General chemoenzymatic route to two-stereocenter triketides employing assembly line ketoreductases

Zhang, Zhicheng; Cepeda, Alexis J.; Robles, Mireya L; Hirsch, Melissa; Kumru, Kaan; Zhou, Jina A; Keatinge‐Clay, Adrian T.

doi:10.1039/c9cc07966a

Cited by 3 publications

(2 citation statements)

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“…Structure–function relationships of KR domains are therefore of eminent importance for rational PKS engineering. Previous in vitro studies of isolated KR domains uncovered relaxed substrate specificity in conjunction with strongly substrate-dependent stereoselectivity. − Whereas a substantial number of KR domains have already been tested, the range of polyketidic substrate surrogates is still restricted to di-, tri-, and tetraketidic SNAC thioesters and a few oxo esters. − Studies with precursor surrogates of KR domains from late PKS modules are largely neglected, probably due to a lack of specific synthetic access to them.…”

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confidence: 99%

Step-Economic Synthesis of Biomimetic β-Ketopolyene Thioesters and Demonstration of Their Usefulness in Enzymatic Biosynthesis Studies

et al. 2020

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Studies on the biosynthetic processing of polyene thioester intermediates are complicated by limited access to appropriate substrate surrogates. We present a step-economic synthetic access to biomimetic β-ketopolyene thioesters that is based on an Ir-catalyzed reductive Horner−Wadsworth−Emmons olefination. New β-ketotriene and pentaenethioates of pantetheine and N-acetylcysteamine were exemplarily synthesized via short and concise routes. The usefulness of these compounds was demonstrated in an in vitro assay with the ketoreductase domain MycKRB from mycolactone biosynthesis.

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confidence: 99%

Step-Economic Synthesis of Biomimetic β-Ketopolyene Thioesters and Demonstration of Their Usefulness in Enzymatic Biosynthesis Studies

et al. 2020

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“…[52] More recently, studies have utilized the inherent stereochemical control of two KR domains (TylKR2 and MycKR6) to generate stereopure linear triketide carboxylic acids (Fig- ure 4B). [53] Additionally, a library of 51 KR enzymes was recently used to provide stereo-enriched pools of pharmaceutically relevant secondary alcohols from ketone substrates also containing halides, esters, and aryl moieties, effectively providing a robust platform to obtain useful building blocks in gramscale quantities. [54] While significant optimization is still required to improve yields in vivo, chemoenzymatic synthesis affords highly stereo-enriched products with the potential to be used as building blocks in future critical advances in the fields of synthetic methodology and chemical biology with potential applications in medicinal chemistry and drug development.…”

Section: Stereoselective Biosynthesis Of Building Blocks For Chemical...mentioning

confidence: 99%

Current State‐of‐the‐Art Toward Chemoenzymatic Synthesis of Polyketide Natural Products

Paulsel,

Williams

2023

ChemBioChem

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Polyketide natural products have significant promise as pharmaceutical targets for human health and as molecular tools to probe disease and complex biological systems. While the biosynthetic logic of polyketide synthases (PKS) is well‐understood, biosynthesis of designer polyketides remains challenging due to several bottlenecks, including substrate specificity constraints, disrupted protein‐protein interactions, and protein solubility and folding issues. Focusing on substrate specificity, PKSs are typically interrogated using synthetic thioesters. PKS assembly lines and their products offer a wealth of information when studied in a chemoenzymatic fashion. This review provides an overview of the past two decades of polyketide chemoenzymatic synthesis and their contributions to the field of chemical biology. These synthetic strategies have successfully yielded natural product derivatives while providing critical insights into enzymatic promiscuity and mechanistic activity.

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Enzyme- and Chemo-enzyme-Catalyzed Stereodivergent Synthesis

Ding

Huang

et al. 2022

Pharmaceutical Fronts

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Multiple stereoisomers can be found when a substance contains chiral carbons in its chemical structure. To obtain the desired stereoisomers, asymmetric synthesis was proposed in the 1970s and developed rapidly at the beginning of this century. Stereodivergent synthesis, an extension of asymmetric synthesis in organic synthesis with the hope to produce all stereoisomers of chiral substances in high conversion and selectivity, enriches the variety of available products and serves as a reference suggestion for the synthesis of their derivatives and other compounds. Since biocatalysis has outstanding advantages of economy, environmental friendliness, high efficiency, and reaction at mild conditions, the biocatalytic reaction is regarded as an efficient strategy to perform stereodivergent synthesis. Thus, in this review, we summarize the stereodivergent synthesis catalyzed by enzymes or chemo-enzymes in cases where a compound contains two or three chiral carbons, i.e., at most four or eight stereoisomers are present. The types of reactions, including reduction of substituent ketones, cyclization reactions, olefin addition, and nonredox transesterification reactions, are also discussed for the understanding of the progress and application of biocatalysis in stereodivergent synthesis.

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General chemoenzymatic route to two-stereocenter triketides employing assembly line ketoreductases

Abstract: Ketoreductases from polyketide assembly lines retain stereocontrol in a general chemoenzymatic route to two-stereocenter triketides.

Cited by 3 publications

References 32 publications

Step-Economic Synthesis of Biomimetic β-Ketopolyene Thioesters and Demonstration of Their Usefulness in Enzymatic Biosynthesis Studies

Step-Economic Synthesis of Biomimetic β-Ketopolyene Thioesters and Demonstration of Their Usefulness in Enzymatic Biosynthesis Studies

Current State‐of‐the‐Art Toward Chemoenzymatic Synthesis of Polyketide Natural Products

Enzyme- and Chemo-enzyme-Catalyzed Stereodivergent Synthesis

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