View source for S-Adenosylmethionine synthetase enzyme

{{DISPLAYTITLE:''S''-Adenosylmethionine synthetase enzyme}}
{{Infobox enzyme
| Name       = Methionine adenosyltransferase
| EC_number  = 2.5.1.6
| CAS_number = 9012-52-6
| GO_code    =
| image      = 5a1i.jpg
| width      = 270
| caption    = S-adenosylmethionine synthase 2, tetramer, Human 
}}
'''''S''-Adenosylmethionine synthetase''' ({{EC number|2.5.1.6}}), also known as '''methionine adenosyltransferase''' ('''MAT'''), is an [[enzyme]] that [[Catalysis|creates]] [[S-Adenosyl methionine|''S''-adenosylmethionine]] (also known as AdoMet, SAM or SAMe) by reacting [[methionine]] (a [[non-polar]] [[amino acid]]) and [[Adenosine triphosphate|ATP]] (the basic currency of energy).<ref name="pmid1696256">{{cite journal |vauthors=Horikawa S, Sasuga J, Shimizu K, Ozasa H, Tsukada K | title = Molecular cloning and nucleotide sequence of cDNA encoding the rat kidney S-adenosylmethionine synthetase | journal = J. Biol. Chem. | volume = 265 | issue = 23 | pages = 13683–6 |date=August 1990 | doi = 10.1016/S0021-9258(18)77403-6 | pmid = 1696256 | doi-access = free }}</ref>

== 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.<ref name="pmid18953685">{{cite journal|vauthors=Markham GD, Pajares MA | title=Structure-function relationships in methionine adenosyltransferases. | journal=Cell Mol Life Sci | year= 2009 | volume= 66 | issue= 4 | pages= 636–48 | pmid=18953685 | doi=10.1007/s00018-008-8516-1 | pmc=2643306 }}</ref>

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]].<ref name="pmid19497982">{{cite journal|vauthors=Reytor E, Pérez-Miguelsanz J, Alvarez L, Pérez-Sala D, Pajares MA | title=Conformational signals in the C-terminal domain of methionine adenosyltransferase I/III determine its nucleocytoplasmic distribution. | journal=FASEB J | year= 2009 | volume= 23 | issue= 10 | pages= 3347–60 | pmid=19497982 | doi=10.1096/fj.09-130187 | doi-access=free | hdl=10261/55151 | s2cid=25548921 | hdl-access=free }}</ref>

SAM is also involved in [[transcription (genetics)|gene transcription]], [[cell proliferation]], and production of secondary metabolites.<ref name="pmid21989639">{{cite journal|vauthors=Yoon S, Lee W, Kim M, Kim TD, Ryu Y | title=Structural and functional characterization of S-adenosylmethionine (SAM) synthetase from Pichia ciferrii. | journal=Bioprocess Biosyst Eng | year= 2012 | volume= 35 | issue= 1–2 | pages= 173–81 | pmid=21989639 | doi=10.1007/s00449-011-0640-x | s2cid=40318843 }}</ref> Hence SAM synthetase is fast becoming a drug target, in particular for the following diseases: [[depression (mood)|depression]], [[dementia]], vacuolar myelopathy, [[liver]] injury, [[migraine]], [[osteoarthritis]], and as a potential [[cancer]] chemopreventive agent.<ref name="pmid18634909">{{cite journal|vauthors=Kamarthapu V, Rao KV, Srinivas PN, Reddy GB, Reddy VD | title=Structural and kinetic properties of Bacillus subtilis S-adenosylmethionine synthetase expressed in Escherichia coli. | journal=Biochim Biophys Acta | year= 2008 | volume= 1784 | issue= 12 | pages= 1949–58 | pmid=18634909 | doi=10.1016/j.bbapap.2008.06.006  }}</ref>

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.<ref name="pmid8550549">{{cite journal|vauthors=Takusagawa F, Kamitori S, Misaki S, Markham GD | title=Crystal structure of S-adenosylmethionine synthetase. | journal=J Biol Chem | year= 1996 | volume= 271 | issue= 1 | pages= 136–47 | pmid=8550549 | doi=  10.1074/jbc.271.1.136| doi-access= free}}</ref>

This enzyme [[catalysis|catalyses]] the following [[chemical reaction]]
: ATP + L-[[methionine]] + H<sub>2</sub>O <math>\rightleftharpoons</math> [[phosphate]] + [[diphosphate]] + [[S-adenosyl-L-methionine]]

==Conserved motifs in the 3'UTR of MAT2A mRNA ==
A computational comparative analysis of vertebrate [[genome sequence]]s have identified a cluster of 6 conserved [[stem-loop|hairpin]] motifs in the [[3'UTR]] of the MAT2A [[MRNA|messenger RNA]] (mRNA) transcript.<ref name="pmid21994249">{{cite journal |vauthors=Parker BJ, Moltke I, Roth A, Washietl S, Wen J, Kellis M, Breaker R, Pedersen JS | title = New families of human regulatory RNA structures identified by comparative analysis of vertebrate genomes | journal = Genome Res. | volume = 21 | issue = 11 | pages = 1929–43 |date=November 2011 | pmid = 21994249 | pmc = 3205577 | doi = 10.1101/gr.112516.110 }}</ref> 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 [[Nucleic acid structure determination#In-line probing|in-line probing]] analysis. No structural changes were observed for any of the hairpins in the presence of metabolites SAM, [[S-adenosylhomocysteine]] or L-Methionine. They are proposed to be involved in transcript stability and their functionality is currently under investigation.<ref name=pmid21994249/>

==Protein overview==
The S-adenosylmethionine synthetase enzyme is found in almost every organism bar parasites which obtain AdoMet from their host. [[Isoenzyme]]s are found in bacteria, [[Saccharomyces cerevisiae|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.<ref name="pmid21605677">{{cite journal|vauthors=Garrido F, Estrela S, Alves C, Sánchez-Pérez GF, Sillero A, Pajares MA | title=Refolding and characterization of methionine adenosyltransferase from Euglena gracilis. | journal=Protein Expr Purif | year= 2011 | volume= 79 | issue= 1 | pages= 128–36 | pmid=21605677 | doi=10.1016/j.pep.2011.05.004 | hdl=10261/55441 | hdl-access=free }}</ref>

==S-adenosylmethionine synthetase N terminal domain==
{{Infobox protein family
| Symbol = S-AdoMet_synt_N
| Name = S-adenosylmethionine synthetase N terminal domain
| image = PDB 1mxb EBI.jpg
| width = 
| caption = S-adenosylmethionine synthetase with ADP
| Pfam = PF00438
| Pfam_clan =  
| InterPro = IPR022628
| SMART = 
| PROSITE = PDOC00369
| MEROPS = 
| SCOP = 1mxa
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
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 (biochemistry)|substrate]] and [[cation]] binding. The [[amino acid|residues]] involved in methionine binding are found in the N-terminal domain.<ref name="pmid21605677"/>

===N terminal domain structure===
The N terminal region contains two [[alpha helix|alpha helices]] and four [[beta strands]].<ref name="pmid8550549"/>

==S-adenosylmethionine synthetase Central domain==
{{Infobox protein family
| Symbol = S-AdoMet_synt_M
| Name =S-adenosylmethionine synthetase Central domain
| image = PDB 1mxb EBI.jpg
| width = 
| caption = S-adenosylmethionine synthetase with ADP
| Pfam = PF02772
| Pfam_clan =  
| InterPro = IPR022629
| SMART = 
| PROSITE = PDOC00369
| MEROPS = 
| SCOP = 1mxa
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}

===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 helix|alpha helices]] and four [[beta strands]].<ref name="pmid8550549"/>

==S-adenosylmethionine synthetase, C terminal domain==
{{Infobox protein family
| Symbol = S-AdoMet_synt_C
| Name = S-adenosylmethionine synthetase, C-terminal domain
| image = PDB 1o92 EBI.jpg
| width = 
| caption = Methionine adenosyltransferase in a complex ADP and l-methionine.
| Pfam = PF02773
| Pfam_clan =  
| InterPro = IPR022630
| SMART = 
| PROSITE = PDOC00369
| MEROPS = 
| SCOP = 1mxa
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
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 [[amino acid|residues]] are scattered along the C-terminal domain sequence however once the protein folds, they position themselves closely together.<ref name="pmid19497982"/>

===C terminal domain structure===

The C-terminal domains contains two alpha-helices and four beta-strands.<ref name="pmid8550549"/>

==References==
{{reflist}}

==External links==
* {{MeshName|Methionine+adenosyltransferase}}
* {{EC number|2.5.1.6}}

{{Amino acid metabolism enzymes}}
{{Alkyl and aryl transferases}}
{{Enzymes}}
{{Portal|Biology}}

{{InterPro content|IPR022630}}

[[Category:Protein domains]]
[[Category:Enzymes]]
[[Category:Methylating agents]]
[[Category:Gene expression]]
[[Category:Protein families]]
[[Category:Transferases]]
[[Category:Metabolism]]
[[Category:EC 2.5.1]]