Stilbenecarboxylate biosynthesis: a new function in the family of chalcone synthase-related proteins

Eckermann, Christian; Schröder, G.; Eckermann, Stefan; Strack, Dieter; Schmidt, Jürgen; Schneider, Bernd; Schröder, Joachim

doi:10.1016/s0031-9422(02)00554-x

Cited by 73 publications

(68 citation statements)

References 44 publications

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“…5). A similar insertion has been also reported for coumaroyltriacetic acid synthase 45) (or stilebenecarboxylate synthase 46) ) from Hydrangea macrophylla, which has a six-amino acid "SIDSII" insertion at the same position.…”

Section: )supporting

confidence: 70%

Engineering of Plant Polyketide Biosynthesis

Abe

2008

Chem. Pharm. Bull.

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A growing number of functionally divergent the chalcone synthase (CHS) superfamily type III polyketide synthases (PKSs) have been cloned and characterized, which include recently obtained pentaketide chromone synthase (PCS) and octaketide synthase (OKS) from aloe (Aloe arborescens). Recombinant PCS expressed in Escherichia coli catalyzes iterative condensations of five molecules of malonyl-CoA to produce a pentaketide, 5,7-dihydroxy-2-methylchromone, while OKS carries out sequential condensations of eight molecules of malonyl-CoA to yield aromatic octaketides, SEK4 and SEK4b, the longest polyketides generated by the structurally simple type III PKS. The two enzymes share 91% amino acid sequence identity, maintaining most of the active-site residues of CHS including the Cys-His-Asn catalytic triad. One of the most characteristic features is that the conserved Thr197 of CHS (numbering in Medicago sativa CHS) is uniquely replaced with Met207 in PCS and with Gly207 in OKS, respectively. Site-directed mutagenesis and X-ray crystallographic studies clearly demonstrated that the chemically inert single residue lining the active-site cavity controls the polyketide chain length and the product specificity depending on the steric bulk of the side chain. Finally, on the basis of the crystal structures of both wild-type and M207G-mutant PCS, a triple mutant PCS F80A/Y82A/M207G was constructed and shown to catalyze condensations of nine molecules of malonyl-CoA to produce a novel nonaketide naphthopyrone with a fused tricyclic ring system. Structure-based engineering of the type III PKS superfamily enzymes would thus lead to further production of chemically and structurally divergent unnatural novel polyketides.

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Section: )supporting

confidence: 70%

Engineering of Plant Polyketide Biosynthesis

Abe

2008

Chem. Pharm. Bull.

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“…ORAS is the first type III PKS that catalyzes the formation of pentaketide resorcylic acids, although there are many type III PKSs that produce tetraketide resorcinols, such as stilbene (18), stilbene carboxylic acid (19), and alkylresorcinol (12). Another unique feature of ORAS is the ability to synthesize resorcylic acids.…”

Section: Discussionmentioning

confidence: 99%

Pentaketide Resorcylic Acid Synthesis by Type III Polyketide Synthase from Neurospora crassa

Funa

Awakawa

Horinouchi

2007

Journal of Biological Chemistry

124

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Type III polyketide synthases (PKSs) are responsible for aromatic polyketide synthesis in plants and bacteria. Genome analysis of filamentous fungi has predicted the presence of fungal type III PKSs, although none have thus far been functionally characterized. In the genome of Neurospora crassa, a single open reading frame, NCU04801.1, annotated as a type III PKS was found. In this report, we demonstrate that NCU04801.1 is a novel type III PKS catalyzing the synthesis of pentaketide alkylresorcylic acids. NCU04801.1, hence named 2-oxoalkylresorcylic acid synthase (ORAS), preferred stearoyl-CoA as a starter substrate and condensed four molecules of malonyl-CoA to give a pentaketide intermediate. For ORAS to yield pentaketide alkylresorcylic acids, aldol condensation and aromatization of the intermediate, which is still attached to the enzyme, are presumably followed by hydrolysis for release of the product as a resorcylic acid. ORAS is the first type III PKS that synthesizes pentaketide resorcylic acids.Polyketides are synthesized by so-called polyketide synthases (PKSs) 2 that fall into three groups, types I to III (1). Ketosynthase, which is a pivotal domain for polyketide synthesis, catalyzes the sequential decarboxylative condensation of extender substrates by a process closely similar to fatty acid biosynthesis. In contrast to type I and II megasynthases composed of ketosynthases and accessory enzymes, type III PKSs are a dimer of ketosynthase that accomplishes a complex set of reactions, such as priming of a starter substrate, decarboxylative condensation of extender substrates, ring closure, and aromatization of the polyketide chain, in a multifunctional active site pocket (2). A growing number of type III PKSs catalyzing the synthesis of aromatic polyketides have been found from plants and bacteria, and their catalytic properties have been characterized. Chalcone synthases, the representative of type III PKSs in plants, catalyze the synthesis of naringenin chalcone, which is a common precursor of all flavonoids produced by plants (2). RppA, the first type III PKS found in bacteria, catalyzes the synthesis of 1,3,6,8-tetrahydroxynaphthalene, which is a precursor of hexahydroxyperylenequinone melanin in a bacterium, Streptomyces griseus (3).Filamentous fungi produce a vast array of polyketides such as melanins, antibiotics, and mycotoxins (4). The pathways and regulation of biosynthesis of the aromatic polyketides in filamentous fungi have been studied extensively for mycotoxins, including aflatoxin and fumonisin, produced by food spoilage fungi (5) and for melanogenesis associated with infection of plant-pathogenic fungi (6). In addition, the clinical benefit of lovastatin, a cholesterol-lowering agent, produced by Aspergillus terreus (7), promotes isolation of the biosynthetic genes for polyketides in fungi. Nevertheless, the enzyme systems for the synthesis of fungal polyketides have been confined to iterative type I PKSs, which are composed of a large multifunctional polypeptide containing discrete fu...

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“…All these residues are promising targets for site-directed mutagenesis and such studies may provide valuable insights into product specificity. Stilbenecarboxylate synthase (STCS) from another Hydrangea variety, H. macrophylla L., was found to utilize p-hydroxyphenylpropionyl-CoA as a starter and carry out three consecutive decarboxylative condensations of malonyl-CoA, followed by a C2 to C7 aldol condensation with retention of the terminal carboxyl group to form 5-hydroxylunularic acid (15) (Scheme 4) [42]. Although not much is known about the mechanism of action, the identification of this new class of type III PKS adds possibilities to direct the synthesis of new polyketides.…”

Section: Truncation Products and Chain Length Specificitymentioning

confidence: 99%

“…Derivatives of dihydrocinnamoyl-CoA possess reduced propanoid moieties and have increased conformational flexibility, giving them more advantage over their rigid counterparts in binding to a contorted coumaroyl-binding pocket in BBS. The flexibility of the tetraketide intermediate due to saturation of the propanoid moiety may also aid it to attain a folded Stilbenecarboxylate synthase (STCS) from another Hydrangea variety, H. macrophylla L., was found to utilize p-hydroxyphenylpropionyl-CoA as a starter and carry out three consecutive decarboxylative condensations of malonyl-CoA, followed by a C2 to C7 aldol condensation with retention of the terminal carboxyl group to form 5-hydroxylunularic acid (15) (Scheme 4) [42]. Although not much is known about the mechanism of action, the identification of this new class of type III PKS adds possibilities to direct the synthesis of new polyketides.…”

Section: Bibenzyl Synthasementioning

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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Stilbenecarboxylate biosynthesis: a new function in the family of chalcone synthase-related proteins

Cited by 73 publications

References 44 publications

Engineering of Plant Polyketide Biosynthesis

Engineering of Plant Polyketide Biosynthesis

Pentaketide Resorcylic Acid Synthesis by Type III Polyketide Synthase from Neurospora crassa

Exploiting the Biosynthetic Potential of Type III Polyketide Synthases

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