2019
DOI: 10.1002/anie.201907245
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Evolved Aliphatic Halogenases Enable Regiocomplementary C−H Functionalization of a Pharmaceutically Relevant Compound

Abstract: Non‐heme iron halogenases are synthetically valuable biocatalysts that are capable of halogenating unactivated sp3‐hybridized carbon centers with high stereo‐ and regioselectivity. The reported substrate scope of these enzymes, however, is limited primarily to the natural substrates and their analogues. We engineered the halogenase WelO5* for chlorination of a martinelline‐derived fragment. Using structure‐guided evolution, a halogenase variant with a more than 290‐fold higher total turnover number and a 400‐f… Show more

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Cited by 78 publications
(88 citation statements)
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“…A phylogenetic tree of all characterized α‐KG‐dependent oxygenases and halogenases was generated and we could speculate that, using the AdeV sequence as a probe, we could find more halogenated nucleotide natural products through genome mining. The nucleoside halogenase may also aid us in creating new nucleoside analogues through biological, chemical, or biochemical routes for clinical use.…”
Section: Resultsmentioning
confidence: 99%
“…A phylogenetic tree of all characterized α‐KG‐dependent oxygenases and halogenases was generated and we could speculate that, using the AdeV sequence as a probe, we could find more halogenated nucleotide natural products through genome mining. The nucleoside halogenase may also aid us in creating new nucleoside analogues through biological, chemical, or biochemical routes for clinical use.…”
Section: Resultsmentioning
confidence: 99%
“…The same chemical principle can also be applied to pull-down experiments for identifying unknown protein targets of specific bioactive plant natural products amenable to site-specific azidation. Moreover, as a rare 2ODH of plant origin, DAH presents a starting point for future directed evolution experiments to further expand substrate specificity and anion selectivity, which will find use in the production of new-to-nature plant natural products through the means of metabolic engineering 34 .…”
Section: Resultsmentioning
confidence: 99%
“…In the first example of engineering freestanding halogenases for the acceptance of non‐indole alkaloid type substrates, Buller and co‐workers tailored WelO5* for the regio‐ and stereoselective chlorination of a martinelline‐derived fragment ( 17 ) with reported anti‐cancer activity (Scheme ) . By screening a set of free‐standing αKGHs (WelO5, AmbO5, WelO5*, and the engineered SadA D157G), WelO5* was the only enzyme identified to halogenate the target substrate.…”
Section: Engineering Substrate Specificity Activity and Reaction Conmentioning
confidence: 99%
“…In vitro , CB2 displayed more than 290‐fold higher TTN and a 400‐fold higher apparent turnover towards 17 compared to the wild type enzyme. CB2 was also shown to brominate 17 , though it had lower preference for bromide than chloride …”
Section: Engineering Substrate Specificity Activity and Reaction Conmentioning
confidence: 99%