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DFT calculations were performed for the methyl group transfer reaction between CH3Co (dmgBF2)py and PPh3Ni(Triphos). The reaction mechanism and its energetics were investigated. This reaction is relevant to the catalytic mechanism of the enzyme acetyl coenzyme A synthase. BP86 and PBE functionals and dispersion corrections were used. It was found that intermolecular interactions are very important for this reaction. The influence of the solvent on the reaction was studied. [ABSTRACT FROM AUTHOR]

The complex of methyltransferase-like proteins 3 and 14 (METTL3-14) is the major enzyme that deposits N6-methyladenosine (m6A) modifications on messenger RNA (mRNA) in humans. METTL3-14 plays key roles in various biological processes through its methyltransferase (MTase) activity. However, little is known about its substrate recognition and methyl transfer mechanism from its cofactor and methyl donor S-adenosylmethionine (SAM). Here, we study the MTase mechanism of METTL3-14 by a combined experimental and multiscale simulation approach using bisubstrate analogues (BAs), conjugates of a SAM-like moiety connected to the N6-atom of adenosine. Molecular dynamics simulations based on crystal structures of METTL3-14 with BAs suggest that the Y406 side chain of METTL3 is involved in the recruitment of adenosine and release of m6A. A crystal structure with a BA representing the transition state of methyl transfer shows a direct involvement of the METTL3 side chains E481 and K513 in adenosine binding which is supported by mutational analysis. Quantum mechanics/molecular mechanics (QM/MM) free energy calculations indicate that methyl transfer occurs without prior deprotonation of adenosine-N6. Furthermore, the QM/MM calculations provide further support for the role of electrostatic contributions of E481 and K513 to catalysis. The multidisciplinary approach used here sheds light on the (co)substrate binding mechanism, catalytic step, and (co)product release, and suggests that the latter step is rate-limiting for METTL3. The atomistic information on the substrate binding and methyl transfer reaction of METTL3 can be useful for understanding the mechanisms of other RNA MTases and for the design of transition state analogues as their inhibitors.

DFT calculations were performed for the methyl group transfer reaction between CH3Co (dmgBF2)py and PPh3Ni(Triphos). The reaction mechanism and its energetics were investigated. This reaction is relevant to the catalytic mechanism of the enzyme acetyl coenzyme A synthase. BP86 and PBE functionals and dispersion corrections were used. It was found that intermolecular interactions are very important for this reaction. The influence of the solvent on the reaction was studied.

Human catechol O-methyltransferase (COMT) has emerged as a model for understanding enzyme-catalyzed methyl transfer from S-adenosylmethionine (AdoMet) to small-molecule catecholate acceptors. Mutation of a single residue (tyrosine 68) behind the methyl-bearing sulfonium of AdoMet was previously shown to impair COMT activity by interfering with methyl donor-acceptor compaction within the activated ground state of the wild type enzyme [J. Zhang, H. J. Kulik, T. J. Martinez, J. P. Klinman, Proc. Natl. Acad. Sci. U.S.A. 112, 7954-7959 (2015)]. This predicts the involvement of spatially defined protein dynamical effects that further tune the donor/acceptor distance and geometry as well as the electrostatics of the reactants. Here, we present a hydrogen/deuterium exchange (HDX)-mass spectrometric study of wild type and mutant COMT, comparing temperature dependences of HDX against corresponding kinetic and cofactor binding parameters. The data show that the impaired Tyr68Ala mutant displays similar breaks in Arrhenius plots of both kinetic and HDX properties that are absent in the wild type enzyme. The spatial resolution of HDX below a break point of 15-20 °C indicates changes in flexibility across ∼40% of the protein structure that is confined primarily to the periphery of the AdoMet binding site. Above 20 °C, Tyr68Ala behaves more like WT in HDX, but its rate and enthalpic barrier remain significantly altered. The impairment of catalysis by Tyr68Ala can be understood in the context of a mutationally induced alteration in protein motions that becomes manifest along and perpendicular to the primary group transfer coordinate.

The PRDM family of methyltransferases has been implicated in cellular proliferation and differentiation and is deregulated in human diseases, most notably in cancer. PRDMs are related to the SET domain family of methyltransferases; however, from the 19 PRDMs only a few PRDMs with defined enzymatic activities are known. PRDM15 is an uncharacterized transcriptional regulator, with significant structural disorder and lack of defined small-molecule binding pockets. Many aspects of PRDM15 are yet unknown, including its structure, substrates, reaction mechanism, and its methylation profile. Here, we employ a series of computational approaches for an exploratory investigation of its potential substrates and reaction mechanism. Using the knowledge of PRDM9 and current knowledge of PRDM15 as basis, we tried to identify genuine substrates of PRDM15. We start from histone-based peptides and learn that the native substrates of PRDM15 may be non-histone proteins. In the future, a combination of sequence-based approaches and signature motif analysis may provide new leads. In summary, our results provide new information about the uncharacterized methyltransferase, PRDM15. [ABSTRACT FROM AUTHOR]

RlmN and Cfr are salient examples of the dual use of SAM as a methyl donor and as a source of the 5'-dA SP • sp radical but also of the use of a single SAM binding site for different functions, which represents an "economy in the evolution of binding sites" [[13], [27]]. Class C RSMases contain a C-terminal domain with high sequence homology with the radical SAM enzyme coproporphyrinogen III oxidase HemN, which is able to catalyze methyl transfer to sp SP 2 sp -hybridized carbons using two SAM molecules simultaneously bound to the active site [[23], [25], [33]]. Radical SAM domain residues are shown in light gray; the cobalamin cofactor is in magenta; the radical SAM [4Fe-4S] cluster is in orange and yellow; SAH and SAM are in green; and the peptide substrate is in cyan. This methyl group is given by the first SAM molecule that binds to the active site, and then a second SAM arrives and undergoes reductive cleavage to generate the 5'-dA SP • sp radical. Cobalamin-Dependent RSMases: Similar Domains, Different Mechanisms The N-terminal cobalamin-binding domain, alongside the radical SAM motif, is a structural hallmark of class B RSMases, although not all cobalamin (Cbl)-dependent radical SAM enzymes are methyltransferases [[57]]. [Extracted from the article]

This review provides an overview of different C1 building blocks as substrates of enzymes, or part of their cofactors, and the resulting- functionalized products. There is an emphasis on the broad range of possibilities of biocatalytic one-carbon extensions with C1 sources of different oxidation states. The identification of uncommon biosynthetic strategies, many of which might serve as templates for synthetic or biotechnological applications, towards one-carbon extensions is supported by recent genomic and metabolomic progress and hence we refer principally to literature spanning from 2014 to 2020. 1 Introduction 2 Methane, Methanol, and Methylamine 3 Glycine 4 Nitromethane 5 SAM and SAM Ylide 6 Other C1 Building Blocks 7 Formaldehyde and Glyoxylate as Formaldehyde Equivalents 8 Cyanide 9 Formic Acid 10 Formyl-CoA and Oxalyl-CoA 11 Carbon Monoxide 12 Carbon Dioxide 13 Conclusions [ABSTRACT FROM AUTHOR]

The triel bond (TrB) formed between Be(CH3)2/Mg(CH3)2 and TrX3 (Tr = B, Al, and Ga; X = H, F, Cl, Br, and I) is investigated via the MP2/aug-cc-pVTZ(PP) quantum chemical protocol. The C atoms of the methyl groups in M(CH3)2 are characterized by a negative electrostatic potential and act as an electron donor in a triel bond with the π-hole above the Tr atom of planar TrX3. The interaction energy spans a wide range between 2 and 69 kcal/mol. Mg(CH3)2 forms a stronger TrB than does Be(CH3)2, which comports with the more negative electrostatic potential on its methyl groups. Some of the complexes involving Mg display a high degree of transfer of the methyl group from Mg to Tr, which is accompanied by an inversion of the bridging methyl and a sizable pyramidalization of the TrX3 unit. The geometries of these complexes have the properties of the long sought pentacoordinate C which has eluded identification and characterization in the past., (© 2024 Wiley‐VCH GmbH.)

The PRDM family of methyltransferases has been implicated in cellular proliferation and differentiation and is deregulated in human diseases, most notably in cancer. PRDMs are related to the SET domain family of methyltransferases; however, from the 19 PRDMs only a few PRDMs with defined enzymatic activities are known. PRDM15 is an uncharacterized transcriptional regulator, with significant structural disorder and lack of defined small-molecule binding pockets. Many aspects of PRDM15 are yet unknown, including its structure, substrates, reaction mechanism, and its methylation profile. Here, we employ a series of computational approaches for an exploratory investigation of its potential substrates and reaction mechanism. Using the knowledge of PRDM9 and current knowledge of PRDM15 as basis, we tried to identify genuine substrates of PRDM15. We start from histone-based peptides and learn that the native substrates of PRDM15 may be non-histone proteins. In the future, a combination of sequence-based approaches and signature motif analysis may provide new leads. In summary, our results provide new information about the uncharacterized methyltransferase, PRDM15.

Methyl transfer is essential in myriad biological pathways found across all domains of life. Unlike conventional methyltransferases that catalyze this reaction through nucleophilic substitution, many members of the radical S-adenosyl-L-methionine (SAM) enzyme superfamily use radical-based chemistry to methylate unreactive carbon centers. These radical SAM methylases reductively cleave SAM to generate a highly reactive 5′-deoxyadenosyl radical, which initiates a broad range of transformations. Recently, crystal structures of several radical SAM methylases have been determined, shedding light on the unprecedented catalytic mechanisms used by these enzymes to overcome the substantial activation energy barrier of weakly nucleophilic substrates. Here, we review some of the discoveries on this topic over the last decade, focusing on enzymes for which three-dimensional structures are available to identify the key players in the mechanisms, highlighting the dual function of SAM as a methyl donor and a 5’-deoxyadenosyl radical or deprotonating base source. We also describe the role of the protein matrix in orchestrating the reaction through different strategies to catalyze such challenging methylations.

Nicotinamide N-methyltransferase (NNMT), a key cytoplasmic protein in the human body, is accountable to catalyze the nicotinamide (NCA) N1-methylation through S-adenosyl-L-methionine (SAM) as a methyl donor, which has been linked to many diseases. Although extensive studies have concerned about the biological aspect, the detailed mechanism study of the enzyme function, especially in the part of protein dynamics is lacking. Here, wild-type nicotinamide N-methyltransferase together with the mutation at position 20 with Y20F, Y20G, and free tryptophan were carried out to explore the connection between protein dynamics and catalysis using time-resolved fluorescence lifetimes. The results show that wild-type nicotinamide N-methyltransferase prefers to adapt a less flexible protein conformation to achieve enzyme catalysis. [ABSTRACT FROM AUTHOR]

The complex of methyltransferase-like proteins 3 and 14 (METTL3-14) is the major enzyme that deposits N 6 -methyladenosine (m 6 A) modifications on messenger RNA (mRNA) in humans. METTL3-14 plays key roles in various biological processes through its methyltransferase (MTase) activity. However, little is known about its substrate recognition and methyl transfer mechanism from its cofactor and methyl donor S -adenosylmethionine (SAM). Here, we study the MTase mechanism of METTL3-14 by a combined experimental and multiscale simulation approach using bisubstrate analogues (BAs), conjugates of a SAM-like moiety connected to the N 6 -atom of adenosine. Molecular dynamics simulations based on crystal structures of METTL3-14 with BAs suggest that the Y406 side chain of METTL3 is involved in the recruitment of adenosine and release of m 6 A. A crystal structure with a BA representing the transition state of methyl transfer shows a direct involvement of the METTL3 side chains E481 and K513 in adenosine binding which is supported by mutational analysis. Quantum mechanics/molecular mechanics (QM/MM) free energy calculations indicate that methyl transfer occurs without prior deprotonation of adenosine-N 6 . Furthermore, the QM/MM calculations provide further support for the role of electrostatic contributions of E481 and K513 to catalysis. The multidisciplinary approach used here sheds light on the (co)substrate binding mechanism, catalytic step, and (co)product release, and suggests that the latter step is rate-limiting for METTL3. The atomistic information on the substrate binding and methyl transfer reaction of METTL3 can be useful for understanding the mechanisms of other RNA MTases and for the design of transition state analogues as their inhibitors., Competing Interests: IC, PV, RB, JD, DC, EB, LI, YL, DH, ME, AC No competing interests declared, QC Senior editor, eLife, (© 2023, Corbeski et al.)

Cobalamins (B12) play various important roles in vivo. Most B12-dependent enzymes are divided into three main subfamilies: adenosylcobalamin-dependent isomerases, methylcobalamin-dependent methyltransferases, and dehalogenases. Mimicking these B12 enzyme functions under non-enzymatic conditions offers good understanding of their elaborate reaction mechanisms. Furthermore, bio-inspiration offers a new approach to catalytic design for green and eco-friendly molecular transformations. As part of a study based on vitamin B12 derivatives including heptamethyl cobyrinate perchlorate, we describe biomimetic and bioinspired catalytic reactions with B12 enzyme functions. The reactions are classified according to the corresponding three B12 enzyme subfamilies, with a focus on our recent development on electrochemical and photochemical catalytic systems. Other important reactions are also described, with a focus on radical-involved reactions in terms of organic synthesis.

Human catechol O-methyltransferase (COMT) has emerged as a model for understanding enzyme-catalyzed methyl transfer from S-adenosylmethionine (AdoMet) to small-molecule catecholate acceptors. Mutation of a single residue (tyrosine 68) behind the methyl-bearing sulfonium of AdoMet was previously shown to impair COMT activity by interfering with methyl donor–acceptor compaction within the activated ground state of the wild type enzyme [J. Zhang, H. J. Kulik, T. J. Martinez, J. P. Klinman, Proc. Natl. Acad. Sci. U.S.A. 112, 7954–7959 (2015)]. This predicts the involvement of spatially defined protein dynamical effects that further tune the donor/acceptor distance and geometry as well as the electrostatics of the reactants. Here, we present a hydrogen/deuterium exchange (HDX)-mass spectrometric study of wild type and mutant COMT, comparing temperature dependences of HDX against corresponding kinetic and cofactor binding parameters. The data show that the impaired Tyr68Ala mutant displays similar breaks in Arrhenius plots of both kinetic and HDX properties that are absent in the wild type enzyme. The spatial resolution of HDX below a break point of 15–20 °C indicates changes in flexibility across ∼40% of the protein structure that is confined primarily to the periphery of the AdoMet binding site. Above 20 °C, Tyr68Ala behaves more like WT in HDX, but its rate and enthalpic barrier remain significantly altered. The impairment of catalysis by Tyr68Ala can be understood in the context of a mutationally induced alteration in protein motions that becomes manifest along and perpendicular to the primary group transfer coordinate. [ABSTRACT FROM AUTHOR]

Background: S-Adenosylmethionine (SAMe) is a dietary supplement used in the management of osteoarthritis (OA) symptoms. Studies evaluating SAMe in the management of OA have been limited to Non Steroidal Anti-inflammatory Drugs ( NSAIDs) for comparison. The present study compares the effectiveness of SAMe to a cyclooxygenase-2 (COX-2) inhibitor ( celecoxib) for pain control, functional improvement and to decrease side effects in people with osteoarthritis of the knee. Methods: A randomized double-blind cross-over study, comparing SAMe ( 1200 mg) with celecoxib ( Celebrex 200 mg) for 16 weeks to reduce pain associated with OA of the knee. Sixty-one adults diagnosed with OA of the knee were enrolled and 56 completed the study. Subjects were tested for pain, functional health, mood status, isometric joint function tests, and side effects. Results: On the first month of Phase 1, celecoxib showed significantly more reduction in pain than SAMe ( p = 0.024). By the second month of Phase 1, there was no significant difference between both groups ( p < 0.01). The duration of treatment and the interaction of duration with type of treatment were statistically significant (ps &LE; 0.029). On most functional health measures both groups showed a notable improvement from baseline, however no significant difference between SAMe and celecoxib was observed. Isometric joint function tests appeared to be steadily improving over the entire study period regardless of treatment. Conclusion: SAMe has a slower onset of action but is as effective as celecoxib in the management of symptoms of knee osteoarthritis. Longer studies are needed to evaluate the long-term effectiveness of SAMe and the optimal dose to be used.

Cobalamins, cobalt glyoximate complexes and nickel complexes with Triphos (bis(diphenylphosphinoethyl)phenylphosphine) and PPh2CH2CH2SEt ligands were studied with the DFT/BP86 method in connection with methyl transfer reactions. Geometries, methyl binding energies and redox potentials were determined for the studied complexes. Three- and four-coordinate structures were considered for nickel complex with PPh2CH2CH2SEt ligand, whereas four- and five-coordinate for its methyl derivative. On the basis of calculations, the possible mechanism of methyl transfer reaction between cobalt and nickel complexes was considered. [ABSTRACT FROM AUTHOR]

Abstract Reactivity of K 2 [PtIVCH 3 Cl 5 ] toward a series of substituted N , N -dimethylanilines 1a-1g , N , N -diisopropylaniline 1h and 2,6-substituted pyridines 2a-2b was investigated in 60% (vol.) aqueous acetone solutions. The reactions result in corresponding N -methylammonium or N -methylpyridinium products, 3 or 4 , with high selectivity for the substrates 1a-1g and 2b , and follow an overall 2nd order kinetics, 1st order in both the PtIV complex and the amines. The reactivity is discussed in terms of the amine electronic properties and steric bulk. For the series of N , N -dimethylanilines 1a-1g , Me 2 NC 6 H 4 R (R = H, m -Cl, p -Cl, m -Me, p -Me, p -MeO, p -Me 2 N), a high quality linear correlation was found between logarithm of the reaction second order rate constant, log(k 2), and pK a of the anilines. At the same time, the reactivity of the bulkier N , N -diisopropylaniline substrate 1h is about 3 orders of magnitude lower than predicted using this correlation. Finally, the pyridines 2a-2b are 3–4 orders of magnitude less reactive than N , N -dimethylanilines of similar pK a. Interestingly, the reactivity of K 2 [PtIVCH 3 Cl 5 ] toward N , N -dimethylanilines is of the same order of magnitude or slightly greater than that of a standard organic methylating agent, dimethylsulfate Me 2 SO 4. A computational (DFT) modeling of the title reaction is consistent with the formation of five-coordinate PtIVMe electrophile, [PtIVCH 3 Cl 4 ]-, which is involved in S N 2 attack at its methyl group carbon by nucleophilic amines. Graphical abstract Image 1 Highlights • N , N -dimethylanilines can be selectively methylated using K 2 [PtIVCH 3 Cl 5 ]. • K 2 [PtIVCH 3 Cl 5 ] is at least as reactive as a methylating agent as (CH 3) 2 SO 4. • Reactivity of substituted N , N -dimethylanilines is a linear function of their pKa. • N , N -diisopropylpyridine and 2,6-dimethylpyridines are about 1000 times less reactive. [ABSTRACT FROM AUTHOR]

[Display omitted] • Mepiquat levels were monitored in five amino acid/PipAc model systems. • The highest level of mepiquat was 1.97% at 260 °C for 60 min (Met/PipAc system). • The methyl groups of amino acids could react with piperidine to form mepiquat. • Oven baking of mushrooms recorded the highest mepiquat (63.22 ± 0.88 μg/kg). • Food constituents are a main source of precursors for mepiquat formation. In the present study, new methylating agents for the formation of N,N-dimethylpiperidinium (mepiquat) were evaluated in both model and mushroom systems. Mepiquat levels were monitored using five model systems; alanine (Ala)/pipecolic acid (PipAc), methionine (Met)/PipAc, valine (Val)/PipAc, leucine (Leu)/PipAc, and isoleucine (Ile)/PipAc. The highest level of mepiquat was 1.97% at 260 °C for 60 min (Met/PipAc model system). Piperidine can actively combine with methyl groups in thermal reactions to form N-methylpiperidine and mepiquat. Additionally, mushrooms rich in amino acids were oven baked, pan cooked, and deep fried, respectively, to investigate the formation of mepiquat. Oven baking led to the highest mepiquat content of 63.22 ± 0.88 μg/kg. In summary, food constituents are the main source of precursors for mepiquat formation, the mechanism of which has been presented in both model systems and mushroom matrices rich in amino acids. [ABSTRACT FROM AUTHOR]

Industrial Fischer-Tropsch processes involve the synthesis of hydrocarbons usually on metal surface catalysts. On the other hand, very few homogeneous catalysts are known to perform a Fischer-Tropsch style of reaction. In recent work, we established the catalytic properties of a diruthenium-platinum carbene complex, [(CpRu)2(μ2-H) (μ2-NHCH3)(μ3-C)PtCH3(P(CH3)3)2](CO)n+ with n = 0, 2 and Cp = η5-C5(CH3)5, and showed it to react efficiently by initial hydrogen atom transfer followed by methyl transfer to form an alkyl chain on the Ru-center. In particular, the catalytic efficiency was shown to increase after the addition of two CO molecules. As such, this system could be viewed as a potential homogeneous Fischer-Tropsch catalyst. Herein, we have engineered the catalytic center of the catalyst and investigated the reactivity of trimetal carbene complexes of the same type using iron, ruthenium and osmium at the central metal scaffold. The work shows that the reactivity should increase from diosmium to diruthenium to diiron; however, a non-linear trend is observed due to multiple factors contributing to the individual barrier heights. We identified all individual components of these reaction steps in detail and established the difference in reactivity of the various complexes.

This study describes, for the first time, the role of pipecolic acid betaine and pipecolic acid, naturally present in some foods, in the formation of the plant growth regulator N,N-dimethylpiperidinium (mepiquat) under dry thermal conditions. The formation of mepiquat and intermediate compounds was investigated in model systems using high performance liquid chromatography-quadrupole/time-of-flight mass spectrometry. Mepiquat is released with a yield of up to 0.66 mol% after thermal treatment (>150 °C) of pipecolic acid betaine. Similar conversion rates are attained with the congener piperidine-2-carboxylic acid ( dl -pipecolic acid), albeit in the presence of alkylating agents, such as choline, glycine betaine or trigonelline, that are fairly widespread in food crops. These new pathways to mepiquat indicate that the occurrence of low levels of this thermally induced compound is probably more widespread in processed foods than initially suspected (see Part 2 of this study on the occurrence of mepiquat in selected foodstuffs). [ABSTRACT FROM AUTHOR]

Modification of the polyketide anthraquinone AQ-256 in the entomopathogenic Photorhabdus luminescens involves several O -methylations, but the biosynthetic gene cluster antA-I lacks corresponding tailoring enzymes. We here describe the identification of five putative, highly homologous O -methyltransferases encoded in the genome of P. luminescens. Activity assays in vitro and deletion experiments in vivo revealed that three of them account for anthraquinone tailoring by producing three monomethylated and two dimethylated species of AQ-256. X-ray structures of all five enzymes indicate high structural and mechanistic similarity. As confirmed by structure-based mutagenesis, a conserved histidine at the active site likely functions as a general base for substrate deprotonation and subsequent methyl transfer in all enzymes. Eight complex structures with AQ-256 as well as mono- and dimethylated derivatives confirm the substrate specificity patterns found in vitro and visualize how single amino acid differences in the active-site pockets impact substrate orientation and govern site-specific methylation. [Display omitted] • O -methyltransferases encoded outside the ant gene cluster methylate anthraquinones • 3 methyltransferases produce 3 mono- and 2 dimethylated anthraquinone derivatives • Structures of 3 active and 2 inactive anthraquinone tailoring enzymes are reported • Ligand complex structures illustrate snapshots of the tailoring reactions Anthraquinones can carry methyl groups, but the corresponding tailoring enzymes have remained elusive. Huber et al. identified a tandem array of five methyltransferase genes, of which three are required for anthraquinone modification. Activity assays and X-ray structures of all five enzymes reveal substrate specificities and illustrate the methylation sequence. [ABSTRACT FROM AUTHOR]

The methyl transfer reaction from activated monomethyltin, via a modified Stille coupling reaction, was studied under “ligandless” conditions on fully deprotected 5'-modified nucleosides and one dinucleotide. The reaction was optimized to proceed in a few minutes and quantitative yield, even under dilute conditions, thus affording a rapid and efficient new method for oligonucleotide labelling with carbon-11.

Tetrel bonds represent a category of non-bonding interaction wherein an electronegative atom donates a lone pair of electrons into the sigma antibonding orbital of an atom in the carbon group of the periodic table. Prior computational studies have implicated tetrel bonding in the stabilization of a preliminary state that precedes the transition state in SN2 reactions, including methyl transfer. Notably, the angles between the tetrel bond donor and acceptor atoms coincide with the prerequisite geometry for the SN2 reaction. Prompted by these findings, we surveyed crystal structures of methyltransferases in the Protein Data Bank and discovered multiple instances of carbon tetrel bonding between the methyl group of the substrate S-adenosylmethionine (AdoMet) and electronegative atoms of small molecule inhibitors, ions, and solvent molecules. The majority of these interactions involve oxygen atoms as the Lewis base, with the exception of one structure in which a chlorine atom of an inhibitor functions as the electron donor. Quantum mechanical analyses of a representative subset of the methyltransferase structures from the survey revealed that the calculated interaction energies and spectral properties are consistent with the values for bona fide carbon tetrel bonds. The discovery of methyl tetrel bonding offers new insights into the mechanism underlying the SN2 reaction catalyzed by AdoMet-dependent methyltransferases. These findings highlight the potential of exploiting these interactions in developing new methyltransferase inhibitors.

In the reaction of methyl 2,3,3,3-tetrafluoro-2-methoxypropanoate with arylamines or arylmethylamines, an unexpected methyl transfer from the ester to the amine by the B Al 2 (S N 2) mechanism was observed leading to the corresponding N -methylamines under specific conditions. The reaction was accompanied by the formation of amides via B Ac 2 mechanism. The unexpected methyl transfer is highly dependent on the structure of the starting amine and is supported by the absence of solvent and high temperature. [ABSTRACT FROM AUTHOR]

DFT calculations for methyl cation complexed within a constrained cage of water molecules permit the controlled manipulation of the 'axial' donor/acceptor distance and the 'equatorial' distance to hydrogen-bond acceptors. The kinetic isotope effect k(CH3)/ k(CT3) for methyl transfer within a cage with a short axial distance becomes less inverse for shorter equatorial C⋅⋅⋅O distances: a decrease of 0.5 Å results in a 3 % increase at 298 K. Kinetic isotope effects in AdoMet-dependent methyltransferases may be m∧odulated by CH⋅⋅⋅O hydrogen bonding, and factors other than axial compression may contribute, at least partially, to recently reported isotope-effect variations for catechol- O-methyltransferase and its mutant structures. [ABSTRACT FROM AUTHOR]

DFT studies on the mechanism of the formation of 'gemini' quaternary ammonium salts in the reaction of 1,4:3,6-dianhydro- d-mannitol ditriflate derivative with trimethylamine and its subsequent conversion to tertiary amine through the methyl-transfer reaction are discussed. Two alternative reaction pathways are presented in the gas phase and in ethanol. Additionally, the transformation of the monotriflate derivative of 1,4:3,6-dianhydro- d-mannitol into the single quaternary ammonium salt is presented. Two functionals (B3LYP, M062X) and two basis sets (6-31+G** and 6-311++G**) were used for the calculations. The effect of the substituent attached to the five-membered rings at the C2 (and/or C5) carbon atom on the activation barrier is described. The trimethylammonium group bond to the five-membered ring greatly reduces the activation barrier height. The preferred reaction pathway for the conversions was established. Including the London dispersion in the calculations increases the stabilization of all the points on the potential energy surface in relation to individual reactants. Graphical Abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Industrial Fischer-Tropsch processes involve the synthesis of hydrocarbons usually on metal surface catalysts. On the other hand, very few homogeneous catalysts are known to perform a Fischer-Tropsch style of reaction. In recent work, we established the catalytic properties of a diruthenium-platinum carbene complex, [(CpRu)2(μ2-H) (μ2-NHCH3)(μ3-C)PtCH3(P(CH3)3)2](CO)n+ with n = 0, 2 and Cp = η5-C5(CH3)5, and showed it to react efficiently by initial hydrogen atom transfer followed by methyl transfer to form an alkyl chain on the Ru-center. In particular, the catalytic efficiency was shown to increase after the addition of two CO molecules. As such, this system could be viewed as a potential homogeneous Fischer-Tropsch catalyst. Herein, we have engineered the catalytic center of the catalyst and investigated the reactivity of trimetal carbene complexes of the same type using iron, ruthenium and osmium at the central metal scaffold. The work shows that the reactivity should increase from diosmium to diruthenium to diiron; however, a non-linear trend is observed due to multiple factors contributing to the individual barrier heights. We identified all individual components of these reaction steps in detail and established the difference in reactivity of the various complexes. [ABSTRACT FROM AUTHOR]

Methyl transfer processes catalyzed by protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs) control important biological events including transcriptional regulation and cell signaling. One important property of these enzymes is that different PKMTs and PRMTs catalyze the formation of different methylated product (product specificity). These different methylation states lead to different biological outcomes. Here, we review the results of quantum mechanics/molecular mechanics molecular dynamics and free energy simulations that have been performed to study the reaction mechanism of PKMTs and PRMTs and the mechanism underlying the product specificity of the methyl transfer processes. [ABSTRACT FROM AUTHOR]

The methyl transfer reaction from activated monomethyltin, via a modified Stille coupling reaction, was studied under "ligandless" conditions on fully deprotected 5'-modified nucleosides and one dinucleotide. The reaction was optimized to proceed in a few minutes and quantitative yield, even under dilute conditions, thus affording a rapid and efficient new method for oligonucleotide labelling with carbon-11. [ABSTRACT FROM AUTHOR]

Abstract: Density functional theory (DFT/BP86) and the Polarizable Continuum Model (PCM/acetonitrile) for solvation have been applied to investigate the methyl transfer reaction from CH3I to Ni(PPh2CH2CH2SEt)2. Two different mechanisms were considered: SN2 and radical one. The reaction paths for both examined mechanism were determined, and the geometries of possible substrates and products were compared. [Copyright &y& Elsevier]

Cyclopropane fatty acid (CFA) synthase catalyzes a remarkable reaction. The cis double bonds of unsaturated fatty acyl chains of phospholipid bilayers are converted to cyclopropane rings by transfer of a methylene moiety from S-adenosyl-L-methionine (SAM). The substrates of this modification are functioning membrane bilayer phospholipids. Indeed, in Escherichia coli the great bulk of phospholipid synthesis occurs during exponential growth phase, but most cyclopropyl synthesis occurs in early stationary phase. In vitro the only active methylene group acceptor substrate is phospholipid bilayers containing unsaturated fatty acyl chains.

Abstract: The catalytic methyl-transfer reaction from methyl tosylate to 1-octanethiol was carried out in the presence of a simple vitamin B12 model complex, [Co(III){(C2C3)(DO)(DOH)pn}Br2], with zinc powder as the reducing reagent at 50°C. Such a catalytic reaction proceeded via the formation and dissociation of a cobalt–carbon bond in the simple vitamin B12 model complex under non-enzymatic conditions. The mechanism for the methyl-transfer reaction was investigated by electronic and mass spectroscopies. The Co(I) species, which is generated from the reduction of the catalyst by the zinc powder, and its methylated CH3–Co complex were found to be indispensable intermediates. [Copyright &y& Elsevier]

Abstract: This paper reports arsenic methylation in betaine–nontronite clay–water suspensions under environmental conditions. Two nontronites (<0.05mm), NAu-1 (green color, Al-enriched) and NAu-2 (brown color, Al-poor, contains tetrahedral Fe) from Uley Mine - South Australia were selected for this study. Betaine (pK a =1.83) was selected as methyl donor. The reaction between 5gL−1 clay, 20ppm As(III), and 0.4M betaine at 7≤pH0 ≤9 under anoxic conditions was studied. The presence of nontronite clays were found to favor As(III) conversion to monomethylarsenic (MMA). Arsenic conversion was found to be as high as 50.2ngMMA/ng As(III)0. Conversion of As was found to be more quantitative in the presence of NAu-2 ((Na0.72) [Si7.55 Al0.16Fe0.29][Al0.34 Fe3.54 Mg0.05] O20(OH)4) than NAu-1 ((Na1.05) [Si6.98 Al0.95Fe0.07][Al0.36 Fe3.61 Mg0.04] O20(OH)4). The inherent negative charge at the nontronite tetrahedral layer stabilizes positively charged organic intermediate-reaction species, thereby leading to decreases in the overall methylation activation energy. The outcome of this work shows that nontronite clays catalyze As methylation to MMA via non-enzymatic pathway(s) under environmental conditions. [Copyright &y& Elsevier]

Abstract: Hybrid density functional theory methods were used to investigate the reaction mechanism of human phenylethanolamine N-methyltransferase (hPNMT). This enzyme catalyzes the S-adenosyl-l-methionine-dependent conversion of norepinephrine to epinephrine, which constitutes the terminal step in the catecholamine biosynthesis. Several models of the active site were constructed based on the X-ray structure. Geometries of the stationary points along the reaction path were optimized and the reaction barrier and energy were calculated and compared to the experimental values. The calculations demonstrate that the reaction takes place via an SN2 mechanism with methyl transfer being rate-limiting, a suggestion supported by mutagenesis studies. Optimal agreement with experimental data is reached using a model in which both active site glutamates are protonated. Overall, the mechanism of hPNMT is more similar to those of catechol O-methyltransferase and glycine N-methyltransferase than to that of guanidinoacetate N-methyltransferase in which methyl transfer is coupled to proton transfer. [Copyright &y& Elsevier]

Abstract: The methylation reaction of arsenic trioxide conducted at 37°C and pH 7.0 for 24h using hydrophobic methylated vitamin B12, (methyl) (aquo) heptamethylcobyrinate perchlorate, CH3B12 ester, as a methyl donor in the presence of reduced glutathione (GSH) yielded monomethylarsonous acid (MMA), dimethylarsinic acid (DMA), and trimethylarsine oxide (TMAO) as products with a methylation rate over 95%. In contrast, when methylcobalamin (CH3B12) was used as the methyl donor, only MMA and DMA were produced and the methylation rate dropped to around 20%. Reductive demethylation of a methyl-corrinoid coordination complex mediated by GSH is suggested as a mechanism of methyl transfer to arsenic trioxide. The differences observed for different corrinoid coordination complexes with respect to the reactivity of methyl transfer to arsenic is ascribable to differences inherent in the base-on (CH3B12) and base-off (CH3B12 ester) natures of the compounds. [Copyright &y& Elsevier]

Abstract: A new synthesis of pyrrolo[3,2-b]quinolines is described. Condensation of anilines with dimethyl 4-oxopyrrolidine-1,3-dicarboxylate yields enaminoesters, which upon reaction with Bredereck''s reagent produce the title compounds. A possible reaction mechanism is briefly discussed. [Copyright &y& Elsevier]

Alkyl sulfate monoesters are involved in cell signaling and structure. Alkyl sulfates are also present in many commercial detergents. Here, we show that monomethyl sulfate acts as an efficient alkylating agent in water, reacting spontaneously with oxygen nucleophiles >100-fold more rapidly than do alkylsulfonium ions, the usual methyl donors in living organisms. These reactions of methyl sulfate, which are much more rapid than its hydrolysis, are insensitive to the nature of the attacking nucleophile, with a Brønsted βnuc value of -0.01. Experiments at elevated temperatures indicate a rate constant of 2 × 10-11 s-1 for the uncatalyzed hydrolysis of methyl sulfate at 25°C (t1/2 = 1,100 y), corresponding to a rate enhancement of ≈-1011-fold by a human alkylsulfatase. Equilibria of formation of methyl sulfate from methanol and sodium hydrogen sulfate indicate a group transfer potential (ΔG′pH7) of -8.g kcal/mol for sulfate ester hydrolysis. The magnitude of that value, involving release of the strong acid HSO4¯, helps to explain the need for harnessing the free energy of hydrolysis of two ATP molecules in activating sulfate for the biosynthesis of sulfate monoesters. The ‘energy-rich’ nature of monoalkyl sulfate esters, coupled with their marked resistance to hydrolysis, renders them capable of acting as sulfating or alkylating agents under relatively mild conditions. These findings raise the possibility that, under appropriate circumstances, alkyl groups may undergo transfer from alkyl sulfate monoesters to biological target molecules. [ABSTRACT FROM AUTHOR]

Abstract: The B vitamins are water-soluble vitamins that are required as coenzymes for reactions essential for cellular function. This review focuses on the essential role of vitamins in maintaining the one-carbon transfer cycles. Folate and choline are believed to be central methyl donors required for mitochondrial protein and nucleic acid synthesis through their active forms, 5-methyltetrahydrofolate and betaine, respectively. Cobalamin (B12) may assist methyltetrahydrofolate in the synthesis of methionine, a cysteine source for glutathione biosynthesis. Pyridoxal, pyridoxine and pyridoxamine (B6) seem to be involved in the regeneration of tetrahydrofolate into the active methyl-bearing form and in glutathione biosynthesis from homocysteine. Other roles of these vitamins that are relevant to mitochondrial functions will also be discussed. However these roles for B vitamins in cell function are mostly theoretically based and still require verification at the cellular level. For instance it is still not known what B vitamins are depleted by xenobiotic toxins or which cellular targets, metabolic pathways or molecular toxic mechanisms are prevented by B vitamins. This review covers the current state of knowledge and suggests where this research field is heading so as to better understand the role vitamin Bs play in cellular function and intermediary metabolism as well as molecular, cellular and clinical consequences of vitamin deficiency. The current experimental and clinical evidence that supplementation alleviates deficiency symptoms as well as the effectiveness of vitamins as antioxidants will also be reviewed. [Copyright &y& Elsevier]