An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid

Rutherford, Trevor J.; Gupta, Deepti; Veprintsev, Dmitry B.; Saxty, Barbara; Freund, Stefan; Bienz, Mariann

doi:10.1038/ncomms1680

Cited by 109 publications

(138 citation statements)

References 53 publications

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“…(B) The biosynthesis of tanshinone and carnosic acid begins with the cyclization of GGPP (12) by a class II diTPS to produce (+) copalyl diphosphate (CPP) (13), which is in turn converted to miltiradiene (14) by a class I diTPS. Spontaneous oxidation of 14 gives rise to abietatriene (15), which is oxidized to ferruginol (16) by a CYP enzyme. However, uncharacterized subsequent events lead to carnosic acid (1) and tanshinones (2-4).…”

Section: Resultsmentioning

confidence: 99%

“…Carnosic acid (1) and carnosol (8) are potent antioxidant (13), antiadipogenic (14), and anticancer agents (15,16), whereas several carnosic-acid-related diterpenes, such as 12-methoxy-carnosic acid (9) and pisiferic acid (7; Fig. 1A) have strong antiparasitic, antifungal, and antibacterial activities (17)(18)(19).…”

mentioning

confidence: 99%

“…Subsequent decoration of the various skeletons by modifying enzymes, such as cytochrome P450s (CYPs) (27), gives rise to a plethora of secondary metabolites (28,29). In Rosmarinus officinalis and Salvia fruticosa, carnosic acid and carnosol are synthesized from (+)-copalyl diphosphate (CPP; 13) through the intermediates miltiradiene (14), abietatriene (15), and ferruginol (16) (Fig. 1B) (30)(31)(32).…”

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confidence: 99%

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Carnosic acid biosynthesis elucidated by a synthetic biology platform

Ignea

Athanasakoglou

Iοannou

et al. 2016

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

142

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Synthetic biology approaches achieving the reconstruction of specific plant natural product biosynthetic pathways in dedicated microbial “chassis” have provided access to important industrial compounds (e.g., artemisinin, resveratrol, vanillin). However, the potential of such production systems to facilitate elucidation of plant biosynthetic pathways has been underexplored. Here we report on the application of a modular terpene production platform in the characterization of the biosynthetic pathway leading to the potent antioxidant carnosic acid and related diterpenes in Salvia pomifera and Rosmarinus officinalis. Four cytochrome P450 enzymes are identified (CYP76AH24, CYP71BE52, CYP76AK6, and CYP76AK8), the combined activities of which account for all of the oxidation events leading to the biosynthesis of the major diterpenes produced in these plants. This approach develops yeast as an efficient tool to harness the biotechnological potential of the numerous sequencing datasets that are increasingly becoming available through transcriptomic or genomic studies.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Carnosic acid biosynthesis elucidated by a synthetic biology platform

Ignea

Athanasakoglou

Iοannou

et al. 2016

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

142

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“…The potential sites of other molecules intervention in the Wnt signaling pathway are shown schematically in Figure 1. LL3 may inhibit a similar axis to small molecule compounds PKF 115-854 and CGP049090, 25 in disrupting the b-catenin/TCF complex, or as carnosic acid inhibiting the interaction of b-catenin and Bcl -9, 21 or alternatively present a novel inhibitory axis between b-catenin and Pontin52. blot.…”

Section: Discussionmentioning

confidence: 99%

“…19 Mutations that over-activate the transcription of Wnt/b-catenin target genes are completely dependent on transcriptionally active nuclear b-catenin, hence disrupting the transcriptional activity of b-catenin is of great therapeutic interest. A number of previous studies have identified small molecule [20][21][22][23][24][25][26][27] and conventional antibody 28 inhibitors of the Wnt signaling pathway, shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Functional inhibition of β-catenin-mediatedWnt signaling by intracellular VHHantibodies

Newnham¹,

Wright²,

Holdsworth³

et al. 2015

mAbs

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(2015) Functional inhibition of β-catenin-mediatedWnt signaling by intracellular VHHantibodies, mAbs, 7:1, 180-191, DOI: 10.4161/19420862.2015.989023 To link to this article: https://doi.org/10. 4161/19420862.2015 The Wnt signaling pathway is of central importance in embryogenesis, development and adult tissue homeostasis, and dysregulation of this pathway is associated with cancer and other diseases. Despite the developmental and potential therapeutic significance of this pathway, many aspects of Wnt signaling, including the control of the master transcriptional co-activator b-catenin, remain poorly understood. In order to explore this aspect, a diverse immune llama VHH phagemid library was constructed and panned against b-catenin. VHH antibody fragments from the library were expressed intracellularly, and a number of antibodies were shown to possess function-modifying intracellular activity in a luciferase-based Wnt signaling HEK293 reporter bioassay. Further characterization of one such VHH (named LL3) confirmed that it bound endogenous b-catenin, and that it inhibited the Wnt signaling pathway downstream of the destruction complex, while production of a control Ala-substituted complementarity-determining region (CDR)3 mutant demonstrated that the inhibition of b-catenin activity by the parent intracellular antibody was dependent on the specific CDR sequence of the antibody.

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Role of the Wnt Signalling Pathway in Cancer

Baskir

Hansen

Lee

2016

Encyclopedia of Life Sciences

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Canonical Wnt/β‐catenin signalling is a highly conserved pathway that plays an essential role during embryonic development. In the adult, the Wnt pathway regulates stem cell maintenance and tissue homeostasis. Inappropriate activation of the Wnt signalling pathway has been implicated in a variety of cancers, most notably in colorectal cancer. Wnt signalling alterations in cancer have been identified at various levels of the pathway: at the membrane, in the cytoplasm and within the nucleus. Given that Wnt signalling plays a critical role in many human cancers, intense investigation has focused on targeting this pathway to develop potential therapeutics for cancer therapy. Key Concepts Wnt signalling is a highly conserved pathway in development. A key role of the Wnt signalling pathway involves the maintenance of stem cell renewal. Somatic mutations in the Wnt pathway components are commonly found in cancer, including over 90% of colorectal cancers. Wnt pathway activation leads to inhibition of the β‐catenin destruction complex consisting of APC, Axin, CK1α and GSK3. Mutations in the tumour suppressor, adenomatous polyposis coli (APC), lead to Wnt pathway activation. Syndromes caused by germline mutations in Wnt pathway genes include familial adenomatous polyposis (FAP), which results in early polyp development and subsequent colorectal cancer. Wnt pathway drugs have been developed to target receptor activation, β‐catenin degradation and nuclear activation, though currently none of these drugs are FDA approved for patient use.

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An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid

Cited by 109 publications

References 53 publications

Carnosic acid biosynthesis elucidated by a synthetic biology platform

Carnosic acid biosynthesis elucidated by a synthetic biology platform

Functional inhibition of β-catenin-mediatedWnt signaling by intracellular VHHantibodies

Role of the Wnt Signalling Pathway in Cancer

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