Cobalamin-Dependent Methionine Synthase:  Probing the Role of the Axial Base in Catalysis of Methyl Transfer between Methyltetrahydrofolate and Exogenous Cob(I)alamin or Cob(I)inamide†

Biochemistry ◽  
2003 ◽  
Vol 42 (49) ◽  
pp. 14653-14662 ◽  
Author(s):  
Jeanne Sirovatka Dorweiler ◽  
Richard G. Finke ◽  
Rowena G. Matthews
Keyword(s):  
Methionine Synthase ◽  
Methyl Transfer

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

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.

scholarly journals Sinorhizobium meliloti Requires a Cobalamin-Dependent Ribonucleotide Reductase for Symbiosis With Its Plant Host

2010 ◽  
Vol 23 (12) ◽  
pp. 1643-1654 ◽  
Author(s):  
Michiko E. Taga ◽  
Graham C. Walker
Keyword(s):  
Ribonucleotide Reductase ◽  
Sinorhizobium Meliloti ◽  
Critical Role ◽  
Methionine Synthase ◽  
Nitrogen Fixing ◽  
Plant Host ◽  
Gene Encoding ◽  
Cobalamin Biosynthesis ◽  
Methionine Synthesis

Vitamin B12 (cobalamin) is a critical cofactor for animals and protists, yet its biosynthesis is limited to prokaryotes. We previously showed that the symbiotic nitrogen-fixing alphaproteobacterium Sinorhizobium meliloti requires cobalamin to establish a symbiotic relationship with its plant host, Medicago sativa (alfalfa). Here, the specific requirement for cobalamin in the S. meliloti–alfalfa symbiosis was investigated. Of the three known cobalamin-dependent enzymes in S. meliloti, the methylmalonyl CoA mutase (BhbA) does not affect symbiosis, whereas disruption of the metH gene encoding the cobalamin-dependent methionine synthase causes a significant defect in symbiosis. Expression of the cobalamin-independent methionine synthase MetE alleviates this symbiotic defect, indicating that the requirement for methionine synthesis does not reflect a need for the cobalamin-dependent enzyme. To investigate the function of the cobalamin-dependent ribonucleotide reductase (RNR) encoded by nrdJ, S. meliloti was engineered to express an Escherichia coli cobalamin-independent (class Ia) RNR instead of nrdJ. This strain is severely defective in symbiosis. Electron micrographs show that these cells can penetrate alfalfa nodules but are unable to differentiate into nitrogen-fixing bacteroids and, instead, are lysed in the plant cytoplasm. Flow cytometry analysis indicates that these bacteria are largely unable to undergo endoreduplication. These phenotypes may be due either to the inactivation of the class Ia RNR by reactive oxygen species, inadequate oxygen availability in the nodule, or both. These results show that the critical role of the cobalamin-dependent RNR for survival of S. meliloti in its plant host can account for the considerable resources that S. meliloti dedicates to cobalamin biosynthesis.

Binding of (6R,S)-Methyltetrahydrofolate to Methyltransferase fromClostridium thermoaceticum:  Role of Protonation of Methyltetrahydrofolate in the Mechanism of Methyl Transfer†

Biochemistry ◽  
1999 ◽  
Vol 38 (18) ◽  
pp. 5736-5745 ◽  
Author(s):  
Javier Seravalli ◽  
Richard K. Shoemaker ◽  
Melissa J. Sudbeck ◽  
Stephen W. Ragsdale
Keyword(s):  
Methyl Transfer

scholarly journals Exploration of the Activation Mechanism of the Epigenetic Regulator MLL3: A QM/MM Study

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1051
Author(s):  
Sebastián Miranda-Rojas ◽  
Kevin Blanco-Esperguez ◽  
Iñaki Tuñón ◽  
Johannes Kästner ◽  
Fernando Mendizábal
Keyword(s):  
Transfer Reaction ◽  
Activation Mechanism ◽  
Epigenetic Mark ◽  
Regulation Mechanism ◽  
Salt Bridges ◽  
Conformational Restriction ◽  
Histone 3 ◽  
Methyl Transfer ◽  
Epigenetic Regulator

The mixed lineage leukemia 3 or MLL3 is the enzyme in charge of the writing of an epigenetic mark through the methylation of lysine 4 from the N-terminal domain of histone 3 and its deregulation has been related to several cancer lines. An interesting feature of this enzyme comes from its regulation mechanism, which involves its binding to an activating dimer before it can be catalytically functional. Once the trimer is formed, the reaction mechanism proceeds through the deprotonation of the lysine followed by the methyl-transfer reaction. Here we present a detailed exploration of the activation mechanism through a QM/MM approach focusing on both steps of the reaction, aiming to provide new insights into the deprotonation process and the role of the catalytic machinery in the methyl-transfer reaction. Our finding suggests that the source of the activation mechanism comes from conformational restriction mediated by the formation of a network of salt-bridges between MLL3 and one of the activating subunits, which restricts and stabilizes the positioning of several residues relevant for the catalysis. New insights into the deprotonation mechanism of lysine are provided, identifying a valine residue as crucial in the positioning of the water molecule in charge of the process. Finally, a tyrosine residue was found to assist the methyl transfer from SAM to the target lysine.

Insights into the role of methionine synthase in the universal 13 C depletion in O - and N -methyl groups of natural products

2017 ◽  
Vol 635 ◽  
pp. 60-65 ◽  
Author(s):  
Katarzyna M. Romek ◽  
Agnieszka Krzemińska ◽  
Gérald S. Remaud ◽  
Maxime Julien ◽  
Piotr Paneth ◽  
...  
Keyword(s):  
Natural Products ◽  
Methionine Synthase ◽  
Methyl Groups

scholarly journals The role of folate metabolism genome in the formation of triiodothyronine in children living in areas affected by the Chernobyl nuclear power plant accident

2019 ◽  
Vol 24 ◽  
pp. 197-201
Author(s):  
Yu. I. Bandazhevsky ◽  
N. F. Dubovaya
Keyword(s):  
Power Plant ◽  
Nuclear Power Plant ◽  
Nuclear Power ◽  
Risk Allele ◽  
Chernobyl Nuclear Power Plant ◽  
Folate Metabolism ◽  
Methionine Synthase ◽  
Blood Levels ◽  
Nuclear Power Plant Accident

Aim. Aim of this study was to determine the role of the genome of folate metabolism in the formation of triiodothyronine in children living in areas affected by the Chernobyl nuclear power plant accident. Methods. Immunochemical, mathematical and statistical. Results. The proportion of cases of elevated blood levels of triiodothyronine is statistically significantly higher in the group of children who are carriers of the G risk allele of the MTR:А2756G genetic polymorphism associated with the В12-dependent methionine synthase enzyme than in the group of children who have no this allele (MTR:2756 A/A genotype). The formation of triiodothyronine is associated with the metabolic conversion of homocysteine involving vitamin В6 as a cofactor of cystathionine β-synthase. Conclusions. The cause of thyrotoxic effects with damage to the cardiovascular system may lie in high levels of homocysteine occurring due to impaired functioning of В12-dependent methionine synthase. Keywords: folate metabolism, triiodothyronine, genetic polymorphisms, radiation-contaminated areas.

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