Harnessing Sugar Biosynthesis and Glycosylation to Redesign Natural Products and to Increase Structural Diversity

Olano, Carlos; Méndez, Cármen; Salas, José A.

doi:10.1002/9781118794623.ch17

Cited by 6 publications

(4 citation statements)

References 96 publications

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“…GTs are also attracting attention in the derivatization of natural products, including polyketides, non-ribosomal peptides, and terpenoids, for the discovery of novel antimicrobial agents with tailored pharmacological properties, including augmented target recognition and improved bio-availability 4 , 20 , 34 , 35 . In this regard, dNDP-glycosides ( Figure 1 ) represent a biosynthetically viable class of saccharide donors for promiscuous and engineered GTs that exhibit substrate tolerances for both the saccharide and aglycone portions of the reaction products.…”

Section: Engineering Small Molecule Discovery Platforms: Derivatizatimentioning

confidence: 99%

Accessing Nature’s diversity through metabolic engineering and synthetic biology

et al. 2016

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In this perspective, we highlight recent examples and trends in metabolic engineering and synthetic biology that demonstrate the synthetic potential of enzyme and pathway engineering for natural product discovery. In doing so, we introduce natural paradigms of secondary metabolism whereby simple carbon substrates are combined into complex molecules through “scaffold diversification”, and subsequent “derivatization” of these scaffolds is used to synthesize distinct complex natural products. We provide examples in which modern pathway engineering efforts including combinatorial biosynthesis and biological retrosynthesis can be coupled to directed enzyme evolution and rational enzyme engineering to allow access to the “privileged” chemical space of natural products in industry-proven microbes. Finally, we forecast the potential to produce natural product-like discovery platforms in biological systems that are amenable to single-step discovery, validation, and synthesis for streamlined discovery and production of biologically active agents.

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Section: Engineering Small Molecule Discovery Platforms: Derivatizatimentioning

confidence: 99%

Accessing Nature’s diversity through metabolic engineering and synthetic biology

et al. 2016

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“…Many important therapeutic compounds, including antiparasitics, antibiotics, antifungals, and anticancer drugs, contain sugars attached to the aglycone core. One well-defined method based on the “sugar biosynthesis plasmids” 57 is to obtain the novel sugar-modified drugs, especially for those compounds with good antitumor activities but severe cytotoxic side effects. By glycosylation of a side chain structure, in some cases, the biological activity of the new compounds can be improved.…”

Section: Pathway-level Combinatorial Biosynthesismentioning

confidence: 99%

Recent advances in combinatorial biosynthesis for drug discovery

Sun

Liu

Zhao

et al. 2015

DDDT

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Because of extraordinary structural diversity and broad biological activities, natural products have played a significant role in drug discovery. These therapeutically important secondary metabolites are assembled and modified by dedicated biosynthetic pathways in their host living organisms. Traditionally, chemists have attempted to synthesize natural product analogs that are important sources of new drugs. However, the extraordinary structural complexity of natural products sometimes makes it challenging for traditional chemical synthesis, which usually involves multiple steps, harsh conditions, toxic organic solvents, and byproduct wastes. In contrast, combinatorial biosynthesis exploits substrate promiscuity and employs engineered enzymes and pathways to produce novel “unnatural” natural products, substantially expanding the structural diversity of natural products with potential pharmaceutical value. Thus, combinatorial biosynthesis provides an environmentally friendly way to produce natural product analogs. Efficient expression of the combinatorial biosynthetic pathway in genetically tractable heterologous hosts can increase the titer of the compound, eventually resulting in less expensive drugs. In this review, we will discuss three major strategies for combinatorial biosynthesis: 1) precursor-directed biosynthesis; 2) enzyme-level modification, which includes swapping of the entire domains, modules and subunits, site-specific mutagenesis, and directed evolution; 3) pathway-level recombination. Recent examples of combinatorial biosynthesis employing these strategies will also be highlighted in this review.

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“…Depending on the nature of the aglycone metabolite, UGTs are involved in a multitude of biological processes, ranging from disease resistance and plant defense to signal transduction and hormone homeostasis (Bowles et al., 2006; Gachon et al., 2005; Tiwari et al., 2016). In addition, because of the importance of glycosylation in modifying the bioactivity or pharmacokinetic parameters of hydrophobic drugs, the diverse catalytical potential of plant UGTs can be harnessed for glycoengineering in drug development (Olano et al., 2014; Unsin et al., 2013).…”

Section: Introductionmentioning

confidence: 99%

UGT76F1 glycosylates an isomer of the C7‐necic acid component of pyrrolizidine alkaloids in Arabidopsis thaliana

Chen

Chapple

et al. 2023

The Plant Journal

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Identification of unknown metabolites and their biosynthetic genes is an active research area in plant specialized metabolism. By following a gene-metabolite association from a genome-wide association study of Arabidopsis stem metabolites, we report a previously unknown metabolite, 2-hydroxy-2-(1-hydroxyethyl)pentanoic acid glucoside, and demonstrated that UGT76F1 is responsible for its production in Arabidopsis. The chemical structure of the glucoside was determined by a series of analyses, including tandem MS, acid and base hydrolysis, and NMR spectrometry. T-DNA knockout mutants of UGT76F1 are devoid of the glucoside but accumulate increased levels of the aglycone. 2-hydroxy-2-(1-hydroxyethyl)pentanoic acid is structurally related to the C7-necic acid component of lycopsamine-type pyrrolizidine alkaloids such as trachelantic acid and viridifloric acid. Feeding norvaline greatly enhances the accumulation of 2-hydroxy-2-(1-hydroxyethyl)pentanoic acid glucoside in wild-type but not the UGT76F1 knockout mutant plants, providing evidence for an orthologous C7-necic acid biosynthetic pathway in Arabidopsis despite the apparent lack of pyrrolizidine alkaloids.

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Harnessing Sugar Biosynthesis and Glycosylation to Redesign Natural Products and to Increase Structural Diversity

Cited by 6 publications

References 96 publications

Accessing Nature’s diversity through metabolic engineering and synthetic biology

Accessing Nature’s diversity through metabolic engineering and synthetic biology

Recent advances in combinatorial biosynthesis for drug discovery

UGT76F1 glycosylates an isomer of the C7‐necic acid component of pyrrolizidine alkaloids in Arabidopsis thaliana

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Harnessing Sugar Biosynthesis and Glycosylation to Redesign Natural Products and to Increase Structural Diversity

Cited by 6 publications

References 96 publications

Accessing Nature’s diversity through metabolic engineering and synthetic biology

Accessing Nature’s diversity through metabolic engineering and synthetic biology

Recent advances in combinatorial biosynthesis for&nbsp;drug discovery

UGT76F1 glycosylates an isomer of the C7‐necic acid component of pyrrolizidine alkaloids in Arabidopsis thaliana

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Recent advances in combinatorial biosynthesis for drug discovery