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Bradley S Moore - One of the best experts on this subject based on the ideXlab platform.

  • A unifying paradigm for naphthoquinone-based Meroterpenoid (bio)synthesis
    Nature Chemistry, 2017
    Co-Authors: Zachary D. Miles, Stefan Diethelm, Henry P. Pepper, David M. Huang, Jonathan H. George, Bradley S Moore
    Abstract:

    Bacterial naphthoquinone Meroterpenoid natural products defy biosynthetic logic via classical biochemical paradigms. Now, an enzyme promoted α-hydroxyketone rearrangement catalysed by vanadium-dependent haloperoxidases reveals a conserved biosynthetic reaction in this molecular class that further has inspired a concise biomimetic synthesis of naphthomevalin, a prominent member of the napyradiomycin meroterpenes. Bacterial Meroterpenoids constitute an important class of natural products with diverse biological properties and therapeutic potential. The biosynthetic logic for their production is unknown and defies explanation via classical biochemical paradigms. A large subgroup of naphthoquinone-based Meroterpenoids exhibits a substitution pattern of the polyketide-derived aromatic core that seemingly contradicts the established reactivity pattern of polyketide phenol nucleophiles and terpene diphosphate electrophiles. We report the discovery of a hitherto unprecedented enzyme-promoted α-hydroxyketone rearrangement catalysed by vanadium-dependent haloperoxidases to account for these discrepancies in the merochlorin and napyradiomycin class of Meroterpenoid antibiotics, and we demonstrate that the α-hydroxyketone rearrangement is potentially a conserved biosynthetic reaction in this molecular class. The biosynthetic α-hydroxyketone rearrangement was applied in a concise total synthesis of naphthomevalin, a prominent member of the napyradiomycin meroterpenes, and sheds further light on the mechanism of this unifying enzymatic transformation.

  • Asymmetric Alkene and Arene Halofunctionalization Reactions in Meroterpenoid Biosynthesis.
    Synlett : accounts and rapid communications in synthetic organic chemistry, 2017
    Co-Authors: Bradley S Moore
    Abstract:

    Meroterpenoid natural products are important bioactive molecules with broad distribution throughout nature. In Streptomyces bacteria, naphthoquinone-based Meroterpenoids comprise a simple yet structurally fascinating group of natural product antibiotics that are enzymatically constructed through a series of asymmetric alkene and arene halofunctionalization reactions. This account article highlights our discovery and characterization of a group of vanadium-dependent chloroperoxidase enzymes that catalyze halogen-assisted cyclization and rearrangement reactions and have inspired biomimetic syntheses of numerous Meroterpenoid natural products.

  • Asymmetric Alkene and Arene Halofunctionalization Reactions in Meroterpenoid Biosynthesis
    Synlett, 2017
    Co-Authors: Bradley S Moore
    Abstract:

    Meroterpenoid natural products are important bioactive molecules with broad distribution throughout nature. In Streptomyces bacteria, naphthoquinone-based Meroterpenoids comprise a simple yet structurally fascinating group of natural product antibiotics that are enzymatically constructed through a series of asymmetric alkene and arene halofunctionalization reactions. This account article highlights our discovery and characterization of a group of vanadium-dependent chloroperoxidase enzymes that catalyze halogen-assisted cyclization and rearrangement reactions and have inspired biomimetic syntheses of numerous Meroterpenoid natural products. 1 Introduction 2 Early Biosynthetic Insights and the Characterization of Alkene Halofunctionalization in Napyradiomycin Biosynthesis 3 Discovery of the Merochlorin Natural Products and Enzymatic Aryl Halofunctionalization 4 Discovery and Development of Unifying THN-Based Meroterpenoid Biosynthesis and Synthesis Approaches 5 Insights into Naphterpin and Marinone Biosynthesis Involving Cryptic Aryl Halofunctionalization Reactions 6 Closing Thoughts

  • Merochlorins A–D, Cyclic Meroterpenoid Antibiotics Biosynthesized in Divergent Pathways with Vanadium-Dependent Chloroperoxidases
    2016
    Co-Authors: Leonard Kaysser, Peter Bernhardt, Sangjip Nam, Sandra Loesgen, Graham J Ruby, Paul R Jensen, William Fenical, Peter Skewes-cox, Bradley S Moore
    Abstract:

    Meroterpenoids are mixed polyketide-terpenoid natural products with a broad range of biological activities. Herein, we present the structures of four new Meroterpenoid antibiotics, merochlorins A–D, produced by the marine bacterium Streptomyces sp. strain CNH-189, which possess novel chemical skeletons unrelated to known bacterial agents. Draft genome sequencing, mutagenesis, and heterologous biosynthesis in the genome-minimized model actinomycete Streptomyces coelicolor provided the 57.6 kb merochlorin gene cluster that contains two genes encoding rare bacterial vanadium-dependent haloperoxidase (VHPO) genes. Pathway expression of two different fosmid clones that differ largely by the presence or absence of the VHPO gene mcl40 resulted in the differential biosynthesis of merochlorin C, suggesting that Mcl40 catalyzes an unprecedented 15-membered chloronium-induced macrocyclization reaction converting merochlorin D to merochlorin C

  • merochlorins a d cyclic Meroterpenoid antibiotics biosynthesized in divergent pathways with vanadium dependent chloroperoxidases
    Journal of the American Chemical Society, 2012
    Co-Authors: Leonard Kaysser, Peter Bernhardt, Sangjip Nam, Sandra Loesgen, Graham J Ruby, Peter Skewescox, Paul R Jensen, William Fenical, Bradley S Moore
    Abstract:

    Meroterpenoids are mixed polyketide-terpenoid natural products with a broad range of biological activities. Herein, we present the structures of four new Meroterpenoid antibiotics, merochlorins A–D, produced by the marine bacterium Streptomyces sp. strain CNH-189, which possess novel chemical skeletons unrelated to known bacterial agents. Draft genome sequencing, mutagenesis, and heterologous biosynthesis in the genome-minimized model actinomycete Streptomyces coelicolor provided the 57.6 kb merochlorin gene cluster that contains two genes encoding rare bacterial vanadium-dependent haloperoxidase (VHPO) genes. Pathway expression of two different fosmid clones that differ largely by the presence or absence of the VHPO gene mcl40 resulted in the differential biosynthesis of merochlorin C, suggesting that Mcl40 catalyzes an unprecedented 15-membered chloronium-induced macrocyclization reaction converting merochlorin D to merochlorin C.

Clay C C Wang - One of the best experts on this subject based on the ideXlab platform.

  • molecular genetic characterization of a cluster in a terreus for biosynthesis of the Meroterpenoid terretonin
    Organic Letters, 2012
    Co-Authors: Chun Jun Guo, Yi Ming Chiang, Berl R Oakley, Benjamin P Knox, James F Sanchez, Kuanhan Lee, Kenneth S Bruno, Clay C C Wang
    Abstract:

    Meroterpenoids are natural products produced from polyketide and terpenoid precursors. A gene targeting system for A. terreus NIH2624 was developed, and a gene cluster for terretonin biosynthesis was characterized. The intermediates and shunt products were isolated from the mutant strains, and a pathway for terretonin biosynthesis is proposed. Analysis of two Meroterpenoid pathways corresponding to terretonin in A. terreus and austinol in A. nidulans reveals that they are closely related evolutionarily.

  • Two separate gene clusters encode the biosynthetic pathway for the Meroterpenoids austinol and dehydroaustinol in Aspergillus nidulans
    Journal of the American Chemical Society, 2012
    Co-Authors: Hsien Chun Lo, Ruth Entwistle, Chun Jun Guo, Manmeet Ahuja, Yi Ming Chiang, Edyta Szewczyk, Jui Hsiang Hung, Berl R Oakley, Clay C C Wang
    Abstract:

    Meroterpenoids are a class of fungal natural products that are produced from polyketide and terpenoid precursors. An understanding of Meroterpenoid biosynthesis at the genetic level should facilitate engineering of second-generation molecules and increasing production of first-generation compounds. The filamentous fungus Aspergillus nidulans has previously been found to produce two Meroterpenoids, austinol and dehydroaustinol. Using targeted deletions that we created, we have determined that, surprisingly, two separate gene clusters are required for Meroterpenoid biosynthesis. One is a cluster of four genes including a polyketide synthase gene, ausA. The second is a cluster of 10 additional genes including a prenyltransferase gene, ausN, located on a separate chromosome. Chemical analysis of mutant extracts enabled us to isolate 3,5-dimethylorsellinic acid and 10 additional Meroterpenoids that are either intermediates or shunt products from the biosynthetic pathway. Six of them were identified as novel me...

Yonghui Zhang - One of the best experts on this subject based on the ideXlab platform.

  • terreuspyridine an unexpected pyridine fused Meroterpenoid alkaloid with a tetracyclic 6 6 6 6 skeleton from aspergillus terreus
    Organic Letters, 2020
    Co-Authors: Wenya Feng, Chunmei Chen, Xin Kang, Shan Yan, Menghang Chao, Weiguang Sun, Jianping Wang, Hucheng Zhu, Yonghui Zhang
    Abstract:

    Terreuspyridine (1), the first 3,5-demethylorsellinic acid (DMOA) derived Meroterpenoid alkaloid, was isolated from the fungus Aspergillus terreus, which represents a new type of Meroterpenoid possessing an unexpected tetracyclic 6/6/6/6 architecture. The structure of 1 with absolute configuration was determined by X-ray diffraction analysis. Biogenetically, it was proposed to be derived from the fusion of a DMOA-Meroterpenoid and a glutamate. Terreuspyridine (1) exhibited moderate inhibitory activity against the BChE with an IC50 value of 16.4 μM.

  • discovery of acylphloroglucinol based Meroterpenoid enantiomers as kshv inhibitors from hypericum japonicum
    RSC Advances, 2018
    Co-Authors: Yanfei Liu, Junjun Liu, Yanxing Wang, Zhenzhen Wang, Jinfeng Huang, Yongbo Xue, Zhenming Liu, Yong Chen, Yonghui Zhang
    Abstract:

    Kaposi's sarcoma associated herpesvirus (KSHV) has gained considerable attention as a type of carcinogenic pathogen. Recent research suggests that KSHV has participated in the pathogenesis of Kaposi's sarcoma-related malignant neoplastic diseases. Viral lytic infection might be pivotal for the etiopathogenesis of KSHV-induced diseases; however, most clinical KSHV lytic replication inhibitors like ganciclovir, nelfinavir, or cidofovir do not restrain virus replication effectively enough to achieve clinical efficacy. In our continued pharmaceutical studies on Chinese herbal medicines, new acylphloroglucinol-based Meroterpenoid enantiomers have been discovered from Hypericum japonicum. Most of these metabolites have potential inhibitory activities that target KSHV lytic replication. Amongst these analogues, compounds 1a and 1b possess an unreported ring system cyclopenta[b]chromene. Compounds 1a with 4a exhibit stronger inhibitory activities towards the lytic replication of KSHV in Vero cells. In addition, 1a and 4a have IC50 values of 8.30 and 4.90 μM and selectivity indexes of 23.49 and 25.70, respectively. Qualitative and quantitative SAR and molecular docking studies for acylphloroglucinol-based Meroterpenoids with regard to anti-KSHV activity were conducted. An explanation for the variation in the activity and selectivity indexes was proposed in accordance with the predicted binding pose found with molecular docking to a putative target, thymidylate synthase (kTS). Compounds 1a and 4a have potential for further development and optimization of their anti-KSHV activities which could lead to new candidate drugs.

Ikuro Abe - One of the best experts on this subject based on the ideXlab platform.

  • Enzymology and biosynthesis of the orsellinic acid derived medicinal Meroterpenoids.
    Current opinion in biotechnology, 2020
    Co-Authors: Hui Tao, Ikuro Abe
    Abstract:

    The advent of synthetic biology has yielded fruitful studies on orsellinic acid-derived Meroterpenoids, which reportedly possess important biological activities. Genomics and transcriptomics have significantly accelerated the discovery of the biosynthetic genes for orsellinic acid-derived fungal and plant Meroterpenoids. Subsequently, a well-developed heterologous host provides a convenient platform to generate a supply of useful natural products. Furthermore, in vitro reconstitution and genome editing tools have been increasingly employed as efficient means to fully understand the enzyme reaction mechanisms. With the knowledge of the biosynthetic machinery, combinatorial and engineered biosyntheses have yielded novel molecules with improved bioactivities. These studies will lay the foundation for the production of Meroterpenoids with novel medicinal properties.

  • Chemistry of fungal Meroterpenoid cyclases.
    Natural product reports, 2020
    Co-Authors: Lena Barra, Ikuro Abe
    Abstract:

    Covering: up to July 2020Fungal Meroterpenoid cyclases are a recently discovered emerging family of membrane-integrated, non-canonical terpene cyclases. They catalyze the conversion of hybrid isoprenic precursors towards complex scaffolds and are therefore of great importance in the structure diversification in Meroterpenoid biosynthesis. The products of these pathways exhibit intriguing molecular scaffolds and highly potent bioactivities, making them privileged structures from Nature and attractive candidates for drug development or industrial applications. This review will provide a comprehensive and comparative view on fungal Meroterpenoid cyclases, their intriguing chemistries and importance for the scaffold formation step towards polycyclic Meroterpenoid natural products.

  • Multidomain P450 Epoxidase and a Terpene Cyclase from the Ascochlorin Biosynthetic Pathway in Fusarium sp.
    2019
    Co-Authors: Zhiyang Quan, Takayoshi Awakawa, Dongmei Wang, Ikuro Abe
    Abstract:

    Ascochlorin is a medicinally important fungal Meroterpenoid. Its biosynthetic pathway in Fusarium sp. was identified, and the stereoselective epoxidation of the farnesyl group by the multidomain, soluble P450 monooxygenase AscE and the subsequent formation of the unique timethylcyclohexanone ring by the membrane-bound cyclase AscF were investigated. Precursor-directed biosynthesis generated novel bromo-substituted derivatives, which exhibited potent cytotoxic activities. This study paves the way for the future metabolic engineering of medicinally important Meroterpenoids for drug discovery

  • Unusual chemistries in fungal Meroterpenoid biosynthesis.
    Current opinion in chemical biology, 2015
    Co-Authors: Yudai Matsuda, Takayoshi Awakawa, Takahiro Mori, Ikuro Abe
    Abstract:

    Meroterpenoids are polyketide and terpenoid hybrid natural products with remarkable biological activities. Recent progress in fungal Meroterpenoid biosynthesis has revealed several unusual enzyme reactions and novel enzymes, including unique terpene cyclization reactions by a novel family of membrane-bound terpene cyclases and post-cyclization modification reactions by oxygenases, such as non-heme iron-dependent dioxygenases, flavin adenine dinucleotide-dependent monooxygenases, and cytochrome P450 monooxygenases. They contribute to the structural diversification and increase in complexity of fungal Meroterpenoids. Structure-function studies of these enzymes provide strategies for engineering the biosynthetic machinery to create novel molecular scaffolds for drug discovery.

  • Identification of a Key Prenyltransferase Involved in Biosynthesis of the Most Abundant Fungal Meroterpenoids Derived from 3,5‐Dimethylorsellinic Acid.
    Chembiochem : a European journal of chemical biology, 2012
    Co-Authors: Takayuki Itoh, Kinya Tokunaga, E. K. Radhakrishnan, Isao Fujii, Ikuro Abe, Yutaka Ebizuka, Tetsuo Kushiro
    Abstract:

    Destroying aromaticity: A novel prenyltransferase (Trt2) involved in fungal Meroterpenoid biosynthesis was shown to catalyze an unusual aromatic addition reaction onto a fully substituted aromatic ring. The prenylated product serves as a key intermediate in the biosynthesis of the most abundant series of Meroterpenoids in fungi.

Hai-yang Liu - One of the best experts on this subject based on the ideXlab platform.

  • Eucalypglobulusals A-J, Formyl-Phloroglucinol-Terpene Meroterpenoids from Eucalyptus globulus Fruits.
    Journal of natural products, 2018
    Co-Authors: Xu-jie Qin, Hui Liu, Ling-yu Jin, Afsar Khan, Huan Yan, Xiao-jiang Hao, Hai-yang Liu
    Abstract:

    Ten new formyl-phloroglucinol–terpene Meroterpenoids, eucalypglobulusals A–J (1–10), and ten known analogues were isolated from Eucalyptus globulus fruits. The structures of 1–10 were determined by spectroscopic analysis, while their absolute configurations were established using calculated and experimental electronic circular dichroism (ECD) spectra. Eucalypglobulusal A was assigned as a new formyl-phloroglucinol–terpene Meroterpenoid with a rearranged sesquiterpene skeleton, and an aldol condensation between C-3 and C-5 of the germacrene C moiety was proposed to be a key step in its putative biosynthetic pathway. Eucalypglobulusal F exhibited cytotoxicity against the human acute lymphoblastic cell line (CCRF-CEM) with an IC50 value of 3.3 μM, while eucalypglobulusal A, eucarobustol C, macrocarpal A, macrocarpal B, and macrocarpal D exhibited DNA topoisomerase I (Top1) inhibition. The compounds eucalypglobulusal A and macrocarpal A act as Top1 catalytic inhibitors and delay Top1 poison-mediated DNA doubl...

  • Structurally Diverse Polymethylated Phloroglucinol Meroterpenoids from Baeckea frutescens.
    Natural products and bioprospecting, 2018
    Co-Authors: Yin-e Zhi, Hui Liu, Yuan Zeng, Zu-ding Wang, Hai-yang Liu
    Abstract:

    Phytochemical investigation of the MeOH extract of twigs and leaves of Baeckea frutescens led to the isolation of seven new polymethylated phloroglucinol Meroterpenoids (PPMs), named baeckfrutones M–S (1–7). Their structures and absolute configurations were determined by spectroscopic analyses, chiral-phase HPLC analysis, and electronic circular dichroism (ECD) calculations. PPM 1 is a novel Meroterpenoid possessing a 6/6/5/3 tetracyclic skeleton in PPMs, whereas 3 and 4 are the first hydroxytasmanone type phloroglucinol-monoterpene hybrids. (+)-2 and 7 displayed potent anti-inflammatory activity with IC50 values of 20.86 ± 0.60 and 36.21 ± 1.18 μΜ, respectively.

  • Eucalyptusdimers A-C, Dimeric Phloroglucinol-Phellandrene Meroterpenoids from Eucalyptus robusta.
    Organic letters, 2018
    Co-Authors: Xu-jie Qin, Hui Liu, Huan Yan, Miyan Feng, Tyler J. Rauwolf, John A. Porco, Hai-yang Liu
    Abstract:

    Eucalyptusdimers A–C, three dimeric phellandrene-derived Meroterpenoids featuring an unprecedented, fused skeleton between two phellandrene and two acylphloroglucinol subunits, along with one biogenetically related intermediate, (±)-eucalyprobusone A, were isolated from the fruits of Eucalyptus robusta. Their structures and absolute configurations were elucidated using spectroscopic data, X-ray crystallography, and electronic circular dichroism analysis. The isolated Meroterpenoids were evaluated for their anti-inflammatory, acetylcholinesterase inhibitory, and protein tyrosine phosphatase 1B inhibitory effects.

  • Eucalypglobulusals A–J, Formyl-Phloroglucinol–Terpene Meroterpenoids from Eucalyptus globulus Fruits
    2018
    Co-Authors: Xu-jie Qin, Hui Liu, Ling-yu Jin, Afsar Khan, Huan Yan, Xiao-jiang Hao, Hai-yang Liu
    Abstract:

    Ten new formyl-phloroglucinol–terpene Meroterpenoids, eucalypglobulusals A–J (1–10), and ten known analogues were isolated from Eucalyptus globulus fruits. The structures of 1–10 were determined by spectroscopic analysis, while their absolute configurations were established using calculated and experimental electronic circular dichroism (ECD) spectra. Eucalypglobulusal A was assigned as a new formyl-phloroglucinol–terpene Meroterpenoid with a rearranged sesquiterpene skeleton, and an aldol condensation between C-3 and C-5 of the germacrene C moiety was proposed to be a key step in its putative biosynthetic pathway. Eucalypglobulusal F exhibited cytotoxicity against the human acute lymphoblastic cell line (CCRF-CEM) with an IC50 value of 3.3 μM, while eucalypglobulusal A, eucarobustol C, macrocarpal A, macrocarpal B, and macrocarpal D exhibited DNA topoisomerase I (Top1) inhibition. The compounds eucalypglobulusal A and macrocarpal A act as Top1 catalytic inhibitors and delay Top1 poison-mediated DNA double-strand damage