4-hydroxy-2-pyrone formation by chalcone and stilbene synthase with nonphysiological substrates

Zuurbier, Karin W.M.; Leser, Jürgen; Berger, Thorsten; Hofte, A.J.P.; Schröder, G.; Verpoorte, Robert; Schröder, Joachim

doi:10.1016/s0031-9422(98)00346-x

Cited by 56 publications

(37 citation statements)

References 15 publications

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“…This observation indicates that the conformation of the tetraketide intermediate differs from that found in either the CHS or ACS active site. Recent experiments demonstrate that mutations of residues lining the active site cavity or use of unnatural starter molecules result in production of polyketide lactones by type III PKS (7,(16)(17)(18)30). Because the overall three-dimensional folds of CHS and the F215S mutant are identical, the structural differences between the N-methylanthraniloyl-and the pcoumaroyl-moieties of the tetraketide likely alter how the starter molecule fits within the active site.…”

Section: Discussionmentioning

confidence: 99%

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Expanding the biosynthetic repertoire of plant type III polyketide synthases by altering starter molecule specificity

Jez

Bowman

Noel

2002

Proc. Natl. Acad. Sci. U.S.A.

130

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Type III polyketide synthases (PKS) generate an array of natural products by condensing multiple acetyl units derived from malonyl-CoA to thioester-linked starter molecules covalently bound in the PKS active site. One strategy adopted by Nature for increasing the functional diversity of these biosynthetic enzymes involves modifying polyketide assembly by altering the preference for starter molecules. Chalcone synthase (CHS) is a ubiquitous plant PKS and the first type III PKS described functionally and structurally. Guided by the three-dimensional structure of CHS, Phe-215 and Phe-265, which are situated at the active site entrance, were targeted for site-directed mutagenesis to diversify CHS activity. The resulting mutants were screened against a panel of aliphatic and aromatic CoA-linked starter molecules to evaluate the degree of starter molecule specificity in CHS. Although wild-type CHS accepts a number of natural CoA thioesters, it does not use N-methylanthraniloyl-CoA as a substrate. Substitution of Phe-215 by serine yields a CHS mutant that preferentially accepts this CoA-thioester substrate to generate a novel alkaloid, namely N-methylanthraniloyltriacetic acid lactone. These results demonstrate that a point mutation in CHS dramatically shifts the molecular selectivity of this enzyme. This structure-based approach to metabolic redesign represents an initial step toward tailoring the biosynthetic activity of plant type III PKS.

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Section: Discussionmentioning

confidence: 99%

“…In vitro, CHS accepts disparate CoA starter molecules, including aromatic and aliphatic CoA-thioesters of different lengths (14)(15)(16)(17)(18). A tunnel extending from the exterior of CHS to an interior cavity provides access to the buried catalytic residues.…”

mentioning

confidence: 99%

Expanding the biosynthetic repertoire of plant type III polyketide synthases by altering starter molecule specificity

Jez

Bowman

Noel

2002

Proc. Natl. Acad. Sci. U.S.A.

130

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“…A mixture of prenylated, geranylated, oxidized and/or cyclized chalcones, of which 30 have been isolated to date, is secreted by the lupulin glands along with the bitter acids and volatile oils (Milligan et al, 1999;Mizobuchi and Sato, 1994;Stevens et al, 1997;Stevens et al, 1999;Stevens et al, 2000;Zuurbier et al, 1998). The chalcone xanthohumol (XH) is the most abundant prenylated flavonoid in fresh and properly preserved hops, present at a concentration of ca.…”

Section: Prenylated Flavonoidsmentioning

confidence: 99%

The pharmacognosy of Humulus lupulus L. (hops) with an emphasis on estrogenic properties

2006

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SummaryAs the population ages, there is an ever-increasing need for therapeutic agents that can be used safely and efficaciously to manage symptoms related to postmenopausal estrogen deficiency. Endogenous estrogens, e.g., 17β-estradiol, of exogenous mammalian origin, e.g., horses, have long been used to manage such symptoms. There are more than twenty different classes of phytochemicals that have demonstrated affinity for human estrogen receptors in vitro. Some studies on exogenous estrogenic substances of botanical origin ("phytoestrogens"), such as standardized formulations of plant extracts with in vitro and in vivo estrogenic activity from soy (Glycine max Merill.) and red clover (Trifolium pratense L.), suggest clinical efficacy. Few clinical data for phytoestrogens other than isoflavonoids are available. In an exhaustive review of the literature through 2003, only two clinical trials were identified that were designed to evaluate the effect of hops (Humulus lupulus L.) on symptoms related to manopause. Folkloric, chemical, and biological literature relating primarily to the use of hops for their estrogenic activity, and two human clinical trials, are reviewed.

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“…Judging from the fact that CTAL or its derivatives have not been reported from any plant sources other than H. macrophylla, it seems that CTAL is a common by-product of all CHSs and STSs but its production is limited to in vitro reactions. Recently, CHS and STS have been shown to produce 4-hydroxy-2-pyrone derivatives in vitro with the nonphysiological substrates, isovaleryl-CoA and isobutyryl-CoA [18].…”

Section: P-coumaroyltriacetic Acid Synthasementioning

confidence: 99%

p‐Coumaroyltriacetic acid synthase, a new homologue of chalcone synthase, from Hydrangea macrophylla var. thunbergii

Akiyama

Shibuya

Liu

et al. 1999

European Journal of Biochemistry

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Chalcone synthase and stilbene synthase are plant-specific polyketide synthases. They catalyze three common consecutive decarboxylative condensations and specific cyclization reactions. They are highly homologous to each other, and are likely to fall into a family of polyketide synthases along with acridone synthase and bibenzyl synthase. Two cDNA clones (named HmC and HmS), both of which show high homology to the known chalcone synthases, were obtained from leaves of Hydrangea macrophylla var. thunbergii. They were expressed in Escherichia coli in order to determine their enzyme functions. Detection of chalcone formation clearly indicated that HmC encoded chalcone synthase, while HmS protein catalyzed the formation of neither chalcone nor stilbene. However, a novel pyrone, a lactonization product of a linear tetraketide was detected in reaction products of HmS protein. This proves that HmS encodes a novel polyketide synthase that catalyzes only chain elongation without cyclization.

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4-hydroxy-2-pyrone formation by chalcone and stilbene synthase with nonphysiological substrates

Cited by 56 publications

References 15 publications

Expanding the biosynthetic repertoire of plant type III polyketide synthases by altering starter molecule specificity

Expanding the biosynthetic repertoire of plant type III polyketide synthases by altering starter molecule specificity

The pharmacognosy of Humulus lupulus L. (hops) with an emphasis on estrogenic properties

p‐Coumaroyltriacetic acid synthase, a new homologue of chalcone synthase, from Hydrangea macrophylla var. thunbergii

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