The Bipartisan Future of Synthetic Chemistry and Synthetic Biology

Sadler, Joanna C.

doi:10.1002/cbic.202000418

Cited by 7 publications

(3 citation statements)

References 26 publications

(37 reference statements)

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“…Synthetic chemists and biochemists alike, including protein engineers, see the opportunities that solutions to the compatibility issue offer. Herein, we discuss some of these recent technologies that each approach brings to the table; indeed, it might appear that several solutions are already in hand, at least judging from all the reviews that have even recently appeared. ,− And while this could be the case, it is important to realize that where the field is today may well be the proverbial “tip of the iceberg.” Clever solutions continue to appear on this front, as it is hard to deny the benefits to be gained: economic, time, efficiency, and especially, environmental; indeed, one could rightly wonder if there are any “downsides” to chemoenzymatic catalysis.…”

Section: Discussionmentioning

confidence: 99%

Where Chemocatalysis Meets Biocatalysis: In Water

2022

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Chemoenzymatic catalysis, by definition, involves the merging of sequential reactions using both chemocatalysis and biocatalysis, typically in a single reaction vessel. A major challenge, the solution to which, however, is associated with numerous advantages, is to run such one-pot processes in water: the majority of enzyme-catalyzed processes take place in water as Nature’s reaction medium, thus enabling a broad synthetic diversity when using water due to the option to use virtually all types of enzymes. Furthermore, water is cheap, abundantly available, and environmentally friendly, thus making it, in principle, an ideal reaction medium. On the other hand, most chemocatalysis is routinely performed today in organic solvents (which might deactivate enzymes), thus appearing to make it difficult to combine such reactions with biocatalysis toward one-pot cascades in water. Several creative approaches and solutions that enable such combinations of chemo- and biocatalysis in water to be realized and applied to synthetic problems are presented herein, reflecting the state-of-the-art in this blossoming field. Coverage has been sectioned into three parts, after introductory remarks: (1) Chapter 2 focuses on historical developments that initiated this area of research; (2) Chapter 3 describes key developments post-initial discoveries that have advanced this field; and (3) Chapter 4 highlights the latest achievements that provide attractive solutions to the main question of compatibility between biocatalysis (used predominantly in aqueous media) and chemocatalysis (that remains predominantly performed in organic solvents), both Chapters covering mainly literature from ca. 2018 to the present. Chapters 5 and 6 provide a brief overview as to where the field stands, the challenges that lie ahead, and ultimately, the prognosis looking toward the future of chemoenzymatic catalysis in organic synthesis.

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Section: Discussionmentioning

confidence: 99%

Where Chemocatalysis Meets Biocatalysis: In Water

2022

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“…Biomanufacturing provides an important means for production of biomolecules for use in medicine and numerous industrial applications. The field is likely to significantly grow in the future due to advances in synthetic biology and a shift to green chemistry (42). The commercial feasibility and success of these processes depend on product yields obtained from bioreactors.…”

Section: Discussionmentioning

confidence: 99%

Single cell mutant selection for metabolic engineering of actinomycetes

Akhgari

Baral

Koroleva

et al. 2022

Preprint

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Actinomycetes are important producers of pharmaceuticals and industrial enzymes. However, wild type strains require laborious development prior to industrial usage. Here we present a generally applicable reporter-guided metabolic engineering tool based on random mutagenesis, selective pressure, and single-cell sorting. We developed fluorescence-activated cell sorting (FACS) methodology capable of reproducibly identifying high-performing individual cells from a mutant population directly from liquid cultures. Genome-mining based drug discovery is a promising source of bioactive compounds, which is complicated by the observation that target metabolic pathways may be silent under laboratory conditions. We demonstrate our technology for drug discovery by activating a silent mutaxanthene metabolic pathway in Amycolatopsis. We apply the method for industrial strain development and increase mutaxanthene yields 9-fold to 99 mg l-1 in a second round of mutant selection. Actinomycetes are an important source of catabolic enzymes, where product yields determine industrial viability. We demonstrate 5-fold yield improvement with an industrial cholesterol oxidase ChoD producer Streptomyces lavendulae to 20.4 U g-1 in three rounds. Strain development is traditionally followed by production medium optimization, which is a time-consuming multi-parameter problem that may require hard to source ingredients. Ultra-high throughput screening allowed us to circumvent medium optimization and we identified high ChoD yield production strains directly from mutant libraries grown under preset culture conditions. In summary, the ability to screen tens of millions of mutants in a single cell format offers broad applicability for metabolic engineering of actinomycetes for activation of silent metabolic pathways and to increase yields of proteins and natural products.

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“…This has prompted researchers to explore opportunities in merging these two traditionally discrete disciplines to benefit from the best of both worlds. 4,5 Through the union of non-enzymatic catalysis and microbial metabolism, reaction sequences may be accessed that would not be possible using either technology in isolation (Fig. 1A and B).…”

Section: Introductionmentioning

confidence: 99%