Pathway and Enzyme Engineering and Applications for Glycodiversification

Zhao, Lishan; Liu, Hung Wen

doi:10.1002/9780470627303.ch10

Cited by 2 publications

(4 citation statements)

References 206 publications

(190 reference statements)

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“…Enzymes, however, catalyze site-specific and stereoselective chemistries in water—often within a microorganism. Numerous enzyme-mediated chemical functionalizations of natural products are known, including scaffold alkylation 14 – 16 , acylation 17 , oxidation 18 , 19 , glycosylation 4 , 20 , and halogenation 21 . Here we focus the discussion of enzyme-tailored scaffold derivatization on the mature cases of natural product tailoring by cytochrome P450 oxidases (P450s or CYPs) and GTs.…”

Section: Engineering Small Molecule Discovery Platforms: Derivatizatimentioning

confidence: 99%

“…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%

“…Metabolic engineering strategies for in vivo combinatorial glyco-derivatization of secondary metabolites have also demonstrated success by combining heterologous saccharide biosynthesis genes into non-natural pathways. In 1998, Madduri et al demonstrated the fermentation of the antitumor drug epirubicin ( Figure 1 ) in Streptomyces peucetius and sparked intense interest in the role of metabolic engineering and combinatorial biosynthesis for the discovery and production of glyco-pharmaceuticals 20 , 41 – 44 . These efforts have begun to impact glyco-engineering in more common microbial hosts, such as an in vivo small molecule “glyco-randomization” study in E. coli by Thorson and co-workers 4 or the variable derivatization of erythromycin by Pfeifer and co-workers 45 ; however, much success for in vivo glyco-derivatization remains in Streptomyces 4 , 41 , 46 – 48 .…”

Section: Engineering Small Molecule Discovery Platforms: Derivatizatimentioning

confidence: 99%

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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%

Section: Engineering Small Molecule Discovery Platforms: Derivatizatimentioning

confidence: 99%

Section: Engineering Small Molecule Discovery Platforms: Derivatizatimentioning

confidence: 99%

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Accessing Nature’s diversity through metabolic engineering and synthetic biology

et al. 2016

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“…Thus, both C-GTs showed strong selectivity for sugar moieties and regiospecifically attached sugar moieties to the different carbon atoms in the angucycline ring of kidamycin. This study provides a basis how enzymatically generates unusual sugars attached angucycline compounds and has paved the way for alteration of these glycosylated compounds via pathway or enzyme engineering ( Blanchard and Thorson, 2006 ; Zhao and Liu, 2010 ; He et al, 2019 ). Streptomyces sp.…”

Section: Discussionmentioning

confidence: 99%

Elucidation of the di-c-glycosylation steps during biosynthesis of the antitumor antibiotic, kidamycin

Heo

Lee

Jang

et al. 2022

Front. Bioeng. Biotechnol.

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Kidamycins belong to the pluramycin family of antitumor antibiotics that contain di-C-glycosylated angucycline. Owing to its interesting biological activity, several synthetic derivatives of kidamycins are currently being developed. However, the synthesis of these complex structural compounds with unusual C-glycosylated residues is difficult. In the kidamycin-producing Streptomyces sp. W2061 strain, the genes encoding the biosynthetic enzymes responsible for the structural features of kidamycin were identified. Two glycosyltransferase-coding genes, kid7 and kid21, were found in the kidamycin biosynthetic gene cluster (BGC). Gene inactivation studies revealed that the subsequent glycosylation steps occurred in a sequential manner, in which Kid7 first attached N,N-dimethylvancosamine to the C10 position of angucycline aglycone, following which Kid21 transferred an anglosamine moiety to C8 of the C10-glycosylated angucycline. Therefore, this is the first report to reveal the sequential biosynthetic steps of the unique C-glycosylated amino-deoxyhexoses of kidamycin. Additionally, we confirmed that all three methyltransferases (Kid4, Kid9, and Kid24) present in this BGC were involved in the biosynthesis of these amino-deoxyhexoses, N,N-dimethylvancosamine and anglosamine. Aglycone compounds and the mono-C-glycosylated compound obtained in this process will be used as substrates for the development of synthetic derivatives in the future.

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Pathway and Enzyme Engineering and Applications for Glycodiversification

Cited by 2 publications

References 206 publications

Accessing Nature’s diversity through metabolic engineering and synthetic biology

Accessing Nature’s diversity through metabolic engineering and synthetic biology

Elucidation of the di-c-glycosylation steps during biosynthesis of the antitumor antibiotic, kidamycin

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