Methionine synthase

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==Methionine synthase==
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This page is being worked on during the Spring 2022 semester.
This page is being worked on during the Spring 2022 semester.
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==Function==
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Methionine is an essential amino acid required by our bodies for healthy cell and tissue growth. It is essential because is not naturally derived, and must be obtained from our diet first in the form of homocysteine. Methionine synthase (abbrev. MS; EC: 2.1.1.13), a B12-dependent enzyme, catalyzes the methylation of homocysteine to regenerate methionine as needed.
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Methionine is an essential amino acid required by our bodies for healthy cell and tissue growth. It is essential because is not naturally derived, and must be obtained from our diet first in the form of homocysteine. Methionine synthase (abbrev. MS; EC: 2.1.1.13), a B12-dependent enzyme, is a critical part of the one-carbon metabolism cycle because it converts homocysteine to methionine.
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[[Image:Overall.jpeg]]
[[Image:Overall.jpeg]]
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PDB ID: 1K7Y, the B12 domain of MS.
PDB ID: 1K7Y, the B12 domain of MS.
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[PICTURE OF B12]
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In aerobic conditions, vitamin B12 Cobalamin(I) occasionally undergoes oxidation and this leads to an inactive Cob(II)alamin enzyme. A buildup of Cob(II)alamin is This is reactivated to Cob(I)alamin via reductive reactivation cycle with S-adenosylmethionine (SAM) as the methyl donor and Flavodoxin as an electron donor. B12 is unique. Conformations of MS allow substrates to be presented to vitamin B12 Cobalamin. A buildup
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In the Cob(I)alamin binding domain, the imidazole side chain containing His 759 replaces the dimethylbenzimidazole (DMB) ligand. His 759 then bonds to Asp 757 and See 810 via hydrogen bonds to create a ligand trifecta that increases the efficiency of the methyl transfer during the catalytic cycle<ref name="Bandarian et al"/>.
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Conformations of MS allow substrates to be presented to Cobalamin.
 
== Oxidation States of Cobalamin ==
== Oxidation States of Cobalamin ==
Catalytic Cycle:
Catalytic Cycle:
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Cobalt in the +1 oxidation state is required in order to carry through with the complex SN2 reaction of breaking the bond between THF and the methyl group.
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The super nucleophile is with Cobalt in the +1 oxidation state in order to carry through with the SN2 reaction of breaking the bond between THF and the methyl group.
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Co(I) - reactive but unstable, high energy
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Co(I) - active, unstable, high energy
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Reactivation Cycle:
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Co(II) - common oxidation state, inactive form
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In aerobic conditions, Cob(I)alamin occasionally undergoes oxidation leading to an inactive Cob(II)alamin enzyme. This is regulated by reductive methylation to ctivate Cob(I)alamin with Flavodoxin as an electron donor, and subsequently regenerating Me-Cob(I)alamin with SAM as the methyl donor.
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</StructureSection>
</StructureSection>

Revision as of 14:27, 13 April 2022

Methionine synthase

This page is being worked on during the Spring 2022 semester.

Methionine is an essential amino acid required by our bodies for healthy cell and tissue growth. It is essential because is not naturally derived, and must be obtained from our diet first in the form of homocysteine. Methionine synthase (abbrev. MS; EC: 2.1.1.13), a B12-dependent enzyme, catalyzes the methylation of homocysteine to regenerate methionine as needed.

Image:Overall.jpeg

The change from homocysteine to methionine is an SN2 reaction, as seen above, where the methyl group on N-5 from methyltetrahydrofolate (MTHF), is donated. MTHF is a product of Methylenetetrahydrofolate reductase (MTHFR) from the folate cycle [link Shaylie's page here]. This is a complex reaction as tetrahydrofolate (THF), the product, is a poor leaving group, thus requiring a "super nucleophile", vitamin B12 cob(I)alamin, to carry out the reaction[1].

Relevance

Methionine deficiency can result in diseases such as birth abnormalities[1].

B12 dependent fragment of E. coli methionine synthase with Cobalt (in pink)

Drag the structure with the mouse to rotate

References

[3] [4]

  1. ↑ 1.0 1.1 Kung Y, Ando N, Doukov TI, Blasiak LC, Bender G, Seravalli J, Ragsdale SW, Drennan CL. Visualizing molecular juggling within a B(12)-dependent methyltransferase complex. Nature. 2012 Mar 14. doi: 10.1038/nature10916. PMID:22419154 doi:10.1038/nature10916
  2. ↑ Bandarian V, Pattridge KA, Lennon BW, Huddler DP, Matthews RG, Ludwig ML. Domain alternation switches B(12)-dependent methionine synthase to the activation conformation. Nat Struct Biol. 2002 Jan;9(1):53-6. PMID:11731805 doi:10.1038/nsb738
  3. ↑ Barra L, Fontenelle C, Ermel G, Trautwetter A, Walker GC, Blanco C. Interrelations between glycine betaine catabolism and methionine biosynthesis in Sinorhizobium meliloti strain 102F34. J Bacteriol. 2006 Oct;188(20):7195-204. doi: 10.1128/JB.00208-06. PMID:17015658 doi:http://dx.doi.org/10.1128/JB.00208-06
  4. ↑ doi: https://dx.doi.org/10.1073/pnas.0906132106

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