Specific Residues Expand the Substrate Scope and Enhance the Regioselectivity of a Plant <i>O</i>‐Methyltransferase

Tang, Qingyun; Bornscheuer, Uwe T.; Pavlidis, Ioannis V.

doi:10.1002/cctc.201900606

Cited by 11 publications

(20 citation statements)

References 34 publications

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“…Naturally,m ethylation is commonly catalyzed by S-adenosyl methionine (SAM)-dependent methyltransferases (MT) which can transfer the methyl group from this cofactor to oxygen, carbon, sulfur,n itrogen, or phosphorous.U ntil recently,t he biocatalytic application of MTs,o fw hich many could be expressed as recombinant enzymes and also engineered for new target reactions, [211] has been hampered by the stoichiometric requirement of SAM (132). One option is the use of pyrophosphate with ap olyphosphate kinase as described above in section 7.1, but this requires in total addition of six enzymes, [209,212] making it rather complex. Another recently published alternative is the use of ah alide methyltransferase (HMT) where methyl iodide is used as donor, and for five different MTs up to 290 cycles were reported (Scheme 46).…”

Section: Methylation and Demethylation Reactionsmentioning

confidence: 99%

Biocatalysis: Enzymatic Synthesis for Industrial Applications

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in 2007, followed by postdoctoral studies at York University (UK) and Greifswald University (Germany). In 2010, she transitionedto industry applying and developing biocatalytic technologies at Novacta in the UK, prior to joining Chemical Process Development at GSK, with responsibility for the development and implementation of new biocatalytic technologyi nboth pre-and post-commercialization routes. Since Dec. 2016, Radka is leading the Bioreactions group in GDC at the Novartis Institute for Biomedical Research in Basel, Switzerland. Jeffrey Moore obtained his PhD in Chemical Engineeringf rom the California Institute of Technology in 1996 as Frances Arnold's first Directed Evolution graduate student. His foundational work led to an evolved p-nitrobenzyl esterase and the Lonza Centenary Prize (1997). In 1996, he joined the Biocatalysis Group of Merck & Co.in Rahway NJ, spending two decades inventing new enzymes and new enzymatic processes. In 2018, he transitionedtothe Merck Protein EngineeringG roup responsible for evolving enzymes for the discovery,d evelopmenta nd commercials cale manufacture of medicines. He has been awarded aUS Presidential Green Chemistry Award (2010), the BioCat2012 Award (2012) and the Thomas Edison Inventorship Award (2014). Kai Baldenius studied chemistry in Hamburg and Southampton. He received his PhD for research in asymmetric organometallic catalysis, supervised by H. tom Dieck and H. B. Kagan. After his postdoc on natural product synthesis with K. C. Nicolaou at the Scripps Research Institute he joined BASF in 1993. Kai served BASF in various functions (R&D, production, marketing, sales) before he took the lead of BASF'sbiocatalysis research for almost ad efcade. He left BASF to become afree-lancing consultanti n2019 and in 2020 he has founded Baldenius Biotech Consulting. Uwe T. Bornscheuer studied chemistry and received his PhD in 1993 at Hannover University followed by apostdoc at Nagoya University (Japan). In 1998, he completed his Habilitation at Stuttgart University about the use of lipases and esterasesi n organic synthesis. He has been Professor at the Institute of Biochemistry at Greifswald University since 1999. Beside other awards, he received in 2008 the BioCat2008 Award. He was just recognized as "Chemistry Europe Fellow". His current research interest focuses on the discovery and engineering of enzymes from various classes for applications in organic synthesis, lipid modification, degradation of plastics or complex marine polysaccharides.

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Section: Methylation and Demethylation Reactionsmentioning

confidence: 99%

Biocatalysis: Enzymatic Synthesis for Industrial Applications

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“…The change of a few residues at the OMT-I substrate-binding site could modify their regioselectivity and substrate specificity. Other rational and semi-rational designs have been performed with CbIEMT1, increasing its substrate scope [ 37 ] or generating a highly specific enzyme [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

Rational Design of Resveratrol O-methyltransferase for the Production of Pinostilbene

Herrera

Chánique

Martínez-Márquez

et al. 2021

IJMS

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Pinostilbene is a monomethyl ether analog of the well-known nutraceutical resveratrol. Both compounds have health-promoting properties, but the latter undergoes rapid metabolization and has low bioavailability. O-methylation improves the stability and bioavailability of resveratrol. In plants, these reactions are performed by O-methyltransferases (OMTs). Few efficient OMTs that monomethylate resveratrol to yield pinostilbene have been described so far. Here, we report the engineering of a resveratrol OMT from Vitis vinifera (VvROMT), which has the highest catalytic efficiency in di-methylating resveratrol to yield pterostilbene. In the absence of a crystal structure, we constructed a three-dimensional protein model of VvROMT and identified four critical binding site residues by applying different in silico approaches. We performed point mutations in these positions generating W20A, F24A, F311A, and F318A variants, which greatly reduced resveratrol’s enzymatic conversion. Then, we rationally designed eight variants through comparison of the binding site residues with other stilbene OMTs. We successfully modified the native substrate selectivity of VvROMT. Variant L117F/F311W showed the highest conversion to pinostilbene, and variant L117F presented an overall increase in enzymatic activity. Our results suggest that VvROMT has potential for the tailor-made production of stilbenes.

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“…Bis vor kurzem war die biokatalytische Anwendung von MTs,v on denen viele als rekombinante Enzyme exprimiert und auch fürn eue Zielreaktionen verbessert werden konnten, [211] dadurch eingeschränkt, dass SAM (132)stçchiometrisch bençtigt wird. Eine Lçsung ist die SAM-Regeneration mit Pyrophosphat, wie im obigen Abschnitt 7.1 beschrieben, bençtigt aber insgesamt sechs Enzyme, [209,212] was dies sehr komplex macht. Eine andere kürzlich publizierte Alternative ist der Einsatz einer Halogenid-Methyltransferase (HMT), bei der Methyliodid als Donor fungiert.…”

Section: Carbonsäure-reduktasenunclassified

Biokatalyse: Enzymatische Synthese für industrielle Anwendungen

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www.angewandte.de 2020 Die Autoren. Verçffentlicht von Wiley-VCH GmbH. Dieser Open Access Beitrag steht unter den Bedingungend er Creative Commons AttributionN on-CommercialN oDerivs License, die eine Nutzung und Verbreitung in allen Medien gestattet, sofern der ursprüngliche Beitrag ordnungsgemäßzitiert und nicht fürkommerzielle Zwecke genutzt wird und keine ¾nderungen und Anpassungen vorgenommen werden.

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Specific Residues Expand the Substrate Scope and Enhance the Regioselectivity of a Plant O‐Methyltransferase

Cited by 11 publications

References 34 publications

Biocatalysis: Enzymatic Synthesis for Industrial Applications

Biocatalysis: Enzymatic Synthesis for Industrial Applications

Rational Design of Resveratrol O-methyltransferase for the Production of Pinostilbene

Biokatalyse: Enzymatische Synthese für industrielle Anwendungen

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