Meroterpenoids Produced by Fungi
TL;DR: In this article, a review deals with the isolation and structure elucidation of meroterpenoids (natural products of mixed biosynthetic origin which are partially derived from terpenoids) from higher and lower fungi.
Abstract: This review deals with the isolation and structure elucidation of meroterpenoids (natural products of mixed biosynthetic origin which are partially derived from terpenoids) from higher and lower fungi, and discusses biosynthetic studies and biological activities as appropriate. It describes 333 fungal meroterpenoids and cites 195 references.
Citations
More filters
TL;DR: The scope and mechanism of nature's halogenation and dehalogenation enzymatic strategies are detailed, gaps in understanding are highlighted, and where new advances in the field might arise in the near future are posits.
Abstract: Naturally produced halogenated compounds are ubiquitous across all domains of life where they perform a multitude of biological functions and adopt a diversity of chemical structures. Accordingly, a diverse collection of enzyme catalysts to install and remove halogens from organic scaffolds has evolved in nature. Accounting for the different chemical properties of the four halogen atoms (fluorine, chlorine, bromine, and iodine) and the diversity and chemical reactivity of their organic substrates, enzymes performing biosynthetic and degradative halogenation chemistry utilize numerous mechanistic strategies involving oxidation, reduction, and substitution. Biosynthetic halogenation reactions range from simple aromatic substitutions to stereoselective C–H functionalizations on remote carbon centers and can initiate the formation of simple to complex ring structures. Dehalogenating enzymes, on the other hand, are best known for removing halogen atoms from man-made organohalogens, yet also function naturally,...
243 citations
TL;DR: This Review examines the different strategies used by nature to create new intra(inter)molecular bonds via redox chemistry, with an emphasis on the former.
Abstract: Oxidative cyclizations are important transformations that occur widely during natural product biosynthesis. The transformations from acyclic precursors to cyclized products can afford morphed scaffolds, structural rigidity, and biological activities. Some of the most dramatic structural alterations in natural product biosynthesis occur through oxidative cyclization. In this Review, we examine the different strategies used by nature to create new intra(inter)molecular bonds via redox chemistry. This Review will cover both oxidation- and reduction-enabled cyclization mechanisms, with an emphasis on the former. Radical cyclizations catalyzed by P450, nonheme iron, α-KG-dependent oxygenases, and radical SAM enzymes are discussed to illustrate the use of molecular oxygen and S-adenosylmethionine to forge new bonds at unactivated sites via one-electron manifolds. Nonradical cyclizations catalyzed by flavin-dependent monooxygenases and NAD(P)H-dependent reductases are covered to show the use of two-electron mani...
237 citations
TL;DR: The successful production of a pyripyropene analogue illustrates the catalytic versatility of these enzymes for the production of novel analogues with useful biological activities.
Abstract: Meroterpenoids are hybrid natural products of both terpenoid and polyketide origin. We identified a biosynthetic gene cluster that is responsible for the production of the meroterpenoid pyripyropene in the fungus Aspergillus fumigatus through reconstituted biosynthesis of up to five steps in a heterologous fungal expression system. The cluster revealed a previously unknown terpene cyclase with an unusual sequence and protein primary structure. The wide occurrence of this sequence in other meroterpenoid and indole-diterpene biosynthetic gene clusters indicates the involvement of these enzymes in the biosynthesis of various terpenoid-bearing metabolites produced by fungi and bacteria. In addition, a novel polyketide synthase that incorporated nicotinyl-CoA as the starter unit and a prenyltransferase, similar to that in ubiquinone biosynthesis, was found to be involved in the pyripyropene biosynthesis. The successful production of a pyripyropene analogue illustrates the catalytic versatility of these enzymes for the production of novel analogues with useful biological activities.
168 citations
Cites background from "Meroterpenoids Produced by Fungi"
...Purification of dihydroxyfarnesyl-HPPO (6)....
[...]
...Purification of HPPO (3)....
[...]
...However, dihydroxyfarnesyl-HPPO (6) (Fig....
[...]
...The attachment site of the farnesyl group to C-3 of the HPPO moiety was confirmed by heteronuclear multiple-bond connectivity (HMBC) correlation between C-1′′ of the farnesyl group and C-2, -3 and -4 of the HPPO moiety (see Supplementary Fig....
[...]
...Further characterization by liquid chromatography– mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy identified the structure of 3 as 4-hydroxy6-(3-pyridinyl)-2H-pyran-2-one (HPPO), an expected polyketide intermediate in the pyripyropene biosynthesis (see Supplementary Fig....
[...]
TL;DR: A brief review of the numerous isoprenoid compounds that have found use as pharmaceuticals, flavors, commodity chemicals, and, most importantly, advanced biofuels is provided, and the metabolic engineering strategies that were used to produce these compounds successfully in microbial hosts are highlighted.
Abstract: Isoprenoids have been identified and used as natural pharmaceuticals, fragrances, solvents, and, more recently, advanced biofuels. Although isoprenoids are most commonly found in plants, researchers have successfully engineered both the eukaryotic and prokaryotic isoprenoid biosynthetic pathways to produce these valuable chemicals in microorganisms at high yields. The microbial synthesis of the precursor to artemisinin--an important antimalarial drug produced from the sweet wormwood Artemisia annua--serves as perhaps the most successful example of this approach. Through advances in synthetic biology and metabolic engineering, microbial-derived semisynthetic artemisinin may soon replace plant-derived artemisinin as the primary source of this valuable pharmaceutical. The richness and diversity of isoprenoid structures also make them ideal candidates for advanced biofuels that may act as "drop-in" replacements for gasoline, diesel, and jet fuel. Indeed, the sesquiterpenes farnesene and bisabolene, monoterpenes pinene and limonene, and hemiterpenes isopentenol and isopentanol have been evaluated as fuels or fuel precursors. As in the artemisinin project, these isoprenoids have been produced microbially through synthetic biology and metabolic engineering efforts. Here, we provide a brief review of the numerous isoprenoid compounds that have found use as pharmaceuticals, flavors, commodity chemicals, and, most importantly, advanced biofuels. In each case, we highlight the metabolic engineering strategies that were used to produce these compounds successfully in microbial hosts. In addition, we present a current outlook on microbial isoprenoid production, with an eye towards the many challenges that must be addressed to achieve higher yields and industrial-scale production.
143 citations
Cites background from "Meroterpenoids Produced by Fungi"
...Meroterpenoids, oxygenated medicinal terpenoids biosynthesized from polyketide and terpenoid precursors [132], serve as attractive examples....
[...]
TL;DR: Screening of the mutant library revealed direct genetic links to two austinol meroterpenoids and expanded the current understanding of the biosynthetic pathways leading to arugosins and violaceols.
Abstract: Fungi possess an advanced secondary metabolism that is regulated and coordinated in a complex manner depending on environmental challenges. To understand this complexity, a holistic approach is necessary. We initiated such an analysis in the important model fungus Aspergillus nidulans by systematically deleting all 32 individual genes encoding polyketide synthases. Wild-type and all mutant strains were challenged on different complex media to provoke induction of the secondary metabolism. Screening of the mutant library revealed direct genetic links to two austinol meroterpenoids and expanded the current understanding of the biosynthetic pathways leading to arugosins and violaceols. We expect that the library will be an important resource towards a systemic understanding of polyketide production in A. nidulans.
107 citations
References
More filters
TL;DR: This review deals with the isolation and structure elucidation of meroterpenoids from higher and lower fungi, and discusses biosynthetic studies and biological activities as appropriate.
316 citations