Asymmetric Formal Synthesis of Trichodermamides B and C

Kimishima, Atsushi; Saito, Hayato; Petrova, V.D.; Arai, Masayoshi

doi:10.1055/s-0040-1720383

Cited by 5 publications

References 18 publications

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Pretrichodermamide A Biosynthesis Reveals the Hidden Diversity of Epidithiodiketopiperazines

et al. 2023

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Fungal epidithiodiketopiperazines (ETPs) possess large structural diversity and complexity due to modifications of the cyclodipeptide skeleton. Elucidation of the biosynthetic pathway of pretrichodermamide A (1) in Trichoderma hypoxylon revealed a flexible catalytic machinery of multiple enzymes for generating ETP diversity. Seven tailoring enzymes encoded by the tda cluster are involved in 1 biosynthesis, that is, four P450s TdaB and TdaQ for 1,2oxazine formation, TdaI for C7'-hydroxylation, and TdaG for C4, C5-epoxidation, two methyltransferases TdaH for C6'and TdaO for C7'-O-methylation, and a reductase TdaD for furan opening. Gene deletions led to the identification of 25 novel ETPs, including 20 shunt products, indicating the catalytic promiscuity of Tda enzymes. Particularly, TdaG and TdaD accept various substrates and catalyze regiospecific reactions at different stages of 1 biosynthesis. Our study not only uncovers a hidden library of ETP alkaloids, but also helps to understand the hidden chemical diversity of natural products by pathway manipulation.

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Pretrichodermamide A Biosynthesis Reveals the Hidden Diversity of Epidithiodiketopiperazines

et al. 2023

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Pretrichodermamide A Biosynthesis Reveals the Hidden Diversity of Epidithiodiketopiperazines

et al. 2023

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Fungal epidithiodiketopiperazines (ETPs) possess large structural diversity and complexity due to modifications of the cyclodipeptide skeleton. Elucidation of the biosynthetic pathway of pretrichodermamide A (1) in Trichoderma hypoxylon revealed a flexible catalytic machinery of multiple enzymes for generating ETP diversity. Seven tailoring enzymes encoded by the tda cluster are involved in 1 biosynthesis, that is, four P450s TdaB and TdaQ for 1,2‐oxazine formation, TdaI for C7′‐hydroxylation, and TdaG for C4, C5‐epoxidation, two methyltransferases TdaH for C6′‐ and TdaO for C7′‐O‐methylation, and a reductase TdaD for furan opening. Gene deletions led to the identification of 25 novel ETPs, including 20 shunt products, indicating the catalytic promiscuity of Tda enzymes. Particularly, TdaG and TdaD accept various substrates and catalyze regiospecific reactions at different stages of 1 biosynthesis. Our study not only uncovers a hidden library of ETP alkaloids, but also helps to understand the hidden chemical diversity of natural products by pathway manipulation.

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Formation of Bridged Disulfide in Epidithiodioxopiperazines

Fan,

Wei,

Yin

2024

ChemBioChem

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Epidithiodioxopiperazine (ETP) alkaloids, featuring a 2,5‐diketopiperazine core and transannular disulfide bridge, exhibit a broad spectrum of biological activities. However, the structural complexity has prevented efficient chemical synthesis and further clinical research. In the past few decades, many achievements have been made in the biosynthesis of ETPs. Here, we discuss the biosynthetic progress and summarize them as two comprehensible metabolic principles for better understanding the complex pathways of α, α′‐ and α, β′‐disulfide bridged ETPs. Specifically, we systematically outline the catalytic machineries to install α, α′‐ and α, β′‐disulfide by flavin‐containing oxygenases. This concept would contribute to the medical and industrial applications of ETPs.

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Asymmetric Formal Synthesis of Trichodermamides B and C

Cited by 5 publications

References 18 publications

Pretrichodermamide A Biosynthesis Reveals the Hidden Diversity of Epidithiodiketopiperazines

Pretrichodermamide A Biosynthesis Reveals the Hidden Diversity of Epidithiodiketopiperazines

Pretrichodermamide A Biosynthesis Reveals the Hidden Diversity of Epidithiodiketopiperazines

Formation of Bridged Disulfide in Epidithiodioxopiperazines

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