A Tandem Chemoenzymatic Methylation by <i>S</i>‐Adenosyl‐<scp>L</scp>‐methionine

Lipson, Joseph M.; Thomsen, Marie; Moore, Bradley S.; Clausen, Rasmus P.; Clair, James J. La; Burkart, Michael D.

doi:10.1002/cbic.201300221

Cited by 29 publications

(42 citation statements)

References 41 publications

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“…The concentrations of AdoMet species and corresponding degradation products were determined and graphed on an XY-scatterplot, and linear regression was performed on each data set to obtain degradation rates (Figure S5) as previously described. 50,89 The t 1/2 of each AdoMet species was determined from the line slope considering zeroth order kinetics, as in the following eq 1:

t_{1 ∕ 2} = \frac{{[AdoMet]}_{0}}{2 k}

where t (1/2) is the time (in min) that it takes for one-half of a chemical species (in this example, AdoMet) to degrade, [AdoMet] 0 is the starting % concentration of a chemical species, and k is the zero-order rate constant of degradation of a chemical species (in % min −1 ).…”

Section: Methodsmentioning

confidence: 99%

Functional AdoMet Isosteres Resistant to Classical AdoMet Degradation Pathways

et al. 2016

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S-adenosyl-l-methionine (AdoMet) is an essential enzyme cosubstrate in fundamental biology with an expanding range of biocatalytic and therapeutic applications. We report the design, synthesis, and evaluation of stable, functional AdoMet isosteres that are resistant to the primary contributors to AdoMet degradation (depurination, intramolecular cyclization, and sulfonium epimerization). Corresponding biochemical and structural studies demonstrate the AdoMet surrogates to serve as competent enzyme cosubstrates and to bind a prototypical class I model methyltransferase (DnrK) in a manner nearly identical to AdoMet. Given this conservation in function and molecular recognition, the isosteres presented are anticipated to serve as useful surrogates in other AdoMet-dependent processes and may also be resistant to, and/or potentially even inhibit, other therapeutically relevant AdoMet-dependent metabolic transformations (such as the validated drug target AdoMet decarboxylase). This work also highlights the ability of the prototypical class I model methyltransferase DnrK to accept non-native surrogate acceptors as an enabling feature of a new high-throughput methyltransferase assay.

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t_{1 ∕ 2} = \frac{{[AdoMet]}_{0}}{2 k}

Section: Methodsmentioning

confidence: 99%

Functional AdoMet Isosteres Resistant to Classical AdoMet Degradation Pathways

et al. 2016

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“…Recently, several groups have demonstrated enzymatic syntheses of AdoMet analogues as well 9, 38. The Thorson group tested a range MAT enzymes for their ability to catalyze the formation of several AdoMet analogues.…”

Section: Labeling Strategies Using Adomet‐dependent Mtasesmentioning

confidence: 99%

“…Furthermore, the synthesized analogues could be successfully used in the alkylation of small molecules (indolocarbazoles) 9b. The Burkart group have demonstrated the chemoenzymatic synthesis of several AdoMet analogues using either a fluorinase (FDAS) from Streptomyces cattleya or a chlorinase (SalL) from marine bacterium Salinaspora tropica 38, 39. Both halogenases are known to catalyze the breakdown of AdoMet to give l ‐Met and fluoro‐5′‐deoxyadenosine (FDA) or 5′‐chloro‐5′‐deoxyadenosine (ClDA).…”

Section: Labeling Strategies Using Adomet‐dependent Mtasesmentioning

confidence: 99%

“…However, the reaction can be reversed at low chloride/fluoride and high l ‐Met concentrations (Scheme 10, bottom). This enzymatic pathway can also be exploited by using various l ‐Met derivatives for the enzymatic synthesis of AdoMet analogues 9a, 38, 40. However, it should be noted that decreased activity of the l ‐Met analogues with increasing size was observed 40…”

Section: Labeling Strategies Using Adomet‐dependent Mtasesmentioning

confidence: 99%

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Methyltransferase‐Directed Labeling of Biomolecules and its Applications

et al. 2017

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Methyltransferases (MTases) form a large family of enzymes that methylate a diverse set of targets, ranging from the three major biopolymers to small molecules. Most of these MTases use the cofactor S‐adenosyl‐l‐Methionine (AdoMet) as a methyl source. In recent years, there have been significant efforts toward the development of AdoMet analogues with the aim of transferring moieties other than simple methyl groups. Two major classes of AdoMet analogues currently exist: doubly‐activated molecules and aziridine based molecules, each of which employs a different approach to achieve transalkylation rather than transmethylation. In this review, we discuss the various strategies for labelling and functionalizing biomolecules using AdoMet‐dependent MTases and AdoMet analogues. We cover the synthetic routes to AdoMet analogues, their stability in biological environments and their application in transalkylation reactions. Finally, some perspectives are presented for the potential use of AdoMet analogues in biology research, (epi)genetics and nanotechnology.

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“…Using this enzyme, different SAM analogs were synthesized and in situ utilized to enzymatically alkylate a small molecule, a peptide and DNA. 35, 36 …”

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confidence: 99%