Biosynthesis of indole diterpenes: a reconstitution approach in a heterologous host

Ozaki, Taro; Minami, Atsushi; Oikawa, Hideaki

doi:10.1039/d2np00031h

Cited by 16 publications

(7 citation statements)

References 72 publications

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“…This process resulted in the identification of 1050 BGCs (including those with a single gene; Supplementary Data 5 ). More than half (690) of the identified BGCs did not contain an additional core protein gene, whereas 182 BGCs possessed at least one PKS gene, and 131 BGCs were found to encode a PaxC-like prenyltransferase, which is specifically required for the biosynthesis of indole sesquiterpenoids and diterpenoids 31 . Thus, except for standalone pyr4 -like genes, the majority of the pyr4 -like genes were clustered with either a PKS gene or a paxC -like gene.…”

Section: Resultsmentioning

confidence: 99%

Discovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining

Tang,

Matsuda

2024

Nat Commun

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Genomics-guided methodologies have revolutionized the discovery of natural products. However, a major challenge in the field of genome mining is determining how to selectively extract biosynthetic gene clusters (BGCs) for untapped natural products from numerous available genome sequences. In this study, we developed a fungal genome mining tool that extracts BGCs encoding enzymes that lack a detectable protein domain (i.e., domainless enzymes) and are not recognized as biosynthetic proteins by existing bioinformatic tools. We searched for BGCs encoding a homologue of Pyr4-family terpene cyclases, which are representative examples of apparently domainless enzymes, in approximately 2000 fungal genomes and discovered several BGCs with unique features. The subsequent characterization of selected BGCs led to the discovery of fungal onoceroid triterpenoids and unprecedented onoceroid synthases. Furthermore, in addition to the onoceroids, a previously unreported sesquiterpene hydroquinone, of which the biosynthesis involves a Pyr4-family terpene cyclase, was obtained. Our genome mining tool has broad applicability in fungal genome mining and can serve as a beneficial platform for accessing diverse, unexploited natural products.

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Section: Resultsmentioning

confidence: 99%

Discovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining

Tang,

Matsuda

2024

Nat Commun

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“…Indole diterpenes (IDTs) constitute a class of structurally unique natural products derived from fungi. Their distinguishing characteristic involves the attachment of a C20 long-chain geranyl–geranyl diphosphate (GGPP) to the indole ring, followed by subsequent modifications, including cyclization, oxidation, prenylation, and other modifications, resulting in structurally complex compounds (Ozaki et al 2023 ). These compounds are primarily derived from fungal species such as Penicillium sp., Aspergillus sp., and Claviceps sp., among others (Reddy et al 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Biochemical characterization of a multiple prenyltransferase from Tolypocladium inflatum

Han,

Peng,

Wang

et al. 2024

Appl Microbiol Biotechnol

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Prenylation plays a pivotal role in the diversification and biological activities of natural products. This study presents the functional characterization of TolF, a multiple prenyltransferase from Tolypocladium inflatum. The heterologous expression of tolF in Aspergillus oryzae, coupled with feeding the transformed strain with paxilline, resulted in the production of 20- and 22-prenylpaxilline. Additionally, TolF demonstrated the ability to prenylated the reduced form of paxilline, β-paxitriol. A related prenyltransferase TerF from Chaunopycnis alba, exhibited similar substrate tolerance and regioselectivity. In vitro enzyme assays using purified recombinant enzymes TolF and TerF confirmed their capacity to catalyze prenylation of paxilline, β-paxitriol, and terpendole I. Based on previous reports, terpendole I should be considered a native substrate. This work not only enhances our understanding of the molecular basis and product diversity of prenylation reactions in indole diterpene biosynthesis, but also provides insights into the potential of fungal indole diterpene prenyltransferase to alter their position specificities for prenylation. This could be applicable for the synthesis of industrially useful compounds, including bioactive compounds, thereby opening up new avenues for the development of novel biosynthetic strategies and pharmaceuticals. Key points • The study characterizes TolF as a multiple prenyltransferase from Tolypocladium inflatum. • TerF from Chaunopycnis alba shows similar substrate tolerance and regioselectivity compared to TolF. • The research offers insights into the potential applications of fungal indole diterpene prenyltransferases. Graphical abstract

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“…There are some reviews related to IDTs have been presented. For example, the synthesis and activity of paspaline-type compounds [ 11 , 12 ], the structural diversity and biological activity [ 5 ], biosynthesis of IDTs are described [ 13 – 15 ]. However, considering that these reviews do not classify these two types of compounds uniformly, and exclude the cover of the latest IDT compounds in recent years.…”

Section: Introductionmentioning

confidence: 99%

The chemical structures and biological activities of indole diterpenoids

Niu

Jing

Wang

et al. 2023

Nat. Prod. Bioprospect.

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Indole diterpenoids (IDTs) are an essential class of structurally diverse fungal secondary metabolites, that generally appear to be restricted to a limited number of fungi, such as Penicillium, Aspergillus, Claviceps, and Epichloe species, etc. These compounds share a typical core structure consisting of a cyclic diterpene skeleton of geranylgeranyl diphosphate (GGPP) and an indole ring moiety derived from indole-3-glycerol phosphate (IGP). 3-geranylgeranylindole (3-GGI) is the common precursor of all IDTs. On this basis, it is modified by cyclization, oxidation, and prenylation to generate a large class of compounds with complex structures. These compounds exhibit antibacterial, anti-insect, and ion channel inhibitory activities. We summarized 204 compounds of IDTs discovered from various fungi over the past 50 years, these compounds were reclassified, and their biological activities were summarized. This review will help to understand the structural diversity of IDTs and provide help for their physiological activities. Graphical Abstract

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Biosynthesis of indole diterpenes: a reconstitution approach in a heterologous host

Abstract: Reconstitution studies applying the 3-stage strategy to the synthesis of highly elaborated indole diterpenes are reviewed.

Cited by 16 publications

References 72 publications

Discovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining

Discovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining

Biochemical characterization of a multiple prenyltransferase from Tolypocladium inflatum

The chemical structures and biological activities of indole diterpenoids

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