Acetylserotonin O-methyltransferase
Encyclopedia
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.
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
.
of the X and Y chromosome, and is most abundantly found in the pineal gland
and retina
of humans.
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.
s, one-carbon group transferers, and methyltransferase
s.
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).
Figure 1.
s and eukaryote
s. 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).
) and the amino acid sequence
is:
MCSQEGEGYSLLKEYANAFMVSQVLFAACELGVFELLAEALEPLDSAAVSSHLGSSPGD
RAATEHLCVPEAAASRREGRKSCVCKHGARQHLPGERQPQVPAGHAAVRGQDRLRLLAP
PGEAVREGRNQYLKAFGIPSEELFSAIYRSEDERLQFMQGLQDVWRLEGATVLAAFDLS
PFPLICDLGGGSGALAKACVSLYPGCRAIVFDIPGVVQIAKRHFSASEDERISFHEGDF
FKDALPEADLYILARVLHDWTDAKCSHLLQRVYRACRTGGGILVIESLLDTDGRGPLTT
LLYSLNMLVQTEGRERTPGRSTARSVGPAASETCGDGGRGEPTMLSWPGNQACSV
For Homo sapiens (human) with 373 Amino Acids the sequence is:
MGSSEDQAYRLLNDYANGFMVSQVLFAACELGVFDLLAEAPGPLDVAAVAAGVRASAHG
TELLLDICVSLKLLKVETRGGKAFYRNTELSSDYLTTVSPTSQCSMLKYMGRTSYRCWG
HLADAVREGRNQYLETFGVPAEELFTAIYRSEGERLQFMQALQEVWSVNGRSVLTAFDL
SVFPLMCDLGGTRIKLETIILSKLSQGQKTKHRVFSLIGGAGALAKECMSLYPGCKITV
FDIPEVVWTAKQHFSFQEEEQIDFQEGDFFKDPLPEADLYILARVLHDWADGKCSHLLE
RIYHTCKPGGGILVIESLLDEDRRGPLLTQLYSLNMLVQTEGQERTPTHYHMLLSSAGF
RDFQFKKTGAIYDAILARK
s. 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.
(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.
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.
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.
Figure 5: Pathway serotonin → melatonin
, 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.
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. 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.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that catalyzes the final reaction in melatonin
Melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...
biosynthesis, converting Normelatonin
Normelatonin
N-Acetylserotonin , also known as normelatonin, is a naturally occurring chemical intermediate in the endogenous production of melatonin from serotonin. It is produced from serotonin by the enzyme aralkylamine N-acetyltransferase and is converted to melatonin by acetylserotonin O-methyltransferase...
to melatonin. This reaction is embedded in the more general tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
metabolism pathway. The enzyme also catalyzes a second reaction in tryptophan metabolism: the conversion of 5-hydroxy-indoleacetate to 5-methoxy-indoleacetate.
In humans the ASMT enzyme is encoded by the ASMT gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. There are two identical copies, one of which resides on the X chromosome
X chromosome
The X chromosome is one of the two sex-determining chromosomes in many animal species, including mammals and is common in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system...
and the other on the Y chromosome
Y chromosome
The Y chromosome is one of the two sex-determining chromosomes in most mammals, including humans. In mammals, it contains the gene SRY, which triggers testis development if present. The human Y chromosome is composed of about 60 million base pairs...
.
Structure and Gene Location
N-Acetylserotonin O-methyltransferase is an enzyme that is coded for by genes located on the pseudoautosomal regionPseudoautosomal region
The pseudoautosomal regions, PAR1 and PAR2 are homologous sequences of nucleotides on the X and Y chromosomes.The pseudoautosomal regions get their name because any genes located within them are inherited just like any autosomal genes...
of the X and Y chromosome, and is most abundantly found in the pineal gland
Pineal gland
The pineal gland is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of wake/sleep patterns and seasonal functions...
and retina
Retina
The vertebrate retina is a light-sensitive tissue lining the inner surface of the eye. The optics of the eye create an image of the visual world on the retina, which serves much the same function as the film in a camera. Light striking the retina initiates a cascade of chemical and electrical...
of humans.
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.
Class of Enzyme and Function
N-Acetylserotonin O-methyltransferase can be classified under three types of enzyme functional groups: transferaseTransferase
In biochemistry, a transferase is an enzyme that catalyzes the transfer of a functional group from one molecule to another . For example, an enzyme that catalyzed this reaction would be a transferase:In this example, A would be the donor, and B would be the acceptor...
s, one-carbon group transferers, and methyltransferase
Methyltransferase
A methyltransferase is a type of transferase enzyme that transfers a methyl group from a donor to an acceptor.Methylation often occurs on nucleic bases in DNA or amino acids in protein structures...
s.
It catalyzes two reactions in the tryptophan
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
metabolism pathway, and both can be traced back to serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
. 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).
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). The most commonly used synonym is Hydroxyindole O-methyltransferase (HIOMT).Organisms
N- Acetylserotonin O-methyltransferase is found in both prokaryoteProkaryote
The prokaryotes are a group of organisms that lack a cell nucleus , or any other membrane-bound organelles. The organisms that have a cell nucleus are called eukaryotes. Most prokaryotes are unicellular, but a few such as myxobacteria have multicellular stages in their life cycles...
s and eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
s. It is found in the bacteria Rhodopirellula baltica and Chromobacterium violaceum
Chromobacterium violaceum
Chromobacterium violaceum is a Gram-negative, facultative anaerobic, non-sporing coccobacillus. It is part of the normal flora of water and soil of tropical and sub-tropical regions of the world. It produces a natural antibiotic called violacein, which may be useful for the treatment of colon and...
. It is also found in the following eukaryotes: Gallus gallus
Red Junglefowl
The Red Junglefowl is a tropical member of the Pheasant family. They are thought to be ancestors of the domestic chicken with some hybridisation with the Grey Junglefowl...
(chicken), Bos Taurus
Cattle
Cattle are the most common type of large domesticated ungulates. They are a prominent modern member of the subfamily Bovinae, are the most widespread species of the genus Bos, and are most commonly classified collectively as Bos primigenius...
(cow), Homo sapiens
Human
Humans are the only living species in the Homo genus...
(human), Macaca mulatta
Rhesus Macaque
The Rhesus macaque , also called the Rhesus monkey, is one of the best-known species of Old World monkeys. It is listed as Least Concern in the IUCN Red List of Threatened Species in view of its wide distribution, presumed large population, and its tolerance of a broad range of habitats...
(rhesus monkey), and Rattus norvegicus
Brown Rat
The brown rat, common rat, sewer rat, Hanover rat, Norway rat, Brown Norway rat, Norwegian rat, or wharf rat is one of the best known and most common rats....
(rat).
Amino Acid Sequences
Bos taurus (cattle) has 350 Amino AcidsAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
) and the amino acid sequence
Peptide sequence
Peptide sequence or amino acid sequence is the order in which amino acid residues, connected by peptide bonds, lie in the chain in peptides and proteins. The sequence is generally reported from the N-terminal end containing free amino group to the C-terminal end containing free carboxyl group...
is:
MCSQEGEGYSLLKEYANAFMVSQVLFAACELGVFELLAEALEPLDSAAVSSHLGSSPGD
RAATEHLCVPEAAASRREGRKSCVCKHGARQHLPGERQPQVPAGHAAVRGQDRLRLLAP
PGEAVREGRNQYLKAFGIPSEELFSAIYRSEDERLQFMQGLQDVWRLEGATVLAAFDLS
PFPLICDLGGGSGALAKACVSLYPGCRAIVFDIPGVVQIAKRHFSASEDERISFHEGDF
FKDALPEADLYILARVLHDWTDAKCSHLLQRVYRACRTGGGILVIESLLDTDGRGPLTT
LLYSLNMLVQTEGRERTPGRSTARSVGPAASETCGDGGRGEPTMLSWPGNQACSV
For Homo sapiens (human) with 373 Amino Acids 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 exonExon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s. The gene can be alternatively spliced
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
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.
Expression in immune cells
Recent studies found messenger RNAMessenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
(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
Precursor mRNA
Precursor mRNA is an immature single strand of messenger ribonucleic acid . pre-mRNA is synthesized from a DNA template in the cell nucleus by transcription. Pre-mRNA comprises the bulk of heterogeneous nuclear RNA...
, 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.
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.
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.
Figure 5: Pathway serotonin → melatonin
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.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 disorderSeasonal affective disorder
Seasonal affective disorder , also known as winter depression, winter blues, summer depression, summer blues, or seasonal depression, is a mood disorder in which people who have normal mental health throughout most of the year experience depressive symptoms in the winter or summer, spring or autumn...
, bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
, 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.
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.Additional research
HIOMT as the limiting reagent in the melatonin biosynthetic pathwayThere 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. 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.