Methionine synthase

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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 as it is not naturally derived, and is obtained from our diet first in the form of homocysteine. Methionine synthase (MetH; EC: 2.1.1.13) is a B12-dependent enzyme that methylates homocysteine to regenerate methionine as needed.

The change from homocysteine to methionine is an SN2 reaction, as seen above, where the methyl group from methyltetrahydrofolate (MTHF), located on N-5, is donated. MTHF is a product of Methylenetetrahydrofolate reductase (MTHFR).

This is a complex reaction as the product, tetrahydrofolate, is a poor leaving group, thus requiring a "super nucleophile"^[1] with a protein-bound vitamin B12 cobalamin as the methyl carrier.

Relevance

Methionine deficiency can result in diseases such as birth abnormalities^[2].

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 has yet to be determined but we understand it contains 4 domains of B12 cobalamin (in pink), methyltetrahydrofolate (blue), homocysteine (yellow), and SAH (as part of the SAM cycle; in red). Each domain with an important function required for catalytic and reactivation cycles[3]. Vitamin B12 PDB ID: 1K7Y refers to the B12 domain of methionine synthase. Oxidation States of Cobalamin Co(I) - active, unstable, high energy Co(II) - common oxidation state

References

^[4]

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. ↑ 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
3. ↑ 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
4. ↑ 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