Chemoenzymatic synthesis of fluorinated polyketides

Rittner, Alexander; Joppe, Mirko; Schmidt, Jennifer J.; Mayer, Lara Maria; Reiners, Simon; Heid, Elia; Herzberg, Dietmar; Sherman, David H.; Grininger, Martin

doi:10.1038/s41557-022-00996-z

Cited by 33 publications

(33 citation statements)

References 42 publications

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“…52 Recent successes have utilized uorinated extender units in engineered polyketide synthases (PKS) to generate previously unknown macrolide products bearing aliphatic C-F bonds. 53,54 In NRPS biosynthesis, uorinated amino acids have been successfully incorporated into peptidyl natural products, however these examples consist almost exclusively of halogen-substituted aromatic a-amino acids. 25,55,56 Owing to the much simpler installation of C-sp 2 -F bonds, these biosynthetic precursors are either commercially available or prepared in few synthetic steps.…”

Section: †)mentioning

confidence: 99%

Synthesis of functionalized 2,3-diaminopropionates and their potential for directed monobactam biosynthesis

et al. 2023

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Section: †)mentioning

confidence: 99%

Synthesis of functionalized 2,3-diaminopropionates and their potential for directed monobactam biosynthesis

et al. 2023

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“…The area of chemoenzymatic synthesis to produce polyketide natural product targets is so critical that it can be said that it is the driver of advancements in the field as a whole. Alison Narayan and David Sherman have been and will continue to build on their pioneering work [ 14 , 18 , 26 , 28 , 36 , 37 , 38 , 39 , 40 ]. The importance of these two scientists to the field is evidenced by the previous coverage in the literature, including other reviews.…”

Section: Selected Natural Product Syntheses Incorporating Chemoenzyma...mentioning

confidence: 99%

Current Progress in the Chemoenzymatic Synthesis of Natural Products

2022

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Natural products, with their array of structural complexity, diversity, and biological activity, have inspired generations of chemists and driven the advancement of techniques in their total syntheses. The field of natural product synthesis continuously evolves through the development of methodologies to improve stereoselectivity, yield, scalability, substrate scope, late-stage functionalization, and/or enable novel reactions. One of the more interesting and unique techniques to emerge in the last thirty years is the use of chemoenzymatic reactions in the synthesis of natural products. This review highlights some of the recent examples and progress in the chemoenzymatic synthesis of natural products from 2019–2022.

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“…The latter has been mainly attempted by engineering of the substrate specificity of AT domains. While AT domain engineering was met with some success in the past 12-18 , these efforts were mainly successful when focused on engineering a terminal or standalone PKS module (see below), which has led to the realization that AT engineering (still) has its limitations.…”

Section: Introductionmentioning

confidence: 99%

“…The latter has been mainly attempted by engineering of the substrate specificity of AT domains. While AT domain engineering was met with some success in the past [12][13][14][15][16][17][18] , these efforts were mainly successful when focused on engineering a terminal or standalone PKS module (see below), which has led to the realization that AT engineering (still) has its limitations. Contrary to the AT, KS domains have received little attention in respect to specificity-engineering approaches, although several studies hint towards KS domains as limiting factor for the incorporation and processing of non-native and non-natural substrates in the growing polyketide chain.…”

Section: Introductionmentioning

confidence: 99%

Ketosynthase engineering enhances activity and shifts specificity towards non-native extender units in type I linear polyketide synthase

Gerlinger

Angelidou

Paczia

et al. 2023

Preprint

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Engineering modular type I polyketide synthases (PKS) for the targeted incorporation of non-natural substrates to create variations in the polyketide backbone is a long-standing goal of PKS research. Thus far, most approaches focused on engineering the acyltransferase domain (AT) of PKS, whereas the effects of other ubiquitous domains such as the ketosynthase domain (KS) have received much less attention. In this work, we investigated the effects of thirteen active site substitutions in the module 3 KS (KS3) of the 6-deoxyerythronolide B synthase (DEBS) on incorporation of non-natural extender units in vitro. Using a truncated and a complete DEBS assembly line, we show that substitutions of F263 in KS3 invert specificity up to 1,250-fold towards incorporation of non-natural extender units in the terminal position. In contrast, substitutions of I444 in KS3 show up to 8-fold increased production of 6-deoxyerythonolide B (6-dEB) analogues with non-natural extender units at internal positions. The latter notably without compromising overall productivity of the assembly line. Our study further elucidates the underlying mechanisms for these different behaviors, highlighting the potential of KS engineering for the production of designer polyketides in the future.

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Chemoenzymatic synthesis of fluorinated polyketides

Cited by 33 publications

References 42 publications

Synthesis of functionalized 2,3-diaminopropionates and their potential for directed monobactam biosynthesis

Synthesis of functionalized 2,3-diaminopropionates and their potential for directed monobactam biosynthesis

Current Progress in the Chemoenzymatic Synthesis of Natural Products

Ketosynthase engineering enhances activity and shifts specificity towards non-native extender units in type I linear polyketide synthase

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