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

'''Methionine synthase''' (abbrev. MS; EC: 2.1.1.13) is a B12-dependent enzyme that catalyzes the methylation of homocysteine to methionine. This enzyme is a critical part of the one-carbon metabolism cycle as methionine is an essential amino acid required by our bodies for healthy cell and tissue growth. It is not naturally derived in our bodies, thus requiring the conversion of homocysteine, obtained from our diet, to methionine. MS mutations and B-12 deficiencies are associated with serious health conditions such as birth abnormalities and anemia.

==Function==

~~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.~~

[[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 and requires a "super nucleophile", vitamin B12 Cob(I)alamin, to carry out the reaction<ref name="Kung et al">DOI: 10.1038/nature10916</ref>; the methyl carrier.

MS undergoes two cycles: catalytic and reductive reactivation cycles.

Catalytic Cycle:

Cob(I)alamin is required in order to carry through with the complex SN2 reaction of breaking the bond between THF and the methyl group.

Co(I) - reactive but unstable, high energy

~~[[Image~~:~~Overall~~.~~jpeg]]~~

Reactivation Cycle:

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.

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, the product, is a poor leaving group and thus requiring a "super nucleophile", vitamin B12 cob(I)alamin, to carry out the reaction<ref name="Kung et al">DOI: 10.1038/nature10916</ref>; the methyl carrier.

== Relevance ==

~~Methionine deficiency~~ can result in diseases ~~such as birth abnormalities~~<ref name="Kung et al"/>.

MS mutations and B-12 deficiencies can result in diseases<ref name="Kung et al"/>.

== Structural highlights ==

~~== Structural highlights ==~~

The full structure of MS has yet to be determined but studies have found it contains <scene name='90/907471/Superposition_1/2'>4 domains</scene>, each domain with a unique function that bind to Cob(I)alamin as the methyl carrier (in pink), methyltetrahydrofolate as the methyl donor in the catalytic cycle (in blue), Homocysteine as the methyl acceptor (in yellow), and S-adenosylmethionine or SAM (in red) as the methyl donor in the reactivation cycle<ref name="Bandarian et al">DOI: 10.1038/nsb738</ref>. During each cycle, the domains must be positioned close enough to the Cobalamin in order for methyl transfer to be successful.

The full structure of MS has yet to be determined but studies have found it contains <scene name='90/907471/Superposition_1/2'>4 domains</scene>, each domain with a unique function that bind to Cob(I)alamin as the methyl carrier (in pink), methyltetrahydrofolate as the methyl donor in the catalytic cycle (in blue), Homocysteine as the methyl acceptor (in yellow), and S-~~adenosyl-L-methionine~~ or SAM (in red) as the methyl donor in the reactivation cycle<ref name="Bandarian et al">DOI: 10.1038/nsb738</ref>. During each cycle, the domains must be positioned close enough to the Cobalamin in order for methyl transfer to be successful.

== Vitamin B12 ==

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Catalytic Cycle:

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.

~~Co(I) - reactive but unstable, high energy~~

Reactivation Cycle:

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 This page is being worked on during the Spring 2022 semester.
+'''Methionine synthase''' (abbrev. MS; EC: 2.1.1.13) is a B12-dependent enzyme that catalyzes the methylation of homocysteine to methionine. This enzyme is a critical part of the one-carbon metabolism cycle as methionine is an essential amino acid required by our bodies for healthy cell and tissue growth. It is not naturally derived in our bodies, thus requiring the conversion of homocysteine, obtained from our diet, to methionine. MS mutations and B-12 deficiencies are associated with serious health conditions such as birth abnormalities and anemia.
 ==Function==
-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.
+[[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 and requires a "super nucleophile", vitamin B12 Cob(I)alamin, to carry out the reaction<ref name="Kung et al">DOI: 10.1038/nature10916</ref>; the methyl carrier.
+MS undergoes two cycles: catalytic and reductive reactivation cycles.
+Catalytic Cycle:
+Cob(I)alamin is required in order to carry through with the complex SN2 reaction of breaking the bond between THF and the methyl group.
+Co(I) - reactive but unstable, high energy
-[[Image:Overall.jpeg]]
+Reactivation Cycle:
+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.
-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, the product, is a poor leaving group and thus requiring a "super nucleophile", vitamin B12 cob(I)alamin, to carry out the reaction<ref name="Kung et al">DOI: 10.1038/nature10916</ref>; the methyl carrier.
 == Relevance ==
-Methionine deficiency can result in diseases such as birth abnormalities<ref name="Kung et al"/>.
+MS mutations and B-12 deficiencies can result in diseases<ref name="Kung et al"/>.
+== Structural highlights ==
 <StructureSection load='1k7y' size='310' side='right' caption='B12 dependent fragment of E. coli methionine synthase with Cobalt (in pink)' scene=''>
-== Structural highlights ==
+The full structure of MS has yet to be determined but studies have found it contains <scene name='90/907471/Superposition_1/2'>4 domains</scene>, each domain with a unique function that bind to Cob(I)alamin as the methyl carrier (in pink), methyltetrahydrofolate as the methyl donor in the catalytic cycle (in blue), Homocysteine as the methyl acceptor (in yellow), and S-adenosylmethionine or SAM (in red) as the methyl donor in the reactivation cycle<ref name="Bandarian et al">DOI: 10.1038/nsb738</ref>. During each cycle, the domains must be positioned close enough to the Cobalamin in order for methyl transfer to be successful.
-The full structure of MS has yet to be determined but studies have found it contains <scene name='90/907471/Superposition_1/2'>4 domains</scene>, each domain with a unique function that bind to Cob(I)alamin as the methyl carrier (in pink), methyltetrahydrofolate as the methyl donor in the catalytic cycle (in blue), Homocysteine as the methyl acceptor (in yellow), and S-adenosyl-L-methionine or SAM (in red) as the methyl donor in the reactivation cycle<ref name="Bandarian et al">DOI: 10.1038/nsb738</ref>. During each cycle, the domains must be positioned close enough to the Cobalamin in order for methyl transfer to be successful.
 == Vitamin B12 ==
@@ Line 32: / Line 44: @@
 Catalytic Cycle:
 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.
-Co(I) - reactive but unstable, high energy
 Reactivation Cycle: