Methionine synthase

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Available structures
PDBOrtholog search: PDBe RCSB
AliasesMTR, HMAG, MS, cblG, 5-methyltetrahydrofolate-homocysteine methyltransferase
External IDsOMIM: 156570 MGI: 894292 HomoloGene: 37280 GeneCards: MTR
EC number2.1.1.13
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 1: 236.8 – 236.92 MbChr 13: 12.2 – 12.27 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

Methionine synthase also known as MS, MeSe, MTR is responsible for the regeneration of methionine from homocysteine. In humans it is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase).[5][6] Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle,[7] 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 (cobalamin)-dependent (MetH) and independent (MetE) forms,[8] although minimal core methionine synthases that do not fit cleanly into either category have also been described in some anaerobic bacteria.[9] The two dominant forms of the enzymes appear to be evolutionary independent and rely on considerably different chemical mechanisms.[10] Mammals and other higher eukaryotes only express the cobalamin-dependent form, whereas the form found in plants is exclusively the cobalamin-independent.[11] Many different microorganisms express both the cobalamin-dependent and cobalamin-independent forms.[12]


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 (N5-MeTHF) to homocysteine, yielding tetrahydrofolate (THF) and methionine.[8] Methionine synthase is the only mammalian enzyme that metabolizes N5-MeTHF to regenerate the active cofactor THF. In the cobalamin-dependent (MetH) form of the enzyme, the reaction proceeds by two steps in a preferred ordered sequential mechanism.[13] The physiological resting state of the enzyme is thought to contain the enzyme-bound(Cob) 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 from activated 5-methyltetrahydrofolate (N5-MeTHF), yielding tetrahydrofolate (THF) and regenerating the methylcoalamin form of the enzyme.[14]

Scavenger Pathway of Methionine Synthase Reductase to Recover Inactivated Methionine Synthase

Under 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 (MTRR), which consists of flavodoxin-like and ferrodoxin-NADP+ oxioreductase (FNR)-like domains.[15] In many bacteria, the reduction is carried out by a single domain flavodoxin protein.[16] 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.[17] 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.[18] 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.[19]

The mechanism of the cobalamin-independent (MetE) form, by contrast, proceeds through a direct methyl transfer from the activated N5-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 [20][8][21][22]


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[22][21] and for fragments of MetH,[23][24][25][26] 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.[27] Cob-dependent MetH is divided into 4 separate domains. The domains, from N- to C-terminus, are denoted homocysteine binding (Hcy domain), N5-methylTHF binding (MTHF domain) Cobalamin-binding (Cob domain) and the S-adenosymethionine-binding or reactivation domain. The reactivation domain binds SAM and is the site of interaction with flavodoxin or Methionine Synthase Reductase during the reactivation cycle of the enzyme.[16][15][19] The cobalamin-binding domain contains two subdomains, with the cofactor bound to the Rossman-fold B12-binding subdomain, which is in turn capped by the other subdomain, the four-helix bundle cap subdomain.[24] 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.[25] Both the Hcy and N5-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 N5-MeTHF binding domain binds and activates N5-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 moves back and forth from the Hcy domain to the N5-MeTHF domain in order for the two methyl transfer reactions to proceed.[23]

The cob-independent MetE consists of two TIM-barrel domains that bind homocysteine and N5-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.[21] 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 glutamate,[22] for which an example is shown on the right.

Biochemical function[edit]

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 acids, histones, phospholipids and various proteins.[28][29] 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 N5-MeTHF as a substrate, to indirectly maintain THF levels.[30][31]

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 of Met, which is one of the 20 canonical amino acids.[32][11] 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.[33]

Clinical significance[edit]

Mutations in the MTR gene have been identified as the underlying cause of methylcobalamin deficiency complementation group G, or methylcobalamin deficiency cblG-type.[5] 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.[34][35] Methionine synthase reductase (MTRR) or 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.[36] One consequence of reduced methionine synthase activity that is measurable by routine clinical blood tests is megaloblastic anemia.


Several cblG-associated polymorphisms in the MTR gene have been identified.[37]

  • 2756D→G (Asp919Gly)
  • 3804C→T (Pro1137Leu)
  • Δ2926A-2928T (ΔIle881)

See also[edit]


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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021311 - Ensembl, May 2017
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  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  22. ^ a b c Koutmos M, Pejchal R, Bomer TM, Matthews RG, Smith JL, Ludwig ML (March 2008). "Metal active site elasticity linked to activation of homocysteine in methionine synthases". Proceedings of the National Academy of Sciences of the United States of America. 105 (9): 3286–3291. doi:10.1073/pnas.0709960105. PMC 2265165. PMID 18296644.
  23. ^ a b Evans JC, Huddler DP, Hilgers MT, Romanchuk G, Matthews RG, Ludwig ML (March 2004). "Structures of the N-terminal modules imply large domain motions during catalysis by methionine synthase". Proceedings of the National Academy of Sciences of the United States of America. 101 (11): 3729–3736. Bibcode:2004PNAS..101.3729E. doi:10.1073/pnas.0308082100. PMC 374312. PMID 14752199.
  24. ^ a b Drennan CL, Huang S, Drummond JT, Matthews RG, Ludwig ML (December 1994). "How a protein binds B12: A 3.0 A X-ray structure of B12-binding domains of methionine synthase". Science. 266 (5191): 1669–1674. doi:10.1126/science.7992050. PMID 7992050.
  25. ^ a b Bandarian V, Pattridge KA, Lennon BW, Huddler DP, Matthews RG, Ludwig ML (January 2002). "Domain alternation switches B(12)-dependent methionine synthase to the activation conformation". Nature Structural Biology. 9 (1): 53–56. doi:10.1038/nsb738. PMID 11731805. S2CID 10529695.
  26. ^ Datta S, Koutmos M, Pattridge KA, Ludwig ML, Matthews RG (March 2008). "A disulfide-stabilized conformer of methionine synthase reveals an unexpected role for the histidine ligand of the cobalamin cofactor". Proceedings of the National Academy of Sciences of the United States of America. 105 (11): 4115–4120. doi:10.1073/pnas.0800329105. PMC 2393809. PMID 18332423.
  27. ^ Pejchal R, Ludwig ML (February 2005). "Cobalamin-independent methionine synthase (MetE): a face-to-face double barrel that evolved by gene duplication". PLOS Biology. 3 (2): e31. doi:10.1371/journal.pbio.0030031. PMC 539065. PMID 15630480.
  28. ^ Broderick JB, Duffus BR, Duschene KS, Shepard EM (April 2014). "Radical S-adenosylmethionine enzymes". Chemical Reviews. 114 (8): 4229–4317. doi:10.1021/cr4004709. PMC 4002137. PMID 24476342.
  29. ^ Shane B (June 2008). "Folate and vitamin B12 metabolism: overview and interaction with riboflavin, vitamin B6, and polymorphisms". Food and Nutrition Bulletin. 29 (2 Suppl): S5–S16. doi:10.1177/15648265080292S103. PMID 18709878. S2CID 21493797.
  30. ^ Watkins D, Ru M, Hwang HY, Kim CD, Murray A, Philip NS, et al. (July 2002). "Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L". American Journal of Human Genetics. 71 (1): 143–153. doi:10.1086/341354. PMC 384971. PMID 12068375.
  31. ^ Ghergurovich JM, Xu X, Wang JZ, Yang L, Ryseck RP, Wang L, Rabinowitz JD (November 2021). "Methionine synthase supports tumour tetrahydrofolate pools". Nature Metabolism. 3 (11): 1512–1520. doi:10.1038/s42255-021-00465-w. PMID 34799699. S2CID 244450216.
  32. ^ Ferla MP, Patrick WM (August 2014). "Bacterial methionine biosynthesis". Microbiology. 160 (Pt 8): 1571–1584. doi:10.1099/mic.0.077826-0. PMID 24939187.
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  34. ^ Banerjee RV, Matthews RG (March 1990). "Cobalamin-dependent methionine synthase". FASEB Journal. 4 (5): 1450–1459. doi:10.1096/fasebj.4.5.2407589. hdl:2027.42/154369. PMID 2407589. S2CID 8210250.
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  37. ^ Gulati S, Baker P, Li YN, Fowler B, Kruger W, Brody LC, Banerjee R (December 1996). "Defects in human methionine synthase in cblG patients". Human Molecular Genetics. 5 (12): 1859–1865. doi:10.1093/hmg/5.12.1859. PMID 8968736.

Further reading[edit]

External links[edit]