Biosynthesis of bioactive natural products from Basidiomycota

Lin, Hsiao‐Ching; Hewage, Ranuka T.; Lu, Yuan-Chun; Chooi, Yit‐Heng

doi:10.1039/c8ob02774a

Cited by 41 publications

(27 citation statements)

References 51 publications

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“…Members of the Agaricomycotina are the other main group of secondary metabolite‐producing fungi (Schüffler & Anke, ; Zhong & Xiao, ; Quin, Flynn & Schmidt‐Dannert, ; Stadler & Hoffmeister, ; Lin et al ., ). HGT seems to be relatively rare among this group, and cluster gene duplication appears to be the main evolutionary force behind metabolic diversification (Wisecaver et al ., ).…”

Section: Metabolic Complexitymentioning

confidence: 97%

Fungal evolution: cellular, genomic and metabolic complexity

Naranjo‐Ortiz

Gabaldón

2020

Biological Reviews

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The question of how phenotypic and genomic complexity are inter‐related and how they are shaped through evolution is a central question in biology that historically has been approached from the perspective of animals and plants. In recent years, however, fungi have emerged as a promising alternative system to address such questions. Key to their ecological success, fungi present a broad and diverse range of phenotypic traits. Fungal cells can adopt many different shapes, often within a single species, providing them with great adaptive potential. Fungal cellular organizations span from unicellular forms to complex, macroscopic multicellularity, with multiple transitions to higher or lower levels of cellular complexity occurring throughout the evolutionary history of fungi. Similarly, fungal genomes are very diverse in their architecture. Deep changes in genome organization can occur very quickly, and these phenomena are known to mediate rapid adaptations to environmental changes. Finally, the biochemical complexity of fungi is huge, particularly with regard to their secondary metabolites, chemical products that mediate many aspects of fungal biology, including ecological interactions. Herein, we explore how the interplay of these cellular, genomic and metabolic traits mediates the emergence of complex phenotypes, and how this complexity is shaped throughout the evolutionary history of Fungi.

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Section: Metabolic Complexitymentioning

confidence: 97%

Fungal evolution: cellular, genomic and metabolic complexity

Naranjo‐Ortiz

Gabaldón

2020

Biological Reviews

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“…Natural products provide a vast array of diverse chemical structures that can be exploited in the agricultural, food/feed, cosmetics, biofuels, textiles, and healthcare industries (Hyde et al 2019). Terpenoids are by far the largest class of natural products, but only four are currently approved as antimicrobial drugs (tiamulin, valnemulin, retapamulin, and lefamulin), and these are all semisynthetic derivatives of the fungal antibiotic pleuromutilin (Mendes et al 2016;Hunt 2019;Lin et al 2019). Basidiomycetes provide a rich source of complex, structurally diverse, and bioactive sesquiterpenoids, and certain protoilludene-type sesquiterpene aryl esters produced by the genus Armillaria (class Agaricomycetes, family Physalacriaceae) are promising leads for the development of new drugs.…”

Section: Introductionmentioning

confidence: 99%

“…The enzymes needed to produce several fungal secondary metabolites are encoded by gene clusters, including pleuromutilin produced by Clitopilus pseudopinsitus and Clitopilus passeckerianus (Bailey et al 2016;Alberti et al 2017;Yamane et al 2017;Lin et al 2019), erinacine diterpenoids produced by Hericium erinaceus (Yang et al 2017), and bovistol and pasteurestin C produced by Cyclocybe aegerita (Surup et al 2019). We therefore tested the hypothesis that the biosynthesis of protoilludene-type sesquiterpenoids in A. gallica may also involve a gene cluster and that the isolation of such a cluster would allow the characterization of the corresponding enzymes.…”

Section: Introductionmentioning

confidence: 99%

Isolation of a gene cluster from Armillaria gallica for the synthesis of armillyl orsellinate–type sesquiterpenoids

Engels

Heinig

McElroy

et al. 2020

Appl Microbiol Biotechnol

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Melleolides and armillyl orsellinates are protoilludene-type aryl esters that are synthesized exclusively by parasitic fungi of the globally distributed genus Armillaria (Agaricomycetes, Physalacriaceae). Several of these compounds show potent antimicrobial and cytotoxic activities, making them promising leads for the development of new antibiotics or drugs for the treatment of cancer. We recently cloned and characterized the Armillaria gallica gene Pro1 encoding protoilludene synthase, a sesquiterpene cyclase catalyzing the pathway-committing step to all protoilludene-type aryl esters. Fungal enzymes representing secondary metabolic pathways are sometimes encoded by gene clusters, so we hypothesized that the missing steps in the pathway to melleolides and armillyl orsellinates might be identified by cloning the genes surrounding Pro1. Here we report the isolation of an A. gallica gene cluster encoding protoilludene synthase and four cytochrome P450 monooxygenases. Heterologous expression and functional analysis resulted in the identification of protoilludene-8α-hydroxylase, which catalyzes the first committed step in the armillyl orsellinate pathway. This confirms that ∆-6-protoilludene is a precursor for the synthesis of both melleolides and armillyl orsellinates, but the two pathways already branch at the level of the first oxygenation step. Our results provide insight into the synthesis of these valuable natural products and pave the way for their production by metabolic engineering. Key points • Protoilludene-type aryl esters are bioactive metabolites produced by Armillaria spp. • The pathway-committing step to these compounds is catalyzed by protoilludene synthase. • We characterized CYP-type enzymes in the cluster and identified novel intermediates.

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“…Similar to ascomycetes, basidiomycetes are one of the microorganisms that make up the fungal kingdom. They are widely known to produce fruiting bodies (mushrooms) for sporulation, and many of them have been used as traditional medicines in the world, while no small numbers of species are toxic to humans [43]. Therefore, basidiomycetes have been recognized as a treasure trove of biologically active substances for the development of drugs.…”

Section: Activation Of the Biosynthetic Pathway In Basidiomycete Fungimentioning

confidence: 99%

Genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function

Tsunematsu

2020

J Nat Med

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Natural products, which can be isolated from living organisms worldwide, have played a pivotal role in drug discovery since ancient times. However, it has become more challenging to identify a structurally novel molecule with promising biological activity for pharmaceutical development, mainly due to the limited methodologies for their acquisition. In this review, we summarize our recent studies that activate the biosynthetic potential of filamentous fungi by genetic engineering to harness the metabolic flow for the efficient production of unprecedented natural products. The recent revolution in genome sequencing technology enables the accumulation of vast amounts of information on biosynthetic genes, the blueprint of the molecular construction. Utilizing the established heterologous expression system, activation of the pathway-specific transcription factor coupled with a knockout strategy, and manipulating the global regulatory gene, the biosynthetic genes were exploited to activate biosynthetic pathways and decipher the encoded enzyme functions. We show that this methodology was beneficial for acquiring fungal treasures for drug discovery. These studies also enabled the investigation of the molecular function of natural products in fungal development.

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Biosynthesis of bioactive natural products from Basidiomycota

Abstract: The club fungi, Basidioycota, produce a wide range of bioactive compounds. Here, we describe recent studies on the biosynthetic pathways and enzymes of bioactive natural products from these fungi.

Cited by 41 publications

References 51 publications

Fungal evolution: cellular, genomic and metabolic complexity

Fungal evolution: cellular, genomic and metabolic complexity

Isolation of a gene cluster from Armillaria gallica for the synthesis of armillyl orsellinate–type sesquiterpenoids

Genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function

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