A polyketoacyl-CoA thiolase-dependent pathway for the synthesis of polyketide backbones

Tan, Zhongyang; Clomburg, James M.; Cheong, Seokjung; Qian, Shuai; González, Ramón

doi:10.1038/s41929-020-0471-8

Cited by 40 publications

(55 citation statements)

References 49 publications

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“…Diversifying substrates for primer and extender units or transferring rBOX into a different organism often requires extensive enzyme and metabolic flux optimization. Recent studies show that substrate specificity and activity of rBOX pathway enzymes can be expanded and optimized via bioprospecting (Mehrer et al, 2018 ; Tan et al, 2020 ; Wang et al, 2021 ) and protein engineering (Blaisse et al, 2018 ; Clomburg et al, 2018 ). Incorporating the rBOX pathway in non-model organisms, such as Clostridium , is more challenging than in common industrial hosts, such as E. coli, S. cerevisiae , and C. glutamicum .…”

Section: Interfacing Rbox With Various Metabolic Pathways and Its Dep...mentioning

confidence: 99%

“…Utilizing elements of the rBOX pathway in a novel way was explored by Tan et al ( 2020 ) for production of polyketide backbones (Tan et al, 2020 ) (Fig. 4 ).…”

Section: Products Of Rbox As Building Blocks For Downstream Pathwaysmentioning

confidence: 99%

“…This expanded functionality makes rBOX capable of synthesizing a wide range of products, such as α,ω-dicarboxylic acids and diols, ω-hydroxyacids and other functionalized fatty acid derivatives, β-hydroxy-ω-lactones, methyl alcohols, and others (Cheong et al, 2016 ). Furthermore, elements of the rBOX carbon chain elongation pathway can be combined with other biochemistries to create new synthetic pathways for the efficient production of more complex molecules such as polyketides (Tan et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Reverse β-oxidation pathways for efficient chemical production

Tarasava

Lee

Chen

et al. 2022

Journal of Industrial Microbiology and Biotechnology

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Microbial production of fuels, chemicals and materials has the potential to reduce greenhouse gas emissions and contribute to a sustainable bioeconomy. While synthetic biology allows readjusting of native metabolic pathways for the synthesis of desired products, often these native pathways do not support maximum efficiency and are affected by complex regulatory mechanisms. A synthetic or engineered pathway that allows modular synthesis of versatile bioproducts with minimal enzyme requirement and regulation while achieving high carbon and energy efficiency could be an alternative solution to address these issues. The reverse b-oxidation (rBOX) pathways enable iterative non-decarboxylative elongation of carbon molecules of varying chain lengths and functional groups with only four core enzymes and no ATP requirement. Here we describe recent developments in rBOX pathway engineering to produce alcohols and carboxylic acids with diverse functional groups, along with other commercially important molecules such as polyketides. We discuss the application of rBOX beyond the pathway itself by its interfacing with various carbon-utilization pathways and deployment in different organisms, which allows feedstock diversification from sugars to glycerol, carbon dioxide, methane and other substrates.

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Section: Interfacing Rbox With Various Metabolic Pathways and Its Dep...mentioning

confidence: 99%

“…Utilizing elements of the rBOX pathway in a novel way was explored by Tan et al ( 2020 ) for production of polyketide backbones (Tan et al, 2020 ) (Fig. 4 ).…”

Section: Products Of Rbox As Building Blocks For Downstream Pathwaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reverse β-oxidation pathways for efficient chemical production

Tarasava

Lee

Chen

et al. 2022

Journal of Industrial Microbiology and Biotechnology

Self Cite

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“…PKs are a natural class of secondary metabolites synthesized by PKSs. To date, more than 10 thousand PK-type compounds are identified from bacteria, fungi, plants, and animals, of which at least 20 were developed as commercial drugs including erythromycin, tetracycline, and lovastatin [77]. The genes encoding PKSs were identified in 1993 during genome sequencing of B. subtilis 168.…”

Section: Antibacterial Pks Synthesized By B Velezensismentioning

confidence: 99%

Antimicrobial Activities of Lipopeptides and Polyketides of Bacillus velezensis for Agricultural Applications

2020

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Since the discovery of penicillin, bacteria are known to be major sources of secondary metabolites that can function as drugs or pesticides. Scientists worldwide attempted to isolate novel compounds from microorganisms; however, only less than 1% of all existing microorganisms have been successfully identified or characterized till now. Despite the limitations and gaps in knowledge, in recent years, many Bacillus velezensis isolates were identified to harbor a large number of biosynthetic gene clusters encoding gene products for the production of secondary metabolites. These chemically diverse bioactive metabolites could serve as a repository for novel drug discovery. More specifically, current projects on whole-genome sequencing of B. velezensis identified a large number of biosynthetic gene clusters that encode enzymes for the synthesis of numerous antimicrobial compounds, including lipopeptides and polyketides; nevertheless, their biological applications are yet to be identified or established. In this review, we discuss the recent research on synthesis of bioactive compounds by B. velezensis and related Bacillus species, their chemical structures, bioactive gene clusters of interest, as well as their biological applications for effective plant disease management.

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“…According toJørgensen et al (2014), there were seven genes identified near PKS14, amongst which one gene encoded for a carboxylase, enzyme likely to catalyze conversion of orsellinic acid to orcinol. Since, polyketides including orcinol can be biosynthesized by iterative decarboxylative Claisen condensation in the presence of polyketide synthases (PKS), an alternate synthesis strategy was proposed where polyketide backbone could be synthesized by non-decarboxylative Claisen condensation in the presence of polyketoacyl-CoA thiolases (PKTs)(Tan et al, 2020).…”

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confidence: 99%

Bioactive polysaccharides and small molecules from the native North American fungus Echinodontium tinctorium

Zeb¹

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Mushrooms, the fruiting bodies of fungi, are known to be powerful sources of nutraceuticals and pharmaceuticals but there are limited studies focusing on exploring the medicinal value of mushrooms native to North America. Here, I describe the isolation of two novel bioactive polysaccharides from the aqueous extracts of the fungus Echinodontium tinctorium: an immunostimulatory complex polysaccharide (EtISPFa) of 1354 kDa, and a growth-inhibitory β-glucan of 275 kDa. In addition, six small molecules including a phenol derivative, a new diphenylmethane derivative and three lanostane-type triterpenes were isolated from the organic extracts of E. tinctorium. The molar mass of these isolated small molecules (labelled 1-6) was determined to be 124, 260, 506, 498, 496, and 440 g/mol respectively.Phase separation, Sephadex LH-20 size exclusion, Sephadex DEAE ion exchange chromatography, Sephacryl S-500 HR size exclusion, silica column chromatography, and HPLC were used for bioactivity-guided purification. Chemical structures and linkages of EtISPFa and EtGIPL1a polysaccharides were determined by gas chromatography mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR). Final structures of small molecules were determined by Fourier transform infrared spectroscopy (FTIR), electrospray ionization mass spectrometry (ESI-MS), NMR, and X-ray crystallography.Immuno-stimulatory activity of EtISPFa was assessed by immunoassay in Raw 264.7 murine macrophage cells and growth-inhibitory activity of EtGIPL1a and small molecules were assessed by MTT growth-inhibitory assay in cancer cell lines. The mechanism of growth inhibition was assessed via apoptosis and cell cycle assays. EtISPFa stimulated the immune response by inducing TNF-α and other inflammatory cytokines in murine macrophage cells. In contrast, EtGIPL1a showed promising anti-proliferative activity against U251 glioblastoma cells and on iii ten other cancer cell lines. EtGIPL1a induced apoptosis in U251 cells with an increased cleaved caspase-3 apoptotic marker and significant DNA fragmentation in cell cycle analysis. Amongst the small molecules, compounds (2), (4) and (5) caused growth-inhibition in U251 cells; compound (4) also showed promising effects on multiple other cancer cell lines; all its bioactivities are reported here for the first time. The crystal structures of compounds (2), (4) and(5) have also been reported for the first time. Molecular targets of (1), ( 2), (4) and (5) by MolTarPred were predicted and warrants further experimental investigation. iv PREFACE This current PhD dissertation has yielded two manuscripts where Chapter 1 and Chapter 2 have been published as:

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A polyketoacyl-CoA thiolase-dependent pathway for the synthesis of polyketide backbones

Cited by 40 publications

References 49 publications

Reverse β-oxidation pathways for efficient chemical production

Reverse β-oxidation pathways for efficient chemical production

Antimicrobial Activities of Lipopeptides and Polyketides of Bacillus velezensis for Agricultural Applications

Bioactive polysaccharides and small molecules from the native North American fungus Echinodontium tinctorium

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