Synthesis of unnatural alkaloid scaffolds by exploiting plant polyketide synthase

Morita, Hiroyuki; Yamashita, Makoto; Shi, She‐Po; Wakimoto, Toshiyuki; Kondo, Satoshi; Kato, Ryohei; Sugio, Shigetoshi; Kohno, Toshiyuki; Abe, Ikuro

doi:10.1073/pnas.1107782108

Cited by 65 publications

(44 citation statements)

References 42 publications

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“…11A), whereas the S348G mutant takes three units of the extender units, yielding a biologically active alkaloid, 1,3-dihydroxy-5H-dibenzo[b,e]azepine-6,11-dioine (Fig. 11B) (48). An earlier research also reported the biosynthesis of 4-hydroxy-2(1H)-quinolones, a novel alkaloidal scaffold, by the BAS from R. palmatum with N-methylanthraniloyl-CoA and anthraniloyl-CoA as the starter units (49).…”

Section: Biosynthesis Of Novel Molecules By Type III Pkss Through Prementioning

confidence: 99%

Type III polyketide synthases in natural product biosynthesis

et al. 2012

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SummaryPolyketides represent an important class of biologically active and structurally diverse compounds in nature. They are synthesized from acyl-coenzyme A substrates by polyketide synthases (PKSs). PKSs are classified into three groups: types I, II, and III. This article introduces recent studies on type III PKSs identified from plants, bacteria, and fungi, and describes the catalytic functions of these enzymes in detail. Plant type III PKSs have been widely studied, as exemplified by chalcone synthase, which plays an important role in the synthesis of plant metabolites. Bacterial type III PKSs fall into five groups, many of which were identified from Streptomyces, a genus that has been well known for its production of bioactive molecules and genetic alterability. Although it was believed that type III PKSs exist exclusively in plants and bacteria, recent fungal genome sequencing projects and biochemical studies revealed the presence of type III PKSs in filamentous fungi, which provides a new chance to study fungal secondary metabolism and synthesize ''unnatural'' natural products. Type III PKSs have been used for the biosynthesis of novel molecules through precursordirected and structure-based mutagenesis approaches.2012 IUBMB IUBMB Life, 64(4): [285][286][287][288][289][290][291][292][293][294][295] 2012

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Section: Biosynthesis Of Novel Molecules By Type III Pkss Through Prementioning

confidence: 99%

Type III polyketide synthases in natural product biosynthesis

et al. 2012

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“…We selected a type III polyketide synthase HsPKS1 from the plant Huperzia serrata to assemble polyketide backbones using malonyl-CoA extender units. HsPKS1 is able to accept a variety of starter units including aromatic and aliphatic (C 6 -C 10 ) CoA thioesters 29 , suggesting that the recognition of the 5-hexynoyl starter unit would be likely. Two plasmids encoding jamABC and hspks1, with each gene regulated by a T7 promoter, were transformed into the E. coli BAP1 strain 30 yielding the strain XZ1 (Supplementary Fig.…”

Section: Engineered Biosynthesis Of Alkyne-tagged Natural Productsmentioning

confidence: 99%

De novo biosynthesis of terminal alkyne-labeled natural products

2014

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Abstract:The terminal alkyne is a functionality widely used in organic synthesis, pharmaceutical science, material science, and bioorthogonal chemistry. This functionality is also found in acetylenic natural products, but the underlying biosynthetic pathways for its formation are not well understood. Here we report the characterization of the first carrier proteindependent terminal alkyne biosynthetic machinery in microbes. We further demonstrate that this enzymatic machinery can be exploited for the in situ generation and incorporation of terminal alkynes into two natural product scaffolds in E. coli. These results highlight the prospect for tagging major classes of natural products, including polyketides and polyketide/non-ribosomal peptide hybrids, using biosynthetic pathway engineering.2 Natural products are important small molecules widely used as drugs, pesticides, herbicides, and biological probes. Tagging natural products with a unique chemical handle enables the visualization, enrichment, quantification, and mode of action study of natural products through bioorthogonal chemistry [1][2][3][4] . One prevalent bioorthogonal reaction is the triazole-forming azide-alkyne [3+2] cycloaddition, often referred to as "click" chemistry 5 . This reaction has enabled selective imaging and study of azide-or alkyne-labeled glycans, proteins, nucleic acids and lipids. Despite the success with macromolecules, the labeling of natural products has not been adequately explored. It is often challenging to obtain tagged natural products through total synthesis because of their structural complexity, or through semi-synthesis because of their chemical lability and the limited supply of most natural products. Alternatively, precursor-directed biosynthesis (PDB) may be employed to produce azide-or alkyne-labeled natural products based on the promiscuity of biosynthetic machinery. Mainly used as a tool to introduce structural diversity, PDB has allowed us and other researchers to generate labeled natural products 3,[6][7][8] . However, the coexistence of diffusible precursors and final products 9 with the same chemical handle introduces significant background in the PDB production system, making it incompatible with in situ bioorthogonal chemical transformations. We report here the de novo biosynthesis of alkyne-labeled natural products without the feeding of alkynoic precursors by characterizing and engineering the novel terminal alkyne synthetic machinery that living systems offer.Many acetylenic natural products contain a terminal alkyne functionality, which seems to be crucial for their bioactivity (Fig. 1) 10,11 . Terminal alkynes can be formed by acetylenases, a special family of desaturases that catalyze O 2 -dependent dehydrogenation of C-C bonds in a diiron dependent mechanism 12 . Several membrane-bound acetylenases have recently been 3 identified from plants, insects, fungi, and bacteria 4,10,[13][14][15][16][17] , but all of these reports have been limited to bioinformatics or in vivo studies through mutagenesis or ...

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“…Simultaneous mutation of the neighbouring Phe66 residue to leucine resulted in an OKS double mutant that is capable of synthesizing an unnatural dodecaketide naphthophenone TW95a (70) by the successive decarboxylative condensations of 12 units of malonyl-CoA, making it one of the longest polyketide synthesized by the structurally simple type III PKS (Scheme 24C) [104]. A recently discovered CHS from a primitive club moss Huperzia serrata (HsPKS1) was found to display unusually broad substrate selectivity and produced unnatural polyketide-alkaloid hybrid molecules [105]. Using precursor-directed approaches, HsPKS1 synthesized a novel pyridoisoindole (74) from the condensation of 2-carbamoylbenzoyl-CoA (71), a synthetic nitrogen-containing non-physiological starter, with two units of malonyl-CoA (Scheme 25A).…”

Section: Structure-based Engineering and The Versatility Of Type III mentioning

confidence: 99%

“…The structure-based S348G mutant (corresponding to Ser338 in alfalfa CHS) results in an expansion of the active site cavity which not only extended the polyketide chain length, but also altered the cyclization mechanism to yield a biologically active, ring-expanded dibenzoazepine (75) from the condensation of 2-carbamoylbenzoyl-CoA with three units of malonyl-CoA (Scheme 25B). A recently discovered CHS from a primitive club moss Huperzia serrata (HsPKS1) was found to display unusually broad substrate selectivity and produced unnatural polyketide-alkaloid hybrid molecules [105]. Using precursor-directed approaches, HsPKS1 synthesized a novel pyridoisoindole (74) from the condensation of 2-carbamoylbenzoyl-CoA (71), a synthetic nitrogen-containing nonphysiological starter, with two units of malonyl-CoA (Scheme 25A).…”

Section: Structure-based Engineering and The Versatility Of Type III mentioning

confidence: 99%

Exploiting the Biosynthetic Potential of Type III Polyketide Synthases

Lim

Yew

2016

Molecules

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Abstract:Polyketides are structurally and functionally diverse secondary metabolites that are biosynthesized by polyketide synthases (PKSs) using acyl-CoA precursors. Recent studies in the engineering and structural characterization of PKSs have facilitated the use of target enzymes as biocatalysts to produce novel functionally optimized polyketides. These compounds may serve as potential drug leads. This review summarizes the insights gained from research on type III PKSs, from the discovery of chalcone synthase in plants to novel PKSs in bacteria and fungi. To date, at least 15 families of type III PKSs have been characterized, highlighting the utility of PKSs in the development of natural product libraries for therapeutic development.

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Synthesis of unnatural alkaloid scaffolds by exploiting plant polyketide synthase

Cited by 65 publications

References 42 publications

Type III polyketide synthases in natural product biosynthesis

Type III polyketide synthases in natural product biosynthesis

De novo biosynthesis of terminal alkyne-labeled natural products

Exploiting the Biosynthetic Potential of Type III Polyketide Synthases

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