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Methionine synthase also known as MS, MeSe, MetH is a enzyme that in humans is encoded by the MTR gene (5-methyltetrahydrofolate-homocysteine methyltransferase).[1][2] This enzyme is responsible for the regeneration of methionine from homocysteine. Methionine synthase forms part of the S-adenosylmethionine (SAMe) biosynthesis and regeneration cycle.[3] Both cobalamin-dependent and cobalamin-independent forms of methionine synthase, which do not rely on an intermediate methyl carrier, exist in nature with animals expressing the former, plants the latter, and microorganisms expressing both. [4]

Mechanism[edit]

The reaction reaction catalyzed by methionine synthase (click to enlarge)

Methionine synthase catalyzes the final step in the regeneration of methionine(Met) from homocysteine(Hcy). The overall reaction transforms 5-methyltetrahydrofolate(N5-MeTHF) into tetrahydrofolate (THF) while transferring a methyl group to Hcy to form Met. Methionine synthase is the only mammalian enzyme that metabolizes N5-MeTHF to regenerate the active cofactor THF. In cobalamin-dependent forms of the enzyme, the reaction proceeds by two steps in a ping-pong reaction. The enzyme is initially primed into a reactive state by the transfer of a methyl group from N5-MeTHF to Co(I) in enzyme-bound cobalamin(Cob), forming methyl-cobalamin(Me-Cob) that now contains Me-Co(III) and activating the enzyme. Then, a Hcy that has coordinated to an enzyme-bound zinc to form a reactive thiolate reacts with the Me-Cob. The activated methyl group is transferred from Me-Cob to the Hcy thiolate, which regenerates Co(I) in cob, and Met is released from the enzyme. The cob-independent mechanism follows the same general pathway but with a direct reaction between the zinc thiolate and N5-MeTHF. [5] [4]

Scavenger Pathway of Methionine Synthase Reductase to Recover Inactivated Methionine Synthase

The mechanism of the enzyme depends on the constant regeneration of Co(I) in cob, but this is not always guaranteed. Instead, every 1-2000 catalytic turnovers, the Co(I) may be oxidized into Co(II), which would permanently shut down catalytic activity. A separate protein, Methionine Synthase Reductase, catalyzes the regeneration of Co(II) and the restoration of enzymatic activity. Because this process inevitably shuts down all methionine synthase activity, defects or deficiencies in methionine synthase reductase have been implicated in some of the disease associations for methionine synthase deficiency discussed below. The two enzymes form a scavenger network seen on the lower left.[6]


Structure[edit]

Homocysteine Binding Domain in Methionine Synthase. His 618, Cys 620, and Cys704 bind Zn(purple) which binds to Homocysteine(Red)

Crystal structures for both cob-independent and cob-dependent MetH have been solved, with little similarity in the overall structure despite the identical net reaction being performed by each and similarities within binding sites such as Hcy binding site.[7] Cob-dependent MetH is divided into 4 separate domains: Activation, Cobalamin-binding(Cob domain), Homocysteine binding(Hyc domain), and N 5-methylTHF binding(MeTHF domain). The activation domain is the site of interaction with Methionine Synthase Reductase and binds SAM that is used as part of the re-activation cycle of the enzyme. The Cob domain contains Cob sandwiched between several large alpha helices and bound to the enzyme so that the cobalt atom of the group is exposed for contact with other domains. The Hcy domain contains the critical zinc-binding site, made up of cysteine or histidine residues coordinated to a zinc ion that can bind Hcy, with an example from a non-Cob dependent MetH shown on the right. The N5-MeTHF binding domain contains a conserved barrel in which N5-MeTHF can hydrogen bond with asparagine , arginine, and aspartic acid residues. The entire structure undergoes a dramatic swinging motion during catalysis as the Cob domain moves back and forth from the Hcy domain to the Fol domain, transferring the active methyl group from the Fol to Hcy domain. [8]

Biological Function[edit]

Methionine synthase is enzyme 4

Methionine synthase's main purpose is to regenerate Met in the S-Adenosyl Methionine cycle, which in a single turnover consumes Met and ATP and generates Hcy. This cycle is critical because S-adenosyl methionine is used extensively in biology as a source of an active methyl group, and so methionine synthase serves an essential function by allowing the SAM cycle to perpetuate without a constant influx of Met. In this way, 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.

In plants and microorganisms, 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. While the 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.[9]

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.[1] Deficiency or deregulation of the enzyme due to deficient methionine synthase reductase can directly result in elevated levels of homocysteine, which is associated with blindness, neurological symptoms, and birth defects. Most cases of methionine synthase deficiency are symptomatic within 2 years of birth with many patients rapidly developing severe encephaloptahy.[10] The consequence of reduced methionine synthase activity is megaloblastic anemia.

Genetics[edit]

Several polymorphisms in the MTR gene have been identified.[citation needed]

  • 2756A→G (Asp919Gly)

See also[edit]

References[edit]

  1. ^ a b "MTR 5-methyltetrahydrofolate-homocysteine methyltransferase (Homo sapiens)". Entrez. 19 May 2009. Retrieved 24 May 2009.
  2. ^ Li YN, Gulati S, Baker PJ, Brody LC, Banerjee R, Kruger WD (December 1996). "Cloning, mapping and RNA analysis of the human methionine synthase gene". Hum. Mol. Genet. 5 (12): 1851–8. doi:10.1093/hmg/5.12.1851. PMID 8968735.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  3. ^ Banerjee RV, Matthews RG (March 1990). "Cobalamin-dependent methionine synthase" (PDF). FASEB J. 4 (5): 1450–9. doi:10.1096/fasebj.4.5.2407589. PMID 2407589.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: unflagged free DOI (link)
  4. ^ a b Zhang, Z.; Tian, C.; Zhou, S.; Wang, W.; Guo, Y.; Xia, J.; Liu, Z.; Wang, B.; Wang, X.; Golding, B. T.; Griff, R. J.; Du, Y.; Liu, J. (2012). "Mechanism-based design, synthesis and biological studies of N5-substituted tetrahydrofolate analogs as inhibitors of cobalamin-dependent methionine synthase and potential anticancer agents". European Journal of Medicinal Chemistry. 58: 228–236. doi:10.1016/j.ejmech.2012.09.027. PMID 23124219.
  5. ^ Matthews, R. G.; Smith, A. E.; Zhou, Z. S.; Taurog, R. E.; Bandarian, V.; Evans, J. C.; Ludwig, M. (2003). "Cobalamin-Dependent and Cobalamin-Independent Methionine Synthases: Are There Two Solutions to the Same Chemical Problem?". Helvetica Chimica Acta. 86 (12): 3939. doi:10.1002/hlca.200390329.
  6. ^ Wolthers, K. R.; Scrutton, N. S. (2007). "Protein Interactions in the Human Methionine Synthase−Methionine Synthase Reductase Complex and Implications for the Mechanism of Enzyme Reactivation†". Biochemistry. 46 (23): 6696–6709. doi:10.1021/bi700339v. PMID 17477549.
  7. ^ Pejchal, R.; Ludwig, M. L. (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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Evans, J. C.; Huddler, D. P.; Hilgers, M. T.; Romanchuk, G.; Matthews, R. G.; Ludwig, M. L. (2004). "Inaugural Article: Structures of the N-terminal modules imply large domain motions during catalysis by methionine synthase". Proceedings of the National Academy of Sciences. 101 (11): 3729–3736. doi:10.1073/pnas.0308082100. PMC 374312. PMID 14752199.
  9. ^ Hesse, H.; Hoefgen, R. (2003). "Molecular aspects of methionine biosynthesis". Trends in Plant Science. 8 (6): 259–262. doi:10.1016/S1360-1385(03)00107-9. PMID 12818659.
  10. ^ Outteryck, O.; De Sèze, J.; Stojkovic, T.; Cuisset, J. -M.; Dobbelaere, D.; Delalande, S.; Lacour, A.; Cabaret, M.; Lepoutre, A. -C.; Deramecourt, V.; Zéphir, H.; Fowler, B.; Vermersch, P. (2012). "Methionine synthase deficiency: A rare cause of adult-onset leukoencephalopathy". Neurology. 79 (4): 386–388. doi:10.1212/WNL.0b013e318260451b. PMID 22786600.

Further reading[edit]

External links[edit]


Category:Enzymes Category:EC 2.1.1 Category:Human proteins

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