/genetic-studies-probe-sleep-hormones-role-in-autism
13. ^{{cite journal |vauthors=Yi H, Donohue SJ, Klein DC, McBride OW | title = Localization of the hydroxyindole-O-methyltransferase gene to the pseudoautosomal region: implications for mapping of psychiatric disorders | journal = Hum. Mol. Genet. | volume = 2 | issue = 2 | pages = 127–31 |date=February 1993 | pmid = 8098975 | doi = 10.1093/hmg/2.2.127 | url = | issn = }}
14. ^{{cite journal |vauthors=Djeridane Y, Touitou Y | title = Chronic diazepam administration differentially affects melatonin synthesis in rat pineal and Harderian glands | journal = Psychopharmacology | volume = 154 | issue = 4 | pages = 403–7 |date=April 2001 | pmid = 11349394 | doi = 10.1007/s002130000631 | url = | issn = }}
15. ^{{cite journal |vauthors=Reiter RJ, Tan DX, Terron MP, Flores LJ, Czarnocki Z | title = Melatonin and its metabolites: new findings regarding their production and their radical scavenging actions | journal = Acta Biochim. Pol. | volume = 54 | issue = 1 | pages = 1–9 | year = 2007 | pmid = 17351668 | doi = | url = http://www.actabp.pl/pdf/1_2007/1.pdf | issn = }}