View source for Methionine synthase

{{Short description|Mammalian protein found in Homo sapiens}}
{{Distinguish|Betaine-homocysteine S-methyltransferase}}
{{Use dmy dates|date=September 2020}}
{{Infobox_gene}}
'''Methionine synthase''' ('''MS''', '''MeSe''', '''MTR''') is primarily responsible for the regeneration of [[methionine]] from [[homocysteine]] in most individuals. In humans it is encoded by the ''MTR'' [[gene]] (5-methyltetrahydrofolate-homocysteine methyltransferase).<ref name="entrez">{{cite web |title= MTR 5-methyltetrahydrofolate-homocysteine methyltransferase (''Homo sapiens'') |url= https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4548 |publisher= Entrez |date= 19 May 2009 |access-date= 24 May 2009 }}</ref><ref name="pmid8968735">{{cite journal | vauthors = Li YN, Gulati S, Baker PJ, Brody LC, Banerjee R, Kruger WD | title = Cloning, mapping and RNA analysis of the human methionine synthase gene | journal = Human Molecular Genetics | volume = 5 | issue = 12 | pages = 1851–1858 | date = December 1996 | pmid = 8968735 | doi = 10.1093/hmg/5.12.1851 | doi-access = free }}</ref> Methionine synthase forms part of the [[S-adenosylmethionine]] (SAMe) [[biosynthesis]] and [[regeneration (biology)|regeneration]] cycle,<ref name="pmid2407589">{{cite journal | vauthors = Banerjee RV, Matthews RG | title = Cobalamin-dependent methionine synthase | journal = FASEB Journal | volume = 4 | issue = 5 | pages = 1450–1459 | date = March 1990 | pmid = 2407589 | doi = 10.1096/fasebj.4.5.2407589 | doi-access = free | hdl-access = free | s2cid = 8210250 | hdl = 2027.42/154369 }}</ref> and is the enzyme responsible for linking the cycle to one-carbon metabolism via the [[folate]] cycle. There are two primary forms of this enzyme, the [[Vitamin B12|Vitamin B<sub>12</sub>]] (cobalamin)-dependent (MetH) and independent (MetE) forms,<ref name="Zinc" /> although minimal core methionine synthases that do not fit cleanly into either category have also been described in some [[Anaerobic organism|anaerobic bacteria]].<ref>{{cite journal | vauthors = Deobald D, Hanna R, Shahryari S, Layer G, Adrian L | title = Identification and characterization of a bacterial core methionine synthase | journal = Scientific Reports | volume = 10 | issue = 1 | page = 2100 | date = February 2020 | pmid = 32034217 | pmc = 7005905 | doi = 10.1038/s41598-020-58873-z | bibcode = 2020NatSR..10.2100D }}</ref> The two dominant forms of the enzymes appear to be evolutionary independent and rely on considerably different chemical mechanisms.<ref>{{cite journal | vauthors = Pejchal R, Ludwig ML | title = Cobalamin-independent methionine synthase (MetE): a face-to-face double barrel that evolved by gene duplication | journal = PLOS Biology | volume = 3 | issue = 2 | pages = e31 | date = February 2005 | pmid = 15630480 | pmc = 539065 | doi = 10.1371/journal.pbio.0030031 | veditors = Stroud RM | doi-access = free }}</ref> [[Mammal]]s and other higher [[eukaryote]]s express only the cobalamin-dependent form. In contrast, the distribution of the two forms in [[Archaeplastida]] ([[plant]]s and [[algae]]) is more complex. Plants exclusively possess the cobalamin-independent form,<ref name=":6">{{cite journal | vauthors = Ravanel S, Gakière B, Job D, Douce R | title = The specific features of methionine biosynthesis and metabolism in plants | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 13 | pages = 7805–7812 | date = June 1998 | pmid = 9636232 | pmc = 22764 | doi = 10.1073/pnas.95.13.7805 | bibcode = 1998PNAS...95.7805R | doi-access = free }}</ref> while algae have either one of the two, depending on species.<ref>{{cite journal | vauthors = Helliwell KE, Wheeler GL, Leptos KC, Goldstein RE, Smith AG | title = Insights into the evolution of vitamin B12 auxotrophy from sequenced algal genomes | journal = Molecular Biology and Evolution | volume = 28 | issue = 10 | pages = 2921–2933 | date = October 2011 | pmid = 21551270 | doi = 10.1093/molbev/msr124 | doi-access = free }}</ref> Many different microorganisms express both the cobalamin-dependent and cobalamin-independent forms.<ref name="Zydowsky 1986">{{cite journal | vauthors = Zydowsky TM |date=1986 |title=Stereochemical analysis of the methyl transfer catalyzed by cobalamin-dependent methionine synthase from Escherichia coli B |journal=Journal of the American Chemical Society |volume=108 |issue=11 |pages=3152–3153 |doi=10.1021/ja00271a081}}</ref>

== Reaction ==
[[File:VitaminB12 2.png|thumb|left|The reaction catalyzed by methionine synthase (click to enlarge)]]
Methionine synthase catalyzes the final step in the regeneration of [[methionine]] (Met) from [[homocysteine]] (Hcy). Both the cobalamin-dependent and cobalamin-independent forms of the enzyme carry out the same overall chemical reaction, the transfer of a methyl group from [[5-methyltetrahydrofolate]] (N<sup>5</sup>-MeTHF) to homocysteine, yielding [[tetrahydrofolate]] (THF) and methionine.<ref name="Zinc" /> Methionine synthase is the only mammalian enzyme that metabolizes N<sup>5</sup>-MeTHF to regenerate the active cofactor THF.
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== Mechanism ==

[[File:Methionine Synthase Reductase Pathway.png|thumb|left|Scavenger Pathway of Methionine Synthase Reductase to Recover Inactivated Methionine Synthase]]

=== Cobalamin-dependent (MetH) ===
Humans, ''E. coli'', and many other organisms have a cobalamin-dependent version. In the [[cobalamin]]-dependent (MetH) form of the enzyme, the reaction proceeds by two steps in a preferred ordered sequential mechanism.<ref>{{cite journal | vauthors = Banerjee RV, Frasca V, Ballou DP, Matthews RG | title = Participation of cob(I) alamin in the reaction catalyzed by methionine synthase from Escherichia coli: a steady-state and rapid reaction kinetic analysis | journal = Biochemistry | volume = 29 | issue = 50 | pages = 11101–11109 | date = December 1990 | pmid = 2271698 | doi = 10.1021/bi00502a013 }}</ref>

The physiological resting state of the enzyme is thought to contain the enzyme-bound(Cob) [[Cofactor (biochemistry)|cofactor]] in the methylcobalamin form, with the cobalt atom in the formal +3 valence state (Cob(III)-Me). The cobalamin is then demethylated by [[zinc]]-activated thiolate homocysteine, generating methionine and reducing the cofactor to a Cob(I) state. When in the Cob(I) form, the enzyme-bound cofactor is now able to abstract a methyl group from activated 5-methyltetrahydrofolate (N<sup>5</sup>-MeTHF), yielding tetrahydrofolate (THF) and regenerating the methylcoalamin form of the enzyme.<ref>{{Cite book |title=Chemistry and biochemistry of B12 |date=1999 |publisher=Wiley |editor=Ruma Banerjee |isbn=0-471-25390-1 |location=New York |oclc=40397055}}</ref>

Under human-physiological conditions, approximately once every 2000 catalytic turnovers the Co(I) may be oxidized into inactive Co(II) in cob-dependent MetH. To account for this effect, the protein contains a self-reactivation mechanism, a reductive methylation process that uses S-adenosylmethionine as a distinct methyl donor. In humans, the enzyme is reduced in this process by [[(methionine synthase) reductase|methionine synthase reductase]] (MTRR), which consists of flavodoxin-like and ferrodoxin-NADP+ oxidoreductase (FNR)-like domains.<ref name=":0">{{cite journal | vauthors = Yamada K, Gravel RA, Toraya T, Matthews RG | title = Human methionine synthase reductase is a molecular chaperone for human methionine synthase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 25 | pages = 9476–9481 | date = June 2006 | pmid = 16769880 | pmc = 1480432 | doi = 10.1073/pnas.0603694103 | bibcode = 2006PNAS..103.9476Y | doi-access = free }}</ref> In many bacteria, the reduction is carried out by a single domain flavodoxin protein.<ref name=":1">{{cite journal | vauthors = Hall DA, Jordan-Starck TC, Loo RO, Ludwig ML, Matthews RG | title = Interaction of flavodoxin with cobalamin-dependent methionine synthase | journal = Biochemistry | volume = 39 | issue = 35 | pages = 10711–10719 | date = September 2000 | pmid = 10978155 | doi = 10.1021/bi001096c }}</ref> The reductase protein is responsible for transfer of an electron from a reduced FMN cofactor to the inactive Cob(II), which enables regeneration of the active methylcobalamin enzyme via methyl transfer from S-adenosylmethionine to the reduced Cob(I) intermediate.<ref>{{cite journal | vauthors = Jarrett JT, Hoover DM, Ludwig ML, Matthews RG | title = The mechanism of adenosylmethionine-dependent activation of methionine synthase: a rapid kinetic analysis of intermediates in reductive methylation of Cob(II)alamin enzyme | journal = Biochemistry | volume = 37 | issue = 36 | pages = 12649–12658 | date = September 1998 | pmid = 9730838 | doi = 10.1021/bi9808565 }}</ref> This process is known as the reactivation cycle, and is thought to be gated from the normal catalytic cycle by large-scale conformational rearrangements within the enzyme.<ref>{{cite journal | vauthors = Jarrett JT, Huang S, Matthews RG | title = Methionine synthase exists in two distinct conformations that differ in reactivity toward methyltetrahydrofolate, adenosylmethionine, and flavodoxin | journal = Biochemistry | volume = 37 | issue = 16 | pages = 5372–5382 | date = April 1998 | pmid = 9548919 | doi = 10.1021/bi9730893 }}</ref> Because the oxidation of Cob(I) inevitably shuts down cob-dependent methionine synthase activity, defects or deficiencies in methionine synthase reductase have been implicated in some of the disease associations for methionine synthase deficiency.<ref Name = reductase>{{cite journal | vauthors = Wolthers KR, Scrutton NS | title = Protein interactions in the human methionine synthase-methionine synthase reductase complex and implications for the mechanism of enzyme reactivation | journal = Biochemistry | volume = 46 | issue = 23 | pages = 6696–6709 | date = June 2007 | pmid = 17477549 | doi = 10.1021/bi700339v }}</ref>

=== Cobalamin-independent (MetE) ===
The mechanism of the cobalamin-independent (MetE) form, by contrast, proceeds through a direct methyl transfer from the activated N<sup>5</sup>-MeTHF to zinc thiolate homocysteine. Although the mechanism is considerably simpler, the direct transfer reaction is much less favorable than the cobalamin-mediated reactions and as a result the turnover rate for MetE is ~100x slower than that of MetH. As it does not contain the cobalamin cofactor, the cobalamin-independent enzyme is not prone to oxidative inactivation <ref name="Anti-Cancer">{{cite journal | vauthors = Zhang Z, Tian C, Zhou S, Wang W, Guo Y, Xia J, Liu Z, Wang B, Wang X, Golding BT, Griff RJ, Du Y, Liu J | display-authors = 6 | title = Mechanism-based design, synthesis and biological studies of N⁵-substituted tetrahydrofolate analogs as inhibitors of cobalamin-dependent methionine synthase and potential anticancer agents | journal = European Journal of Medicinal Chemistry | volume = 58 | pages = 228–236 | date = December 2012 | pmid = 23124219 | doi = 10.1016/j.ejmech.2012.09.027 }}</ref><ref name="Zinc">{{Cite journal | vauthors = Matthews RG, Smith AE, Zhou ZS, Taurog RE, Bandarian V, Evans JC, Ludwig M | doi = 10.1002/hlca.200390329 | title = Cobalamin-Dependent and Cobalamin-Independent Methionine Synthases: Are There Two Solutions to the Same Chemical Problem? | journal = Helvetica Chimica Acta | volume = 86 | issue = 12 | pages = 3939–3954 | year = 2003 }}</ref><ref name=":2">{{cite journal | vauthors = Ubhi DK, Robertus JD | title = The cobalamin-independent methionine synthase enzyme captured in a substrate-induced closed conformation | journal = Journal of Molecular Biology | volume = 427 | issue = 4 | pages = 901–909 | date = February 2015 | pmid = 25545590 | doi = 10.1016/j.jmb.2014.12.014 | doi-access = free }}</ref><ref name=":3">{{cite journal | vauthors = Koutmos M, Pejchal R, Bomer TM, Matthews RG, Smith JL, Ludwig ML | title = Metal active site elasticity linked to activation of homocysteine in methionine synthases | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 9 | pages = 3286–3291 | date = March 2008 | pmid = 18296644 | pmc = 2265165 | doi = 10.1073/pnas.0709960105 | bibcode = 2008PNAS..105.3286K | doi-access = free }}</ref>

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== Structure ==
[[File:Homocysteine Binding Site.png|thumb|left| Homocysteine Binding Domain in Methionine Synthase. His 618, Cys 620, and Cys704 bind Zn(purple) which binds to Homocysteine(Red)]]
High-resolution structures have been solved by [[X-ray crystallography]] for intact MetE both in the absence and presence of substrates<ref name=":3" /><ref name=":2" /> and for fragments of MetH,<ref name="Structure" /><ref name=":4">{{cite journal | vauthors = Drennan CL, Huang S, Drummond JT, Matthews RG, Ludwig ML | title = How a protein binds B12: A 3.0 A X-ray structure of B12-binding domains of methionine synthase | journal = Science | volume = 266 | issue = 5191 | pages = 1669–1674 | date = December 1994 | pmid = 7992050 | doi = 10.1126/science.7992050 }}</ref><ref name=":5">{{cite journal | vauthors = Bandarian V, Pattridge KA, Lennon BW, Huddler DP, Matthews RG, Ludwig ML | title = Domain alternation switches B(12)-dependent methionine synthase to the activation conformation | journal = Nature Structural Biology | volume = 9 | issue = 1 | pages = 53–56 | date = January 2002 | pmid = 11731805 | doi = 10.1038/nsb738 | s2cid = 10529695 }}</ref><ref>{{cite journal | vauthors = Datta S, Koutmos M, Pattridge KA, Ludwig ML, Matthews RG | title = A disulfide-stabilized conformer of methionine synthase reveals an unexpected role for the histidine ligand of the cobalamin cofactor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 11 | pages = 4115–4120 | date = March 2008 | pmid = 18332423 | pmc = 2393809 | doi = 10.1073/pnas.0800329105 | bibcode = 2008PNAS..105.4115D | doi-access = free }}</ref> although no structural description exists of a fully intact MetH enzyme. The available structures and accompanying bioinformatic analysis indicate minimal similarity in the overall structure, although there are similarities within the substrate-binding sites themselves.<ref Name = Independent>{{cite journal | vauthors = Pejchal R, Ludwig ML | title = Cobalamin-independent methionine synthase (MetE): a face-to-face double barrel that evolved by gene duplication | journal = PLOS Biology | volume = 3 | issue = 2 | pages = e31 | date = February 2005 | pmid = 15630480 | pmc = 539065 | doi = 10.1371/journal.pbio.0030031 | doi-access = free }}</ref>

Cob-dependent MetH is divided into 4 separate domains. The domains, from N- to C-terminus, are denoted homocysteine binding (Hcy domain), N<sup>5</sup>-methylTHF binding (MTHF domain) [[Vitamin B12-binding domain|Cobalamin-binding (Cob domain)]] and the S-adenosymethionine-binding or reactivation domain. The reactivation domain binds [[S-Adenosyl methionine|SAM]] and is the site of interaction with flavodoxin or Methionine Synthase Reductase during the reactivation cycle of the enzyme.<ref name=":1" /><ref name=":0" /><ref name="reductase"/> The cobalamin-binding domain contains two subdomains, with the cofactor bound to the [[Rossmann fold|Rossman-fold]] B<sub>12</sub>-binding subdomain, which is in turn capped by the other subdomain, the four-helix bundle cap subdomain.<ref name=":4" /> The four-helix bundle serves to protect the cobalamin cofactor from unwanted reactivity, but can significantly change conformations to expose the cofactor allow it access to the other substrates during turnover.<ref name=":5" /> Both the Hcy and N<sup>5</sup>-MeTHF domains adopt a [[TIM barrel]] architecture; the Hcy domain contains the zinc-binding site, which in MetH consists of three [[cysteine]] residues coordinated to a zinc ion which in turn binds and activates Hcy. The N<sup>5</sup>-MeTHF binding domain binds and activates  N<sup>5</sup>-MeTHF via a hydrogen bonding network with several [[asparagine]], [[arginine]], and [[aspartic acid]] residues. During turnover, the enzyme undergoes significant conformational changes that involve moving the Cob-domain back and forth from the Hcy domain to the N<sup>5</sup>-MeTHF domain in order for the two methyl transfer reactions to proceed.<ref Name = Structure>{{cite journal | vauthors = Evans JC, Huddler DP, Hilgers MT, Romanchuk G, Matthews RG, Ludwig ML | title = Structures of the N-terminal modules imply large domain motions during catalysis by methionine synthase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 11 | pages = 3729–3736 | date = March 2004 | pmid = 14752199 | pmc = 374312 | doi = 10.1073/pnas.0308082100 | doi-access = free | bibcode = 2004PNAS..101.3729E }}</ref>

The cob-independent MetE consists of two TIM-barrel domains that bind homocysteine and N<sup>5</sup>-MeTHF individually. The two domains adopt a face-to-face double barrel architecture, which requires a "closing" of the structure upon binding of both substrates to enable the direct methyl transfer.<ref name=":2" /> Substrate-binding strategies are similar to MetH, although in the case of MetE the zinc atom is instead coordinated to two cysteines, a [[histidine]] and a [[Glutamic acid|glutamate]],<ref name=":3" /> for which an example is shown on the right.

== Biochemical function ==
[[File:Met pathway.svg|thumb|left|Methionine synthase is enzyme 4]]
In humans the enzyme's main purpose is to regenerate Met in the S-adenosylmethionine (SAM) cycle. The SAM cycle in a single turnover consumes Met and ATP and generates Hcy, and can involve any of a number of critical enzymatic reactions that use S-adenosylmethionine as the source of an active methyl group for methylation of [[nucleic acid]]s, [[histone]]s, [[phospholipid]]s and various [[protein]]s.<ref>{{cite journal | vauthors = Broderick JB, Duffus BR, Duschene KS, Shepard EM | title = Radical S-adenosylmethionine enzymes | journal = Chemical Reviews | volume = 114 | issue = 8 | pages = 4229–4317 | date = April 2014 | pmid = 24476342 | pmc = 4002137 | doi = 10.1021/cr4004709 }}</ref><ref>{{cite journal | vauthors = Shane B | title = Folate and vitamin B12 metabolism: overview and interaction with riboflavin, vitamin B6, and polymorphisms | journal = Food and Nutrition Bulletin | volume = 29 | issue = 2 Suppl | pages = S5–S16 | date = June 2008 | pmid = 18709878 | doi = 10.1177/15648265080292S103 | s2cid = 21493797 }}</ref> As such, methionine synthase serves an essential function by allowing the SAM cycle to perpetuate without a constant influx of Met. As a secondary effect, methionine synthase also serves to maintain low levels of Hcy and, because methionine synthase is one of the few enzymes that used N<sup>5</sup>-MeTHF as a substrate, to indirectly maintain THF levels.<ref>{{cite journal | vauthors = Watkins D, Ru M, Hwang HY, Kim CD, Murray A, Philip NS, Kim W, Legakis H, Wai T, Hilton JF, Ge B, Doré C, Hosack A, Wilson A, Gravel RA, Shane B, Hudson TJ, Rosenblatt DS | display-authors = 6 | title = Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L | journal = American Journal of Human Genetics | volume = 71 | issue = 1 | pages = 143–153 | date = July 2002 | pmid = 12068375 | pmc = 384971 | doi = 10.1086/341354 }}</ref><ref>{{cite journal | vauthors = Ghergurovich JM, Xu X, Wang JZ, Yang L, Ryseck RP, Wang L, Rabinowitz JD | title = Methionine synthase supports tumour tetrahydrofolate pools | journal = Nature Metabolism | volume = 3 | issue = 11 | pages = 1512–1520 | date = November 2021 | pmid = 34799699 | doi = 10.1038/s42255-021-00465-w | pmc = 9284419 | s2cid = 244450216 }}</ref>

In bacteria and plants, methionine synthase serves a dual purpose of both perpetuating the SAM cycle and catalyzing the final synthetic step in the [[De novo synthesis|''de novo'']] synthesis of Met, which is one of the 20 canonical [[amino acid]]s.<ref>{{cite journal | vauthors = Ferla MP, Patrick WM | title = Bacterial methionine biosynthesis | journal = Microbiology | volume = 160 | issue = Pt 8 | pages = 1571–1584 | date = August 2014 | pmid = 24939187 | doi = 10.1099/mic.0.077826-0 | doi-access = free }}</ref><ref name=":6" /> While the chemical reaction is exactly the same for both processes, the overall function is distinct from methionine synthase in humans because Met is an [[essential amino acid]] that is not synthesized ''de novo'' in the body.<ref Name = Plants>{{cite journal | vauthors = Hesse H, Hoefgen R | title = Molecular aspects of methionine biosynthesis | journal = Trends in Plant Science | volume = 8 | issue = 6 | pages = 259–262 | date = June 2003 | pmid = 12818659 | doi = 10.1016/S1360-1385(03)00107-9 }}</ref>

== Clinical significance ==

Mutations in the MTR gene have been identified as the underlying cause of methylcobalamin deficiency complementation group G, or methylcobalamin deficiency cblG-type.<ref name="entrez" /> Deficiency or deregulation of the enzyme due to deficient methionine synthase reductase can directly result in elevated levels of homocysteine ([[hyperhomocysteinemia]]), which is associated with blindness, neurological symptoms, and birth defects.<ref>{{cite journal | vauthors = Banerjee RV, Matthews RG | title = Cobalamin-dependent methionine synthase | journal = FASEB Journal | volume = 4 | issue = 5 | pages = 1450–1459 | date = March 1990 | pmid = 2407589 | doi = 10.1096/fasebj.4.5.2407589 | doi-access = free | s2cid = 8210250 | hdl = 2027.42/154369 | hdl-access = free }}</ref><ref>{{cite journal | vauthors = Kim J, Kim H, Roh H, Kwon Y | title = Causes of hyperhomocysteinemia and its pathological significance | journal = Archives of Pharmacal Research | volume = 41 | issue = 4 | pages = 372–383 | date = April 2018 | pmid = 29552692 | doi = 10.1007/s12272-018-1016-4 | s2cid = 3986295 }}</ref> [[(Methionine synthase) reductase|Methionine synthase reductase]] (MTRR) or [[Methylenetetrahydrofolate reductase|methylene-tetrahydrofolate reductase]] (MTHFR) deficiencies can also result in the condition. Most cases of methionine synthase deficiency are symptomatic within 2 years of birth with many patients rapidly developing severe [[encephalopathy]].<ref Name = CaseStudy>{{cite journal | vauthors = Outteryck O, de Sèze J, Stojkovic T, Cuisset JM, Dobbelaere D, Delalande S, Lacour A, Cabaret M, Lepoutre AC, Deramecourt V, Zéphir H, Fowler B, Vermersch P | display-authors = 6 | title = Methionine synthase deficiency: a rare cause of adult-onset leukoencephalopathy | journal = Neurology | volume = 79 | issue = 4 | pages = 386–388 | date = July 2012 | pmid = 22786600 | doi = 10.1212/WNL.0b013e318260451b | s2cid = 207121496 }}</ref> One consequence of reduced methionine synthase activity that is measurable by routine clinical blood tests is [[megaloblastic anemia]].

== Genetics ==

Several cblG-associated polymorphisms in the MTR gene have been identified.<ref>{{cite journal | vauthors = Gulati S, Baker P, Li YN, Fowler B, Kruger W, Brody LC, Banerjee R | title = Defects in human methionine synthase in cblG patients | journal = Human Molecular Genetics | volume = 5 | issue = 12 | pages = 1859–1865 | date = December 1996 | pmid = 8968736 | doi = 10.1093/hmg/5.12.1859 | doi-access = free }}</ref>
* 2756D→G (Asp<sup>919</sup>Gly)
* 3804C→T (Pro<sup>1137</sup>Leu)
* Δ2926A-2928T (ΔIle<sup>881</sup>)

== See also ==
* [[Methyltransferase]]
* [[Arakawa's syndrome II]]
* [[Betaine—homocysteine S-methyltransferase]]

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Ludwig ML, Matthews RG | title = Structure-based perspectives on B12-dependent enzymes | journal = Annual Review of Biochemistry | volume = 66 | pages = 269–313 | year = 1997 | pmid = 9242908 | doi = 10.1146/annurev.biochem.66.1.269 }}
* {{cite journal | vauthors = Matthews RG, Sheppard C, Goulding C | title = Methylenetetrahydrofolate reductase and methionine synthase: biochemistry and molecular biology | journal = European Journal of Pediatrics | volume = 157 | pages = S54–S59 | date = April 1998 | issue = Suppl 2 | pmid = 9587027 | doi = 10.1007/PL00014305 | s2cid = 8709190 | url = http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1120&context=lawfacpub | hdl = 2027.42/42254 | hdl-access = free }}
* {{cite journal | vauthors = Garovic-Kocic V, Rosenblatt DS | title = Methionine auxotrophy in inborn errors of cobalamin metabolism | journal = Clinical and Investigative Medicine | volume = 15 | issue = 4 | pages = 395–400 | date = August 1992 | pmid = 1516297 }}
* {{cite journal | vauthors = O'Connor DL, Moriarty P, Picciano MF | title = The impact of iron deficiency on the flux of folates within the mammary gland | journal = International Journal for Vitamin and Nutrition Research | volume = 62 | issue = 2 | pages = 173–180 | year = 1992 | pmid = 1517041 }}
* {{cite journal | vauthors = Everman BW, Koblin DD | title = Aging, chronic administration of ethanol, and acute exposure to nitrous oxide: effects on vitamin B12 and folate status in rats | journal = Mechanisms of Ageing and Development | volume = 62 | issue = 3 | pages = 229–243 | date = March 1992 | pmid = 1583909 | doi = 10.1016/0047-6374(92)90109-Q | s2cid = 11766691 | doi-access = free }}
* {{cite journal | vauthors = Vassiliadis A, Rosenblatt DS, Cooper BA, Bergeron JJ | title = Lysosomal cobalamin accumulation in fibroblasts from a patient with an inborn error of cobalamin metabolism (cblF complementation group): visualization by electron microscope radioautography | journal = Experimental Cell Research | volume = 195 | issue = 2 | pages = 295–302 | date = August 1991 | pmid = 2070814 | doi = 10.1016/0014-4827(91)90376-6 }}
* {{cite journal | vauthors = Li YN, Gulati S, Baker PJ, Brody LC, Banerjee R, Kruger WD | title = Cloning, mapping and RNA analysis of the human methionine synthase gene | journal = Human Molecular Genetics | volume = 5 | issue = 12 | pages = 1851–1858 | date = December 1996 | pmid = 8968735 | doi = 10.1093/hmg/5.12.1851 | doi-access = free }}
* {{cite journal | vauthors = Gulati S, Baker P, Li YN, Fowler B, Kruger W, Brody LC, Banerjee R | title = Defects in human methionine synthase in cblG patients | journal = Human Molecular Genetics | volume = 5 | issue = 12 | pages = 1859–1865 | date = December 1996 | pmid = 8968736 | doi = 10.1093/hmg/5.12.1859 | doi-access = free }}
* {{cite journal | vauthors = Leclerc D, Campeau E, Goyette P, Adjalla CE, Christensen B, Ross M, Eydoux P, Rosenblatt DS, Rozen R, Gravel RA | display-authors = 6 | title = Human methionine synthase: cDNA cloning and identification of mutations in patients of the cblG complementation group of folate/cobalamin disorders | journal = Human Molecular Genetics | volume = 5 | issue = 12 | pages = 1867–1874 | date = December 1996 | pmid = 8968737 | doi = 10.1093/hmg/5.12.1867 | doi-access = free }}
* {{cite journal | vauthors = Chen LH, Liu ML, Hwang HY, Chen LS, Korenberg J, Shane B | title = Human methionine synthase. cDNA cloning, gene localization, and expression | journal = The Journal of Biological Chemistry | volume = 272 | issue = 6 | pages = 3628–3634 | date = February 1997 | pmid = 9013615 | doi = 10.1074/jbc.272.6.3628 | doi-access = free }}
* {{cite journal | vauthors = Wilson A, Leclerc D, Saberi F, Campeau E, Hwang HY, Shane B, Phillips JA, Rosenblatt DS, Gravel RA | display-authors = 6 | title = Functionally null mutations in patients with the cblG-variant form of methionine synthase deficiency | journal = American Journal of Human Genetics | volume = 63 | issue = 2 | pages = 409–414 | date = August 1998 | pmid = 9683607 | pmc = 1377317 | doi = 10.1086/301976 }}
* {{cite journal | vauthors = Salomon O, Rosenberg N, Zivelin A, Steinberg DM, Kornbrot N, Dardik R, Inbal A, Seligsohn U | display-authors = 6 | title = Methionine synthase A2756G and methylenetetrahydrofolate reductase A1298C polymorphisms are not risk factors for idiopathic venous thromboembolism | journal = The Hematology Journal | volume = 2 | issue = 1 | pages = 38–41 | year = 2002 | pmid = 11920232 | doi = 10.1038/sj.thj.6200078 }}
* {{cite journal | vauthors = Watkins D, Ru M, Hwang HY, Kim CD, Murray A, Philip NS, Kim W, Legakis H, Wai T, Hilton JF, Ge B, Doré C, Hosack A, Wilson A, Gravel RA, Shane B, Hudson TJ, Rosenblatt DS | display-authors = 6 | title = Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L | journal = American Journal of Human Genetics | volume = 71 | issue = 1 | pages = 143–153 | date = July 2002 | pmid = 12068375 | pmc = 384971 | doi = 10.1086/341354 }}
* {{cite journal | vauthors = De Marco P, Calevo MG, Moroni A, Arata L, Merello E, Finnell RH, Zhu H, Andreussi L, Cama A, Capra V | display-authors = 6 | title = Study of MTHFR and MS polymorphisms as risk factors for NTD in the Italian population | journal = Journal of Human Genetics | volume = 47 | issue = 6 | pages = 319–324 | year = 2002 | pmid = 12111380 | doi = 10.1007/s100380200043 | doi-access = free }}
* {{cite journal | vauthors = Doolin MT, Barbaux S, McDonnell M, Hoess K, Whitehead AS, Mitchell LE | title = Maternal genetic effects, exerted by genes involved in homocysteine remethylation, influence the risk of spina bifida | journal = American Journal of Human Genetics | volume = 71 | issue = 5 | pages = 1222–1226 | date = November 2002 | pmid = 12375236 | pmc = 385102 | doi = 10.1086/344209 }}
* {{cite journal | vauthors = Zhu H, Wicker NJ, Shaw GM, Lammer EJ, Hendricks K, Suarez L, Canfield M, Finnell RH | display-authors = 6 | title = Homocysteine remethylation enzyme polymorphisms and increased risks for neural tube defects | journal = Molecular Genetics and Metabolism | volume = 78 | issue = 3 | pages = 216–221 | date = March 2003 | pmid = 12649067 | doi = 10.1016/S1096-7192(03)00008-8 }}
{{refend}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1328/  GeneReviews/NCBI/NIH/UW entry on Disorders of Intracellular Cobalamin Metabolism]
* [http://www.expasy.org/cgi-bin/enzyme-search-ec ENZYME: EC 2.1.1.13] {{Webarchive|url=https://web.archive.org/web/20110622005536/http://www.expasy.org/cgi-bin/enzyme-search-ec |date=22 June 2011 }}
* {{MeshName|5-Methyltetrahydrofolate-Homocysteine+S-Methyltransferase}}

{{PDB Gallery|geneid=4548}}
{{Amino acid metabolism enzymes}}
{{One carbon transferases}}
{{Enzymes}}
{{Portal bar|Biology|border=no}}

{{DEFAULTSORT:5-Methyltetrahydrofolate-Homocysteine Methyltransferase}}
[[Category:EC 2.1.1]]
[[Category:Human proteins]]
[[Category:Zinc enzymes]]