Acetylserotonin O-methyltransferase

acetylserotonin O-methyltransferase
Identifiers
EC number 2.1.1.4
CAS number 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 / EGO
Acetylserotonin O-methyltransferase
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ASMT ; ASMTY; HIOMT; HIOMTY
External IDs OMIM: 402500 MGI: 96090 HomoloGene: 48261 GeneCards: ASMT Gene
EC number 2.1.1.4
Orthologs
Species Human Mouse
Entrez 438 n/a
Ensembl ENSG00000196433 n/a
UniProt P46597 n/a
RefSeq (mRNA) NM_001171038 n/a
RefSeq (protein) NP_001164509 n/a
Location (UCSC) Chr X:
1.62 – 1.64 Mb		 n/a
PubMed search n/a

N-Acetylserotonin O-methyltransferase also known as ASMT 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]

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

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.[4] 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

N-Acetylserotonin O-methyltransferase can be classified under three types of enzyme functional groups: transferases, one-carbon group transferers, and methyltransferases.[6]

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

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).[6]

Amino Acid Sequences

Bos taurus (cattle) has 350 Amino Acids[6] and the amino acid sequence is:

MCSQEGEGYSLLKEYANAFMVSQVLFAACELGVFELLAEALEPLDSAAVSSHLGSSPGD RAATEHLCVPEAAASRREGRKSCVCKHGARQHLPGERQPQVPAGHAAVRGQDRLRLLAP PGEAVREGRNQYLKAFGIPSEELFSAIYRSEDERLQFMQGLQDVWRLEGATVLAAFDLS PFPLICDLGGGSGALAKACVSLYPGCRAIVFDIPGVVQIAKRHFSASEDERISFHEGDF FKDALPEADLYILARVLHDWTDAKCSHLLQRVYRACRTGGGILVIESLLDTDGRGPLTT LLYSLNMLVQTEGRERTPGRSTARSVGPAASETCGDGGRGEPTMLSWPGNQACSV

For Homo sapiens (human) with 373 Amino Acids [6] 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.[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 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.[6]

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.[6]

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.[9]

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.[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 HOIMT 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 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

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.[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. ↑ 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: D354–357. doi:10.1093/nar/gkj102. PMC 1347464. PMID 16381885. [See also comments in Thomson's website]
  2. ↑ 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.
  3. 1 2 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. PMID 7989373.
  4. ↑ Online 'Mendelian Inheritance in Man' (OMIM) x-chromosomal ASMT -300015
  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. 1 2 3 4 5 6 7 Enzyme 2.1.1.4 at KEGG Pathway Database.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ http://sfari.org/news-and-opinion/conference-news/2011/society-for-neuroscience-2011/genetic-studies-probe-sleep-hormones-role-in-autism
  13. ↑ 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.
  14. ↑ Djeridane Y, Touitou Y (April 2001). "Chronic diazepam administration differentially affects melatonin synthesis in rat pineal and Harderian glands". Psychopharmacology (Berl.) 154 (4): 403–7. doi:10.1007/s002130000631. PMID 11349394.
  15. ↑ 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. PMID 17351668.

Further reading

External links

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