Methionine synthase

==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.

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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<ref name="Kung et al">DOI: 10.1038/nature10916</ref>.

== Relevance ==

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

<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-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 to allow for methyl transfer to occur.

== Vitamin B12 ==

PDB ID: 1K7Y, the B12 domain of MS.

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

== Oxidation States of Cobalamin ==

Catalytic Cycle:

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.

Co(I) - active, unstable, high energy

Co(II) - common oxidation state, inactive form

</StructureSection>

== References ==

<ref>DOI: 10.1128/JB.00208-06</ref>

<ref>DOI: 10.1073/pnas.0906132106</ref>

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