Covering: up to September 2015. Meroterpenoids are hybrid natural products that partially originate from the terpenoid pathway. The meroterpenoids derived from fungi display quite diverse structures, ...with a wide range of biological properties. This review summarizes the molecular bases for their biosyntheses, which were recently elucidated with modern techniques, and also discusses the plausible biosynthetic pathways of other related natural products lacking genetic information. (Complementary to the coverage of literature by Geris and Simpson in Nat. Prod. Rep., 2009, 26, 1063-1094.).
Recent research progress on the “second generation” type III polyketide synthases is summarized. This class of enzymes catalyzes unusual condensation chemistries of CoA thioesters to generate various ...core structures of medicinally important plant secondary metabolites, including the R
1
–C–R
2
scaffold of alkyl quinolones, curcuminoids, as well as the 8-azabicyclo3.2.1octane ring of tropane alkaloids. The discovery of this fascinating enzyme superfamily provides excellent opportunities for the manipulation of the enzyme reactions to expand the supply of natural and unnatural molecules for future drug development.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Teleocidin B, with its unique indolactam-terpenoid scaffold, is a potent activator of protein kinase C. This short review summarizes our recent research progress on the biosynthesis of teleocidins in ...Streptomyces blastmyceticus NBRC 12747. We first identified the biosynthetic genes for teleocidin B, which include genes encoding a non-ribosomal peptide synthetase (tleA), a cytochrome P450 monooxygenase (tleB), an indol prenyltransferase (tleC), and a C-methyltransferase (tleD). Notably, the tleD gene is located outside the tleABC cluster. Our in vivo and in vitro analyses revealed that TleD not only catalyzes the C-methylation of the prenyl chain but also produces the indole-fused cyclic terpene structure. This is the first report of terpene cyclization initiated by the C-methylation of the prenyl double bond. In contrast, TleC catalyzes the geranylation of the C-7 position of the indole ring, in the reverse fashion. Our X-ray crystallographic analyses provided the structural basis for the reverse prenylation reactions, and structure-based mutagenesis successfully resulted in the production of unnatural, novel prenylated indolactams.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
This review summarizes the recent progress in research on the non-heme Fe(II)- and 2-oxoglutarate-dependent dioxygenases, which are involved in the biosynthesis of pharmaceutically important fungal ...meroterpenoids. This enzyme class activates a selective C–H bond of the substrate and catalyzes a wide range of chemical reactions, from simple hydroxylation to dynamic carbon skeletal rearrangements, thereby significantly contributing to the structural diversification and complexification of the molecules. Structure–function studies of these enzymes provide an excellent platform for the development of useful biocatalysts for synthetic biology to create novel molecules for future drug discovery.
Covering: up to July 2020
Fungal 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.
Complex cyclization reactions of fungal meroterpenoid cyclases.
Covering: 2002 to 2009
This review covers recent advances in structure and function studies on the chalcone synthase (CHS) superfamily of plant type III polyketide synthases (PKSs), which catalyze ...iterative decarboxylative condensations of malonyl unit with a CoA-linked starter molecule to produce structurally diverse, pharmaceutically important plant secondary metabolites. The functional diversity and catalytic potential of the type III PKSs are remarkable. Studies on the enzymes are now progressing rapidly; recent crystallographic and site-directed mutagenesis studies have revealed intimate structural details of the enzyme reactions, which enabled the structure-based and precursor-directed engineered biosynthesis of unnatural novel polyketides. The literature of type III PKSs of plant origin published over the last eight years will be reviewed, and is intended to compliment the coverage of the literature by Austin and Noel in
Nat. Prod. Rep.
, 2003,
20
, 79-110.
This review covers recent advances in chemistry and enzymology of type III polyketide synthases of plant origin. The literature published from 2002 through 2009 is reviewed.
Prenyltransferase (PT) and terpene synthase (TPS) are key enzymes in the formation of the basic carbon skeletons of terpenoids. The PTs determine the prenyl carbon chain length, whereas TPSs generate ...the structural complexity of the molecular scaffolds, forming various ring structures. Normally, PTs and TPSs are separate, independent enzymes. However, in 2007, a chimeric enzyme, in which the PT was fused with the TPS, was found in a fungus. Recent studies have revealed that such chimeric TPSs are widely distributed in fungi and function in the biosyntheses of various terpene natural products, including sesterterpenes, which are a relatively rare group of terpenoids. This review summarizes the accumulated knowledge of these recently discovered, unique, chimeric TPSs.
Split personalities: The basic carbon skeleton of terpenoids is mainly formed by only two families of enzymes, prenyltransferases (PTs) and terpene synthases (TPSs). Regular PTs and TPSs are independent separate enzymes. However, in fungi, some TPSs and PTs are linked together to form chimeric enzymes. This review highlights this fascinating class of chimeric TPSs.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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•Orsellinic acid derived meroterpenoids contain several promising drug candidates.•Recent studies have elucidated the molecular bases for their biosynthetic machineries.•Enzymology of ...biosynthetic enzymes provides strategies for engineered biosynthesis.•Engineered biosynthesis contributes to generate a supply of novel molecules for drug discovery.
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Type III polyketide synthases (PKSs) produce an incredibly diverse group of plant specialized metabolites with medical importance despite their structural simplicity compared with the modular type I ...and II PKS systems. The type III PKSs use homodimeric proteins to construct the molecular scaffolds of plant polyketides by iterative condensations of starter and extender CoA thioesters. Ever since the structure of chalcone synthase (CHS) was disclosed in 1999, crystallographic and mutational studies of the type III PKSs have explored the intimate structural features of these enzyme reactions, revealing that seemingly minor alterations in the active site can drastically change the catalytic functions and product profiles. New structures described in this review further build on this knowledge, elucidating the detailed catalytic mechanism of enzymes that make curcuminoids, use extender substrates without the canonical CoA activator, and use noncanonical starter substrates, among others. These insights have been critical in identifying structural features that can serve as a platform for enzyme engineering via structure-guided and precursor-directed engineered biosynthesis of plant polyketides. In addition, we describe the unique properties of the recently discovered “second-generation” type III PKSs that catalyzes the one-pot formation of complex molecular scaffolds from three distinct CoA thioesters or from “CoA-free” substrates, which are also providing exciting new opportunities for synthetic biology approaches. Finally, we consider post-type III PKS tailoring enzymes, which can also serve as useful tools for combinatorial biosynthesis of further unnatural novel molecules. Recent progress in the field has led to an exciting time of understanding and manipulating these fascinating enzymes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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