Activation of Methyltetrahydrofolate by Cobalamin-Independent Methionine Synthase†

AbstractObjectiveTo examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response.MethodsWe screened 224 subjects (52% female, mean age 39 ± 11 years) with SCID-diagnosed major depressive disorder (MDD), and obtained 194 genetic samples. 49 subjects (49% female, mean age 36 ± 11 years) participated in a 12-week open clinical trial of fluoxetine 20–60 mg/day. Association between clinical response and C677T and A2756G polymorphisms, folate, B12, and homocysteine was examined.ResultsPrevalence of the C677T and A2756G polymorphisms was consistent with previous reports (C/C = 41%, C/T = 47%, T/T = 11%, A/A = 66%, A/G = 29%, G/G = 4%). In the fluoxetine-treated subsample (n = 49), intent-to-treat (ITT) response rates were 47% for C/C subjects and 46% for pooled C/T and T/T subjects (nonsignificant). ITT response rates were 38% for A/A subjects and 60% for A/G subjects (nonsignificant), with no subjects exhibiting the G/G homozygote. Mean baseline plasma B12 was significantly lower in A/G subjects compared to A/A, but folate and homocysteine levels were not affected by genetic status. Plasma folate was negatively associated with treatment response.ConclusionThe C677T and A2756G polymorphisms did not significantly affect antidepressant response. These preliminary findings require replication in larger samples.

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Influence of Vitamin B12 Status on the Inactivation of Methionine Synthase by Nitrous Oxide

Survey of Anesthesiology ◽

10.1097/00132586-199304000-00007 ◽

1993 ◽

Vol 37 (2) ◽

pp. 63

Author(s):

M. J. LANDON ◽

P. CREAGH-BARRY ◽

S. McARTHUR ◽

A. CHARLETT

Keyword(s):

Nitrous Oxide ◽

Vitamin B12 ◽

Methionine Synthase

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Haplotype analysis of the folate-related genes MTHFR, MTRR, and MTR and migraine with aura

Cephalalgia ◽

10.1177/0333102413477738 ◽

2013 ◽

Vol 33 (7) ◽

pp. 469-482 ◽

Cited By ~ 6

Author(s):

Kathryn A Roecklein ◽

Ann I Scher ◽

Albert Smith ◽

Tamara Harris ◽

Gudny Eiriksdottir ◽

...

Keyword(s):

Migraine With Aura ◽

Multiple Testing ◽

Haplotype Analysis ◽

Methylenetetrahydrofolate Reductase ◽

Population Based ◽

Methionine Synthase ◽

Association Testing ◽

Methionine Synthase Reductase ◽

Increased Risk ◽

Genes Encoding

Aims The C677T variant in the methylenetetrahydrofolate reductase ( MTHFR; EC 1.5.1.20) enzyme, a key player in the folate metabolic pathway, has been associated with increased risk of migraine with aura. Other genes encoding molecular components of this pathway include methionine synthase ( MTR; EC 2.1.1.13) and methionine synthase reductase ( MTRR; EC 2.1.1.135) among others. We performed a haplotype analysis of migraine risk and MTHFR, MTR, and MTRR. Methods Study participants are from a random sub-sample participating in the population-based AGES-Reykjavik Study, including subjects with non-migraine headache ( n = 367), migraine without aura ( n = 85), migraine with aura ( n = 167), and no headache ( n = 1347). Haplotypes spanning each gene were constructed using Haploview. Association testing was performed on single SNP and haplotypes using logistic regression, controlling for demographic and cardiovascular risk factors and correcting for multiple testing. Results Haplotype analysis suggested an association between MTRR haplotypes and reduced risk of migraine with aura. All other associations were not significant after correcting for multiple testing. Conclusions These results suggest that MTRR variants may protect against migraine with aura in an older population.

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Human Methionine Synthase

Journal of Biological Chemistry ◽

10.1074/jbc.272.6.3628 ◽

1997 ◽

Vol 272 (6) ◽

pp. 3628-3634 ◽

Cited By ~ 123

Author(s):

Linda H. Chen ◽

Mei-Lan Liu ◽

Hye-Yeon Hwang ◽

Li-Sheng Chen ◽

Julie Korenberg ◽

...

Keyword(s):

Methionine Synthase

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Methionine Synthase Deficiency: Variable Clinical Presentation And Benefit Of Early Diagnosis And Treatment

Journal of Inherited Metabolic Disease ◽

10.1002/jimd.12448 ◽

2021 ◽

Author(s):

Kimberly A. Kripps ◽

Leighann Sremba ◽

Austin A. Larson ◽

Johan L.K. Van Hove ◽

Hoanh Nguyen ◽

...

Keyword(s):

Early Diagnosis ◽

Clinical Presentation ◽

Methionine Synthase ◽

Diagnosis And Treatment ◽

Variable Clinical Presentation

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The folate-binding module ofThermus thermophiluscobalamin-dependent methionine synthase displays a distinct variation of the classical TIM barrel: a TIM barrel with a `twist'

Acta Crystallographica Section D Structural Biology ◽

10.1107/s2059798317018290 ◽

2018 ◽

Vol 74 (1) ◽

pp. 41-51

Author(s):

Kazuhiro Yamada ◽

Markos Koutmos

Keyword(s):

Tertiary Amine ◽

Thermus Thermophilus ◽

Methionine Synthase ◽

Structural Studies ◽

Binding Domains ◽

Methyl Transfer ◽

Structural Differences ◽

Tim Barrel ◽

Eukaryotic Organisms

Methyl transfer between methyltetrahydrofolate and corrinoid molecules is a key reaction in biology that is catalyzed by a number of enzymes in many prokaryotic and eukaryotic organisms. One classic example of such an enzyme is cobalamin-dependent methionine synthase (MS). MS is a large modular protein that utilizes an SN2-type mechanism to catalyze the chemically challenging methyl transfer from the tertiary amine (N5) of methyltetrahydrofolate to homocysteine in order to form methionine. Despite over half a century of study, many questions remain about how folate-dependent methyltransferases, and MS in particular, function. Here, the structure of the folate-binding (Fol) domain of MS fromThermus thermophilusis reported in the presence and absence of methyltetrahydrofolate. It is found that the methyltetrahydrofolate-binding environment is similar to those of previously described methyltransferases, highlighting the conserved role of this domain in binding, and perhaps activating, the methyltetrahydrofolate substrate. These structural studies further reveal a new distinct and uncharacterized topology in the C-terminal region of MS Fol domains. Furthermore, it is found that in contrast to the canonical TIM-barrel β8α8fold found in all other folate-binding domains, MS Fol domains exhibit a unique β8α7fold. It is posited that these structural differences are important for MS function.

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