Methionine synthase
From Proteopedia
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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. | ||
| - | '''Methionine synthase''' ( | + | '''Methionine synthase''' (MS; EC: 2.1.1.13) is an important enzyme in [[one-carbon metabolism]]. MS catalyzes the transfer of a methyl group from methyltetrahydrofolate (MTHF) to homocysteine, resulting in the formation of methionine. 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 in our bodies, thus requiring the conversion of homocysteine to methionine as needed. |
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==Function== | ==Function== | ||
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[[Image:Overall.jpeg]] | [[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 [[MTHFR]]. 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>DOI:10.1146/annurev.biochem.72.121801.161828</ref><ref name="Kung et al">DOI: 10.1038/nature10916</ref>; the methyl carrier. | + | 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 [[MTHFR]]. 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>DOI:10.1146/annurev.biochem.72.121801.161828</ref><ref name="Kung et al">DOI: 10.1038/nature10916</ref>; the methyl carrier. |
| - | MS | + | MS is a B12-dependent enzyme responsible for regenerating methionine from homocysteine and uses vitamin B12 Cobalamin as a cofactor. Therefore, any B12 deficiencies can effect the remethylation process. |
| - | 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. | ||
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| - | 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 activate Cob(I)alamin with Flavodoxin as an electron donor, and subsequently regenerating Me-Cob(I)alamin with SAM as the methyl donor. | ||
== Relevance == | == Relevance == | ||
| - | MS | + | As stated previously, MS is an important enzyme responsible for generating methionine, required by our bodies for healthy cell and tissue growth. Any MS and/or B12 deficiencies can result in diseases such as abnormal birth defects or anemia<ref name="Kung et al"/>. |
== Structural highlights == | == Structural highlights == | ||
<StructureSection load='1bmt' size='310' side='right' caption='B12 dependent fragment of E. coli methionine synthase with Cobalt (in pink)' scene=''> | <StructureSection load='1bmt' size='310' side='right' caption='B12 dependent fragment of E. coli methionine synthase with Cobalt (in pink)' scene=''> | ||
| - | The full structure of MS has yet to be determined but studies have found it contains | + | |
| + | The full structure of MS has yet to be determined but studies have found it contains four doamins, each with a unique function that bind to Cob(I)alamin as the methyl carrier, MTHF as the methyl donor in the catalytic cycle, homocysteine as the methyl acceptor, and S-adenosylmethionine or SAM, 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 Cobalamin in order for methyl transfers to be successful. Conformations of MS allows substrates to be presented to Cobalamin for reactions to occur. | ||
== Vitamin B12 == | == Vitamin B12 == | ||
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[[Image:cob_1_alamin.jpeg|800px]] | [[Image:cob_1_alamin.jpeg|800px]] | ||
| - | In the Cob(I)alamin binding domain, the imidazole side chain containing His 759 replaces the dimethylbenzimidazole (DMB) ligand. His 759 | + | The vitamin B12 Cobalamin binding domain has a special characteristic in that, it is most naturally found in a protective conformation to prevent unwanted chemistry from occuring. This is referred to as a 'capping' mechanism. In the Cob(I)alamin binding domain, the imidazole side chain containing His 759 replaces the dimethylbenzimidazole (DMB) ligand. His 759 bonds to Asp 757 and Ser 810 via hydrogen bonds to create a ligand trifecta that increases the efficiency of the methyl transfer during the catalytic cycle. With His on, the cap is off of Cobalamin to allow for it to hold onto the methyl from MTHF. With His off, the cap is on thus no reaction.<ref name="Bandarian et al"/>. |
| - | Conformations of MS allow substrates to be presented to Cobalamin. | ||
== Oxidation States of Cobalamin == | == Oxidation States of Cobalamin == | ||
| - | + | Cobalamin exists in three different oxidation states during the MS cycle. | |
| - | Cobalt in the +1 oxidation state is required | + | |
| - | + | Cob(I)alamin: Cobalt in the +1 oxidation state is nicknamed "super nucleophile" as its high energy is required to carry out the complex SN2 reaction of breaking the bond between tetrahydrofolate and the methyl group, in the catalytic cycle. | |
| - | + | ||
| - | + | Co(III)alamin: Cobalt in +3 oxidation state occurs when His 759 replaces the dimethylbenzimidazole (DMB) ligand to allow for the methyl to be accepted by Cob(I)alamin, forming Me-Cob(III)alamin. | |
| + | |||
| + | Cob(II)alamin: Under aerobic conditions, Cob(I)alamin occasionally undergoes oxidation leading to an inactive Cob(II)alamin enzyme in the +2 oxidation state. This is regulated by reductive methylation by using Flavodoxin as an electron donor to reactivate Cob(I)alamin, and subsequently regenerates Me-Cob(III)alamin with a methyl being donated from SAM. | ||
</StructureSection> | </StructureSection> | ||
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<ref>DOI: 10.1128/JB.00208-06</ref> | <ref>DOI: 10.1128/JB.00208-06</ref> | ||
| + | <ref>DOI:10.1073/pnas.1133218100</ref> | ||
<references/> | <references/> | ||
[[Category:One-carbon metabolism]] | [[Category:One-carbon metabolism]] | ||
Revision as of 22:50, 19 April 2022
This page is being worked on during the Spring 2022 semester.
Methionine synthase (MS; EC: 2.1.1.13) is an important enzyme in one-carbon metabolism. MS catalyzes the transfer of a methyl group from methyltetrahydrofolate (MTHF) to homocysteine, resulting in the formation of methionine. 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 in our bodies, thus requiring the conversion of homocysteine to methionine as needed.
Contents |
Function
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 MTHFR. 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[1][2]; the methyl carrier.
MS is a B12-dependent enzyme responsible for regenerating methionine from homocysteine and uses vitamin B12 Cobalamin as a cofactor. Therefore, any B12 deficiencies can effect the remethylation process.
Relevance
As stated previously, MS is an important enzyme responsible for generating methionine, required by our bodies for healthy cell and tissue growth. Any MS and/or B12 deficiencies can result in diseases such as abnormal birth defects or anemia[2].
Structural highlights
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References
- ↑ Banerjee R, Ragsdale SW. The many faces of vitamin B12: catalysis by cobalamin-dependent enzymes. Annu Rev Biochem. 2003;72:209-47. doi: 10.1146/annurev.biochem.72.121801.161828. PMID:14527323 doi:http://dx.doi.org/10.1146/annurev.biochem.72.121801.161828
- ↑ 2.0 2.1 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
- ↑ 3.0 3.1 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
- ↑ 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
- ↑ Bandarian V, Ludwig ML, Matthews RG. Factors modulating conformational equilibria in large modular proteins: a case study with cobalamin-dependent methionine synthase. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8156-63. doi:, 10.1073/pnas.1133218100. Epub 2003 Jun 27. PMID:12832615 doi:http://dx.doi.org/10.1073/pnas.1133218100
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