Discovery of the Biosynthetic Pathway of Beticolin 1 Reveals a Novel Non‐Heme Iron‐Dependent Oxygenase for Anthraquinone Ring Cleavage

Hou, Xiaodong; Xu, Huibin; Deng, Zhiwei; Yan, Yijun; Yuan, Zhenbo; Liu, Xuanzhong; Su, Zengping; Yang, Shaoming; Zhang, Yan; Rao, Yijian

doi:10.1002/anie.202208772

Cited by 10 publications

(26 citation statements)

References 44 publications

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“…Identification and characterization of an anthrol reductase CbAR with a broad substrate scope Based on sequence homology screening, CbAR was identified as a putative anthrol reductase from Cercospora sp. JNU001, which is supposed to be involved in the biosynthesis of phytotoxin beticolin 1 based on the recent study 28 . It belongs to the SDR superfamily and shares the highest sequence identity of 86.6% with 17β-HSDcl from Curvularia lunata (Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural analysis of an anthrol reductase inspires enantioselective synthesis of enantiopure hydroxycycloketones and β-halohydrins

Hou

Yuan

et al. 2023

Nat Commun

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Asymmetric reduction of prochiral ketones, particularly, reductive desymmetrization of 2,2-disubstituted prochiral 1,3-cyclodiketones to produce enantiopure chiral alcohols is challenging. Herein, an anthrol reductase CbAR with the ability to accommodate diverse bulky substrates, like emodin, for asymmetric reduction is identified. We firstly solve crystal structures of CbAR and CbAR-Emodin complex. It reveals that Tyr210 is critical for emodin recognition and binding, as it forms a hydrogen-bond interaction with His162 and π-π stacking interactions with emodin. This ensures the correct orientation for the stereoselectivity. Then, through structure-guided engineering, variant CbAR-H162F can convert various 2,2-disubstituted 1,3-cyclodiketones and α-haloacetophenones to optically pure (2S, 3S)-ketols and (R)-β-halohydrins, respectively. More importantly, their stereoselectivity mechanisms are also well explained by the respective crystal structures of CbAR-H162F-substrate complex. Therefore, this study demonstrates that an in-depth understanding of catalytic mechanism is valuable for exploiting the promiscuity of anthrol reductases to prepare diverse enantiopure chiral alcohols.

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Section: Resultsmentioning

confidence: 99%

Structural analysis of an anthrol reductase inspires enantioselective synthesis of enantiopure hydroxycycloketones and β-halohydrins

Hou

Yuan

et al. 2023

Nat Commun

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“…BTG7 and BTG13 are involved in the biosynthetic pathway of beticolin (157) (Scheme 18B). 190 Namely, the NADPHdependent reductase BTG7 reduces 154 to the hydroquinone intermediate 155. BTG13 then catalyzes the oxidative cleavage of the C10−C4a bond in 155 to generate 156, a secoanthraquinone precursor to beticolin.…”

Section: C−c Bond Cleavage Reactionsmentioning

confidence: 99%

“…A possible mechanism for the BTG13-catalyzed oxidative C− C bond cleavage is shown in Scheme 18C. 190 Based on the crystal structure of BTG13, His53 is proposed to function as a base to deprotonate C10 and generate 158. Meanwhile, O 2 is activated by the active site Fe(II) via single electron transfer to form Fe(III) and a superoxide anion.…”

Section: C−c Bond Cleavage Reactionsmentioning

confidence: 99%

“…BTG7 and BTG13 are involved in the biosynthetic pathway of beticolin ( 157 ) (Scheme B) . Namely, the NADPH-dependent reductase BTG7 reduces 154 to the hydroquinone intermediate 155 .…”

Section: Mononuclear Nonheme Iron Enzymesmentioning

confidence: 99%

“…A possible mechanism for the BTG13-catalyzed oxidative C–C bond cleavage is shown in Scheme C . Based on the crystal structure of BTG13, His53 is proposed to function as a base to deprotonate C10 and generate 158 .…”

Section: Mononuclear Nonheme Iron Enzymesmentioning

confidence: 99%

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Unusual Dioxygen-Dependent Reactions Catalyzed by Nonheme Iron Enzymes in Natural Product Biosynthesis

Ushimaru

Abe

2022

ACS Catal.

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Nonheme iron-dependent enzymatic reactions play crucial roles in building and modifying bioactive organic molecules in all major classes of natural product pathways. While the enzymes have evolved to use a limited repertoire of protein folding and metal binding sites, the oxidation reactions they catalyze are astonishingly diverse, spanning from complex rearrangements to uncommon bond formation and cleavage reactions. This review summarizes recent discoveries that have significantly expanded our understanding of unusual nonheme iron enzyme catalysis in natural product biosynthesis, covering the literature published between 2017 and August 2022.

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Synthetic Biology‐based Construction of Unnatural Perylenequinones with Improved Photodynamic Anticancer Activities

Su,

Guo,

et al. 2024

Angewandte Chemie

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The construction of structural complexity and diversity of natural products is crucial for drug discovery and development. To overcome high dark toxicity and poor photostability of natural photosensitizer perylenequinones (PQs) for photodynamic therapy, herein, we aim to introduce the structural complexity and diversity to biosynthesize the desired unnatural PQs in fungus Cercospora through synthetic biology‐based strategy. Thus, we first elucidate the intricate biosynthetic pathways of class B PQs and reveal how the branching enzymes create their structural complexity and diversity from a common ancestor. This enables the rational reprogramming of cercosporin biosynthetic pathway in Cercospora to generate diverse unnatural PQs without chemical modification. Among them, unnatural cercosporin A displays remarkably low dark toxicity and high photostability with retention of great photodynamic anticancer and antimicrobial activities. Moreover, it is found that, unlike cercosporin, the unnatural cercosporin A could be selectively accumulated in cancer cells, providing potential targets for drug development. Therefore, this work provides a comprehensive foundation for preparing unnatural products with customized functions through synthetic biology‐based strategies, thus facilitating drug discovery pipelines from nature.

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Discovery of the Biosynthetic Pathway of Beticolin 1 Reveals a Novel Non‐Heme Iron‐Dependent Oxygenase for Anthraquinone Ring Cleavage

Cited by 10 publications

References 44 publications

Structural analysis of an anthrol reductase inspires enantioselective synthesis of enantiopure hydroxycycloketones and β-halohydrins

Structural analysis of an anthrol reductase inspires enantioselective synthesis of enantiopure hydroxycycloketones and β-halohydrins

Unusual Dioxygen-Dependent Reactions Catalyzed by Nonheme Iron Enzymes in Natural Product Biosynthesis

Synthetic Biology‐based Construction of Unnatural Perylenequinones with Improved Photodynamic Anticancer Activities

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