Facile Chemoenzymatic Strategies for the Synthesis and Utilization of <i>S</i>‐Adenosyl‐<scp>L</scp>‐Methionine Analogues

Singh, Shanteri; Zhang, Jianjun; Huber, Tyler D.; Sunkara, Manjula; Hurley, Katherine A.; Goff, Randal D.; Wang, Guojun; Zhang, Wen; Liu, Chunming; Rohr, Jürgen; Lanen, Steven G. Van; Morris, Andrew J.; Thorson, Jon S.

doi:10.1002/anie.201308272

Cited by 125 publications

(146 citation statements)

References 59 publications

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“…[9b], [13] Such diversifications can also be readily expanded by using recently developed variants of SAM methyltransferases into transferases of other alkyl groups. [14] …”

Section: Resultsmentioning

confidence: 99%

Enzymatic Methylation and Structure–Activity‐Relationship Studies on Polycarcin V, a Gilvocarcin‐Type Antitumor Agent

et al. 2014

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Polycarcin V, a polyketide natural product of Streptomyces polyformus, was chosen to study structure-activity-relationships of the gilvocarcin group of antitumor antibiotics, because of a similar chemical structure and comparable bioactivity with gilvocarcin V, the principle compound of this group, and the feasibility of enzymatic modifications of its sugar moiety by auxiliary O-methyltransferases. Such enzymes were used to modify the interaction of the drug with histone H3, the biological target that interacts with the sugar moiety. Cytotoxicity assays revealed that a free 2’-OH group of the sugar moiety is essential to maintain the bioactivity of polycarcin V, apparently an important H-bond donor for the interaction with histone H3, while converting 3'-OH into an OCH3 group improved the bioactivity. Bis-methylated polycarcin derivatives revealed weaker activity than the parent compound, indicating that at least two H-bond donors in the sugar are necessary for optimal binding.

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“…[9b], [13] Such diversifications can also be readily expanded by using recently developed variants of SAM methyltransferases into transferases of other alkyl groups. [14] …”

Section: Resultsmentioning

confidence: 99%

Enzymatic Methylation and Structure–Activity‐Relationship Studies on Polycarcin V, a Gilvocarcin‐Type Antitumor Agent

et al. 2014

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“…[11] Products 4a-c were obtained with re values of approximately + 90 %with Y200L compared to + 33-45 %with WT COMT. Ethyl vanillin 4a,ahigh-value food and flavor agent, was subsequently produced in 58 %y ield of isolated product in aone-pot tandem enzyme transformation from 1a,ethionine (6), and ATP, using am utant human methionine-adenosyltransferase hMAT2A (I322V) [11b,d] and COMT Y200L (see Figure 4, Figure S14).…”

Section: Angewandte Chemiementioning

confidence: 99%

Effects of Active‐Site Modification and Quaternary Structure on the Regioselectivity of Catechol‐O‐Methyltransferase

et al. 2016

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Catechol-O-methyltransferase (COMT), an important therapeutic target in the treatment of Parkinsons disease, is also being developed for biocatalytic processes,i ncluding vanillin production, although lacko fr egioselectivity has precluded its more widespread application. By using structural and mechanistic information, regiocomplementary COMT variants were engineered that deliver either meta-or paramethylated catechols. X-ray crystallography further revealed howt he active-site residues and quaternary structure govern regioselectivity.Finally,analogues of AdoMet are accepted by the regiocomplementary COMT mutants and can be used to prepare alkylated catechols, including ethyl vanillin.Rational design or directed evolution has often been used to improve or alter the enantioselectivity or regioselectivity of enzymes for biocatalytic applications.[1] Nature has evolved regiocomplementary enzymes for certain transformations; [2] however, where no suitable native enzyme exists,engineering regiocomplementary variants to deliver defined regioisomeric products is an enticing prospect. One example where the lack of enzyme regioselectivity limits potential commercial productivity is the engineered biosynthesis of the flavor and fragrance agent vanillin 2a.[3] Catechol-O-methyltransferase (COMT) has been used to methylate 3,4-dihydroxybenzaldehyde (DHBAL, 1a)a nd 3,4-dihydroxybenzoic acid (DHBA, 1b)inengineered strains of Escherichia coli and fission yeast for the production of vanillin 2a from glucose ( Figure 1A and Figure S1 in the Supporting Information). [3, 4] However, the lack of regioselectivity of COMT results in am ixture of 2a and the undesired para-methylated isovanillin 3a,w hich are difficult to separate.R egioselective COMT variants would greatly improve the more sustainable biochemical route for the production of vanillin in am icrobial host. Additionally, regiocomplementary variants that deliver either meta-o r para-methylated catechols would be of interest because such moieties are found within an umber of pharmaceuticals (see Figure S2 for examples).Structural and mechanistic information suggest that the regioselectivity of COMT can be attributed to the concerted action of a"hydrophobic wall" found in the active site of the enzyme, [5] and the substrate properties ( Figure 1B).[6] Polar and ionisable substituents (R groups), such as those found on catecholamines,t he natural substrates for COMT,a re more likely to orientate out of the active site and into the solvent, thereby resulting in meta-methylation.[6a,b] Fore xample, norepinephrine shows a meta/para ratio of 7:1.[6b] Conversely, para-methylation is likely to be more evident for substrates with neutral or more hydrophobic substituents that can be orientated towards the hydrophobic wall. [6a,b] Therelative pK a values and nucleophilicity of the two hydroxy groups could also affect the regiochemical outcome of the reaction. [5a,b, 6c] TheC OMT-catalyzed methylation of catechols (1)i s irreversible,r esulting in ak inetically contr...

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“…31, 32 This reaction has been utilized to prepare a library of non-native S/Se-containing modified SAM analogs and to alkylate small molecules in situ . 33 Alternatively, chemoenzymatic synthesis of several SAM analogs has been demonstrated using SalL, a chlorinase from Salinaspora tropica. 34 This halogenase is known to naturally catalyze the breakdown of SAM to l -methionine and 5’-chloro-5’-deoxyadenosine (ClDA), but the reaction can be reversed in vitro, at low chloride and high l -methionine concentrations.…”

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confidence: 99%

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

et al. 2016

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Facile Chemoenzymatic Strategies for the Synthesis and Utilization of S‐Adenosyl‐L‐Methionine Analogues

Cited by 125 publications

References 59 publications

Enzymatic Methylation and Structure–Activity‐Relationship Studies on Polycarcin V, a Gilvocarcin‐Type Antitumor Agent

Enzymatic Methylation and Structure–Activity‐Relationship Studies on Polycarcin V, a Gilvocarcin‐Type Antitumor Agent

Effects of Active‐Site Modification and Quaternary Structure on the Regioselectivity of Catechol‐O‐Methyltransferase

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

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