Chemoenzymatic synthesis and utilization of a SAM analog with an isomorphic nucleobase

Vranken, Charlotte; Fin, Andréa; Tufar, Peter; Hofkens, Johan; Burkart, Michael D.; Tor, Yitzhak

doi:10.1039/c6ob00844e

Cited by 22 publications

(24 citation statements)

References 42 publications

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“…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%

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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Section: Labeling Strategies Using Adomet‐dependent Mtasesmentioning

confidence: 99%

Methyltransferase‐Directed Labeling of Biomolecules and its Applications

et al. 2017

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“…[20,21] One limitation of this process is the need to prepare these cofactors by chemical synthesis,w hich is laborious,l ow yielding,a nd produces both epimers at the sulfur center. [15,29,30] One example of this one-pot process is the generation of cofactor analogues in situ from either ClDAo rA TP and (m)ethionine, [15,[29][30][31][32][33] followed by C-(m)ethyl transfer catalyzed by aM Tase (Figure 1b). [27,28] Am ore step-and atom-efficient strategy is to couple cofactor formation with C-alkyl transfer.…”

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confidence: 99%

“…[15,29,30] One example of this one-pot process is the generation of cofactor analogues in situ from either ClDAo rA TP and (m)ethionine, [15,[29][30][31][32][33] followed by C-(m)ethyl transfer catalyzed by aM Tase (Figure 1b). [14,30] Herein, we showcase am ethod to address these limitations by strategic modifications to SAM and S-adenosyl ethionine (SAE, Figure 1c). [15,27,29,35,36] Although in-depth knowledge of the substrate promiscuity of C-MTases has been garnered from structural and mutagenesis studies, [17,19,20,37] little is known about how the structural features of the SAM cofactor itself influences the yield and scope of C-alkylation.…”

mentioning

confidence: 99%

“…[27,28] Am ore step-and atom-efficient strategy is to couple cofactor formation with C-alkyl transfer. [15,29,30] One example of this one-pot process is the generation of cofactor analogues in situ from either ClDAo rA TP and (m)ethionine, [15,[29][30][31][32][33] followed by C-(m)ethyl transfer catalyzed by aM Tase (Figure 1b). [34] ClDAi sashelf-stable,a tom-economical adenosine source for such aprocess catalyzed by SalL compared to ATP, which is asubstrate for SAM production by methionine adenosyltransferase (MAT).…”

mentioning

confidence: 99%

“…[15,27,29,35,36] Although in-depth knowledge of the substrate promiscuity of C-MTases has been garnered from structural and mutagenesis studies, [17,19,20,37] little is known about how the structural features of the SAM cofactor itself influences the yield and scope of C-alkylation. [14,30] Herein, we showcase am ethod to address these limitations by strategic modifications to SAM and S-adenosyl ethionine (SAE, Figure 1c).…”

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confidence: 99%

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S‐Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C‐Alkylation

et al. 2019

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Atandem enzymatic strategy to enhance the scope of C-alkylation of small molecules via the in situ formation of Sadenosyl methionine (SAM) cofactor analogues is described. As olvent-exposed channel present in the SAM-forming enzyme SalL tolerates 5'-chloro-5'-deoxyadenosine (ClDA) analogues modified at the 2-position of the adenine nucleobase.C oupling SalL-catalyzed cofactor production with C-(m)ethyl transfer to coumarin substrates catalyzedb yt he methyltransferase (MTase) NovOf orms C-(m)ethylated coumarins in superior yield and greater substrate scope relative to that obtained using cofactors lacking nucleobase modifications.E stablishing the molecular determinants that influence C-alkylation provides the basis to develop al ate-stage enzymatic platform for the preparation of high value small molecules.

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Die Methyltransferase‐gesteuerte Markierung von Biomolekülen und ihre Anwendungen

et al. 2017

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Methyltransferasen (MTasen) bilden eine große Familie von Enzymen, die vielfältige Zielstrukturen methylieren, von DNA, RNA und Proteinen bis zu niedermolekularen Verbindungen. Die meisten MTasen nutzen S‐Adenosyl‐l‐methionin (AdoMet) als Methylquelle. In den letzten Jahren wurde intensiv an der Entwicklung von AdoMet‐Analoga gearbeitet, mit dem Ziel, andere Einheiten als einfache Methylgruppen zu übertragen. Derzeit gibt es zwei Hauptklassen von AdoMet‐Analoga – doppelt aktivierte Moleküle und Moleküle auf Aziridinbasis – die jeweils einen anderen Ansatz zur Transalkylierung des Zielmoleküls verfolgen. Dieser Aufsatz erörtert die Methoden zur Markierung und Funktionalisierung von Biomolekülen unter Verwendung von AdoMet‐abhängigen MTasen und AdoMet‐Analoga. Er behandelt die Synthesewege hin zu AdoMet‐Analoga, die Stabilität von AdoMet‐Analoga in biologischen Umgebungen und ihre Anwendung in Transalkylierungen. Schließlich werden einige Perspektiven für die Anwendung von AdoMet‐Analoga in der biologischen Forschung, Genetik oder Epigenetik und Nanotechnologie aufgezeigt.

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Chemoenzymatic synthesis and utilization of a SAM analog with an isomorphic nucleobase

Cited by 22 publications

References 42 publications

Methyltransferase‐Directed Labeling of Biomolecules and its Applications

Methyltransferase‐Directed Labeling of Biomolecules and its Applications

S‐Adenosyl Methionine Cofactor Modifications Enhance the Biocatalytic Repertoire of Small Molecule C‐Alkylation

Die Methyltransferase‐gesteuerte Markierung von Biomolekülen und ihre Anwendungen

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