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 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 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.

THE ROLE OF VITAMIN B12 IN METHYL TRANSFER TO HOMOCYSTEINE*

2006 ◽  
Vol 112 (2) ◽  
pp. 756-773 ◽  
Author(s):  
J. M. Buchanan ◽  
H. L. Elford ◽  
R. E. Loughlin ◽  
B. M. McDougall ◽  
S. Rosenthal
Keyword(s):  
Vitamin B12 ◽  
Methyl Transfer

Mn2+ coordinates Cap-0-RNA to align substrates for efficient 2′-O-methyl transfer by SARS-CoV-2 nsp16

2021 ◽  
Author(s):  
George Minasov ◽  
Monica Rosas-Lemus ◽  
Ludmilla Shuvalova ◽  
Nicole L. Inniss ◽  
Joseph S. Brunzelle ◽  
...  
Keyword(s):  
Divalent Cations ◽  
Critical Role ◽  
Messenger Rnas ◽  
Innate Immune Responses ◽  
Methyl Transfer ◽  
Backbone Conformation ◽  
Binding Groove ◽  
Rna Capping ◽  
Aspartate Residue

AbstractCapping viral messenger RNAs is essential for efficient translation and prevents their detection by host innate immune responses. For SARS-CoV-2, RNA capping includes 2′-O-methylation of the first ribonucleotide by methyltransferase nsp16 in complex with activator nsp10. The reaction requires substrates, a short RNA and SAM, and is catalyzed by divalent cations, with preference for Mn2+. Crystal structures of nsp16-nsp10 with capped RNAs revealed a critical role of metal ions in stabilizing interactions between ribonucleotides and nsp16, resulting in precise alignment of the substrates for methyl transfer. An aspartate residue that is highly conserved among coronaviruses alters the backbone conformation of the capped RNA in the binding groove. This aspartate is absent in mammalian methyltransferases and is a promising site for designing coronavirus-specific inhibitors.

scholarly journals The role of tetrahydromethanopterin and cytoplasmic cofactor in methane synthesis

1986 ◽  
Vol 235 (2) ◽  
pp. 453-458 ◽  
Author(s):  
F D Sauer ◽  
B A Blackwell ◽  
S Mahadevan
Keyword(s):  
Experimental Evidence ◽  
Membrane Fraction ◽  
Methanobacterium Thermoautotrophicum ◽  
Supernatant Fraction ◽  
Original Activity ◽  
Methyl Transfer ◽  
14C Labelling ◽  
First Time ◽  
Kinetics Of

A fraction previously isolated from acid-treated supernatant fraction of Methanobacterium thermoautotrophicum by DEAE-Sephadex chromatography [Sauer, Mahadevan & Erfle (1984) Biochem. J. 221, 61-97] which was absolutely required for methane synthesis, has been separated into two compounds, tetrahydromethanopterin (H4MPT) and an as-yet-unidentified cofactor we call ‘cytoplasmic cofactor’. H4MPT was identified by its u.v. spectrum and by 13C- and 1H-n.m.r. spectroscopy. The reduction of 2-(methylthio)ethanesulphonic acid (CH3-S-CoM) to methane by the membrane fraction from M. thermoautotrophicum was completely dependent on the addition of cytoplasmic cofactor. Methane synthesis from CO2, however, was only partially dependent on cofactor addition, and 57% of the original activity was retained in its absence. The kinetics of 14C labelling were consistent with the scheme methyl-H4MPT→CH3-S-CoM→methane, as has been proposed. This is the first time that direct experimental evidence has been presented to show that the proposed methyl transfer from H4MPT to coenzyme M (HS-CoM) actually occurs.

Role of vitamin B12 in methyl transfer for methane biosynthesis by Methanosarcina barkeri

Science ◽  
1982 ◽  
Vol 216 (4543) ◽  
pp. 303-305 ◽  
Author(s):  
J. Wood ◽  
I Moura ◽  
J. Moura ◽  
M. Santos ◽  
A. Xavier ◽  
...  
Keyword(s):  
Vitamin B12 ◽  
Methanosarcina Barkeri ◽  
Methyl Transfer
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