Summary: S-adenosylmethionine synthetase, N-terminal domain
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S-adenosylmethionine synthetase enzyme Edit Wikipedia article
| Methionine adenosyltransferase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 S-adenosylmethionine synthase 2, tetramer, Human | |||||||||
| Identifiers | |||||||||
| EC number | 2.5.1.6 | ||||||||
| CAS number | 9012-52-6 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
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S-adenosylmethionine synthetase (EC 2.5.1.6) (also known as methionine adenosyltransferase (MAT)) is an enzyme that creates S-adenosylmethionine (a.k.a. AdoMet, SAM or SAMe) by reacting methionine (a non-polar amino acid) and ATP (the basic currency of energy).[1]
Contents
Function
AdoMet is a methyl donor for transmethylation. It gives away its methyl group and is also the propylamino donor in polyamine biosynthesis. S-adenosylmethionine synthesis can be considered the rate-limiting step of the methionine cycle.[2]
As a methyl donor SAM allows DNA methylation. Once DNA is methylated, it switches the genes off and therefore, S-adenosylmethionine can be considered to control gene expression.[3]
SAM is also involved in gene transcription, cell proliferation, and production of secondary metabolites.[4] Hence SAM synthetase is fast becoming a drug target, in particular for the following diseases: depression, dementia, vacuolar myelopathy, liver injury, migraine, osteoarthritis, and as a potential cancer chemopreventive agent.[5]
This article discusses the protein domains that make up the SAM synthetase enzyme and how these domains contribute to its function. More specifically, this article explores the shared pseudo-3-fold symmetry that makes the domains well-adapted to their functions.[6]
This enzyme catalyses the following chemical reaction
- ATP + L-methionine + H2O phosphate + diphosphate + S-adenosyl-L-methionine
Conserved motifs in the 3'UTR of MAT2A mRNA
A computational comparative analysis of vertebrate genome sequences have identified a cluster of 6 conserved hairpin motifs in the 3'UTR of the MAT2A messenger RNA (mRNA) transcript.[7] The predicted hairpins (named A-F) have strong evolutionary conservation and 3 of the predicted RNA structures (hairpins A, C and D) have been confirmed by in-line probing analysis. No structural changes were observed for any of the hairpins in the presence of metabolites SAM, S-adenosylhomocysteine or L-Methioninine. They are proposed to be involved in transcript stability and their functionality is currently under investigation.[7]
Protein overview
The S-adenosylmethionine synthetase enzyme is found in almost every organism bar parasites which obtain AdoMet from their host. Isoenzymes are found in bacteria, budding yeast and even in mammalian mitochondria. Most MATs are homo-oligomers and the majority are tetramers. The monomers are organised into three domains formed by nonconsecutive stretches of the sequence, and the subunits interact through a large flat hydrophobic surface to form the dimers.[8]
S-adenosylmethionine synthetase N terminal domain
| S-adenosylmethionine synthetase N terminal domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 S-adenosylmethionine synthetase with ADP | |||||||||
| Identifiers | |||||||||
| Symbol | S-AdoMet_synt_N | ||||||||
| Pfam | PF00438 | ||||||||
| InterPro | IPR022628 | ||||||||
| PROSITE | PDOC00369 | ||||||||
| SCOPe | 1mxa / SUPFAM | ||||||||
| |||||||||
In molecular biology the protein domain S-adenosylmethionine synthetase N terminal domain is found at the N-terminal of the enzyme.
N terminal domain function
The N terminal domain is well conserved across different species. This may be due to its important function in substrate and cation binding. The residues involved in methionine binding are found in the N-terminal domain.[8]
N terminal domain structure
The N terminal region contains two alpha helices and four beta strands.[6]
S-adenosylmethionine synthetase Central domain
| S-adenosylmethionine synthetase Central domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
S-adenosylmethionine synthetase with ADP | |||||||||
| Identifiers | |||||||||
| Symbol | S-AdoMet_synt_M | ||||||||
| Pfam | PF02772 | ||||||||
| InterPro | IPR022629 | ||||||||
| PROSITE | PDOC00369 | ||||||||
| SCOPe | 1mxa / SUPFAM | ||||||||
| |||||||||
Central terminal domain function
The precise function of the central domain has not been fully elucidated, but it is thought to be important in aiding catalysis.
Central domain Structure
The central region contains two alpha helices and four beta strands.[6]
S-adenosylmethionine synthetase, C terminal domain
| S-adenosylmethionine synthetase, C-terminal domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Methionine adenosyltransferase in a complex ADP and l-methionine. | |||||||||
| Identifiers | |||||||||
| Symbol | S-AdoMet_synt_C | ||||||||
| Pfam | PF02773 | ||||||||
| InterPro | IPR022630 | ||||||||
| PROSITE | PDOC00369 | ||||||||
| SCOPe | 1mxa / SUPFAM | ||||||||
| |||||||||
In molecular biology, the protein domain S-adenosylmethionine synthetase, C-terminal domain refers to the C terminus of the S-adenosylmethionine synthetase
C terminal domain function
The function of the C-terminal domain has been experimentally determined as being important for cytoplasmic localisation. The residues are scattered along the C-terminal domain sequence however once the protein folds, they position themselves closely together.[3]
C terminal domain Structure
The C-terminal domains contains two alpha-helices and four beta-strands.[6]
References
- ^ Horikawa S, Sasuga J, Shimizu K, Ozasa H, Tsukada K (August 1990). "Molecular cloning and nucleotide sequence of cDNA encoding the rat kidney S-adenosylmethionine synthetase". J. Biol. Chem. 265 (23): 13683–6. PMID 1696256.
- ^ Markham GD, Pajares MA (2009). "Structure-function relationships in methionine adenosyltransferases". Cell Mol Life Sci. 66 (4): 636–48. doi:10.1007/s00018-008-8516-1. PMC 2643306. PMID 18953685.
- ^ a b Reytor E, Pérez-Miguelsanz J, Alvarez L, Pérez-Sala D, Pajares MA (2009). "Conformational signals in the C-terminal domain of methionine adenosyltransferase I/III determine its nucleocytoplasmic distribution". FASEB J. 23 (10): 3347–60. doi:10.1096/fj.09-130187. hdl:10261/55151. PMID 19497982.
- ^ Yoon S, Lee W, Kim M, Kim TD, Ryu Y (2012). "Structural and functional characterization of S-adenosylmethionine (SAM) synthetase from Pichia ciferrii". Bioprocess Biosyst Eng. 35 (1–2): 173–81. doi:10.1007/s00449-011-0640-x. PMID 21989639.
- ^ Kamarthapu V, Rao KV, Srinivas PN, Reddy GB, Reddy VD (2008). "Structural and kinetic properties of Bacillus subtilis S-adenosylmethionine synthetase expressed in Escherichia coli". Biochim Biophys Acta. 1784 (12): 1949–58. doi:10.1016/j.bbapap.2008.06.006. PMID 18634909.
- ^ a b c d Takusagawa F, Kamitori S, Misaki S, Markham GD (1996). "Crystal structure of S-adenosylmethionine synthetase". J Biol Chem. 271 (1): 136–47. doi:10.1074/jbc.271.1.136. PMID 8550549.
- ^ a b Parker BJ, Moltke I, Roth A, Washietl S, Wen J, Kellis M, Breaker R, Pedersen JS (November 2011). "New families of human regulatory RNA structures identified by comparative analysis of vertebrate genomes". Genome Res. 21 (11): 1929–43. doi:10.1101/gr.112516.110. PMC 3205577. PMID 21994249.
- ^ a b Garrido F, Estrela S, Alves C, Sánchez-Pérez GF, Sillero A, Pajares MA (2011). "Refolding and characterization of methionine adenosyltransferase from Euglena gracilis". Protein Expr Purif. 79 (1): 128–36. doi:10.1016/j.pep.2011.05.004. hdl:10261/55441. PMID 21605677.
External links
- Methionine+adenosyltransferase at the US National Library of Medicine Medical Subject Headings (MeSH)
- EC 2.5.1.6
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S-adenosylmethionine synthetase, N-terminal domain Provide feedback
The three domains of S-adenosylmethionine synthetase have the same alpha+beta fold.
Literature references
-
Takusagawa F, Kamitori S, Markham GD; , Biochemistry 1996;35:2586-2596.: Structure and function of S-adenosylmethionine synthetase: crystal structures of S-adenosylmethionine synthetase with ADP, BrADP, and PPi at 28 angstroms resolution. PUBMED:8611562 EPMC:8611562
External database links
| HOMSTRAD: | S-AdoMet_synt S-AdoMet_synt_NC |
| PROSITE: | PDOC00369 |
| SCOP: | 1mxa |
This tab holds annotation information from the InterPro database.
InterPro entry IPR022628
S-adenosylmethionine synthetase (MAT, EC ) is the enzyme that catalyzes the formation of S-adenosylmethionine (AdoMet) from methionine and ATP [ PUBMED:1696256 ]. AdoMet is an important methyl donor for transmethylation and is also the propylamino donor in polyamine biosynthesis.
In bacteria there is a single isoform of AdoMet synthetase (gene metK), there are two in budding yeast (genes SAM1 and SAM2) and in mammals while in plants there is generally a multigene family.
The sequence of AdoMet synthetase is highly conserved throughout isozymes and species. The active sites of both the Escherichia coli and rat liver MAT reside between two subunits, with contributions from side chains of residues from both subunits, resulting in a dimer as the minimal catalytic entity. The side chains that contribute to the ligand binding sites are conserved between the two proteins. In the structures of complexes with the E. coli enzyme, the phosphate groups have the same positions in the (PPi plus Pi) complex and the (ADP plus Pi) complex and are located at the bottom of a deep cavity with the adenosyl group nearer the entrance [ PUBMED:1213535 ].
The three domains of S-adenosylmethionine synthetase have the same alpha+beta fold. This entry represents the N-terminal domain of S-adenosylmethionine synthetase and is found in association with and .
Gene Ontology
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
| Molecular function | methionine adenosyltransferase activity (GO:0004478) |
| Biological process | S-adenosylmethionine biosynthetic process (GO:0006556) |
Domain organisation
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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Alignments
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| Seed (405) |
Full (11435) |
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| RP15 (1749) |
RP35 (5640) |
RP55 (11106) |
RP75 (17805) |
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| PP/heatmap | 1 | ||||||
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| Seed (405) |
Full (11435) |
Representative proteomes | UniProt (45350) |
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| RP15 (1749) |
RP35 (5640) |
RP55 (11106) |
RP75 (17805) |
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| Raw Stockholm | |||||||
| Gzipped | |||||||
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
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Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
Curation
| Seed source: | Prosite |
| Previous IDs: | S-AdoMet_synt; |
| Type: | Domain |
| Sequence Ontology: | SO:0000417 |
| Author: |
Finn RD  , Griffiths-Jones SR
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| Number in seed: | 405 |
| Number in full: | 11435 |
| Average length of the domain: | 98.90 aa |
| Average identity of full alignment: | 55 % |
| Average coverage of the sequence by the domain: | 25.23 % |
HMM information
| HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
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| Model details: |
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| Model length: | 99 | ||||||||||||
| Family (HMM) version: | 22 | ||||||||||||
| Download: | download the raw HMM for this family |
Species distribution
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Colour assignments
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Structures
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the S-AdoMet_synt_N domain has been found. There are 114 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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