Methionine synthase

From Proteopedia

proteopedia linkproteopedia link

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

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.

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].

spinqualitylabelsall models B12 dependent fragment of E. coli methionine synthase with Cobalt (in pink) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Structural highlights The full structure of MS has yet to be determined but studies have found it contains , 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[2]. 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. [PICTURE OF B12] 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[2]. Conformations of MS allow substrates to be presented to Cobalamin. Oxidation States of Cobalamin 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: 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.

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. ↑ ^{2.0 2.1} 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