The genomes of medicinal skullcaps reveal the polyphyletic origins of clerodane diterpene biosynthesis in the family Lamiaceae

Li, Haixiu; Wu, Song; Lin, Ruoxi; Xiao, Yiren; Morotti, Ana Luisa Malaco; Wang, Ya; Galilee, Meytal; Qin, Haowen; Huang, Tao; Zhao, Yong; Zhou, Xun; Yang, Jeong-Mo; Zhao, Qing; Kanellis, Angelos K.; Martin, Cathie; Tatsis, Evangelos C.

doi:10.1016/j.molp.2023.01.006

Cited by 21 publications

(10 citation statements)

References 86 publications

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“…Very recently, Li et al. (2023) have identified a mono‐functional (−)‐KPS (SbbdiTPS2.1) and an isokolavenyl diphosphate synthase (same as neo ‐cleroda‐4(18),13 E ‐dienyl diphosphate synthase, SbbdiTPS2.3) from S. barbata (Li et al., 2023). Interestingly, we identified the same mono‐functional (−)‐KPS (SbarKPS1), while SbarKPS2 was demonstrated to produce two products with major neo ‐cleroda‐4(18),13 E ‐dienyl diphosphate and a small amount of (−)‐KPP in our study.…”

Section: Discussionmentioning

confidence: 99%

“…To our knowledge, only two types of mono-functional class II diTPSs have been reported in clerodane pathways including (À)-KPS and neo-cleroda-4 (18),13E-dienyl diphosphate synthase (Andersen-Ranberg et al, 2016;Chen et al, 2017;Hansen et al, 2017;Hamilton et al, 2020;Pelot et al, 2017). Very recently, Li et al (2023) have identified a mono-functional (À)-KPS (SbbdiTPS2.1) and an isokolavenyl diphosphate synthase (same as neo-cleroda-4(18),13E-dienyl diphosphate synthase, SbbdiTPS2.3) from S. barbata (Li et al, 2023). Interestingly, we identified the same mono-functional (À)-KPS (SbarKPS1), while SbarKPS2 was demonstrated to produce two products with major neo-cleroda-4(18),13E-dienyl diphosphate and a small amount of (À)-KPP in our study.…”

Section: Discussionmentioning

confidence: 99%

“…In angiosperms, class I diTPSs catalyze the dephosphorylation and rearrangement of the bicyclic prenyl diphosphate products from class II diTPSs and form the skeleton of labdane-related diterpenoids. Only several extremely promiscuous class I diTPSs from plants and bacteria have been reported to work on clerodane class II diTPS products (Jia et al, 2019), until very recently Li et al (2023) reported two class I diTPSs (SbbdiTPS1.2, SbbdiTPS1.4) from S. barbata both of which can catalyze the dephosphorylation of (À)-KPP and neo-cleroda-4 (18),13E-dienyl diphosphate to form kolavenol and isokolavenol, respectively. Here we identified the same class I diTPSs (named as SbarKSL3 and SbarKSL4) and performed in vitro characterization in couple with four different class II diTPSs (SbarKPS1, SbarKPS2, SbarCPS2 and SbarCPS4) without or with phosphatase inhibitor cocktails.…”

Section: Discussionmentioning

confidence: 99%

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Tandem duplication and sub‐functionalization of clerodane diterpene synthase originate the blooming of clerodane diterpenoids in Scutellaria barbata

Qiu

et al. 2023

The Plant Journal

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SUMMARYScutellaria barbata is a traditional Chinese herb medicine and a major source of bioactive clerodane diterpenoids. However, barely clerodanes have been isolated from the closely related S. baicalensis. Here we assembled a chromosome‐level genome of S. barbata and identified three class II clerodane diterpene synthases (SbarKPS1, SbarKPS2 and SbaiKPS1) from these two organisms. Using in vitro and in vivo assays, SbarKPS1 was characterized as a monofunctional (−)‐kolavenyl diphosphate synthases ((−)‐KPS), while SbarKPS2 and SbaiKPS1 produced major neo‐cleroda‐4(18),13E‐dienyl diphosphate with small amount of (−)‐KPP. SbarKPS1 and SbarKPS2 shared a high protein sequence identity and formed a tandem gene pair, indicating tandem duplication and sub‐functionalization probably led to the evolution of monofunctional (−)‐KPS in S. barbata. Additionally, SbarKPS1 and SbarKPS2 were primarily expressed in the leaves and flowers of S. barbata, which was consistent with the distribution of major clerodane diterpenoids scutebarbatine A and B. In contrast, SbaiKPS1 was barely expressed in any tissue of S. baicalensis. We further explored the downstream class I diTPS by functional characterizing of SbarKSL3 and SbarKSL4. Unfortunately, no dephosphorylated product was detected in the coupled assays with SbarKSL3/KSL4 and four class II diTPSs (SbarKPS1, SbarKPS2, SbarCPS2 and SbarCPS4) when a phosphatase inhibitor cocktail was included. Co‐expression of SbarKSL3/KSL4 with class II diTPSs in yeast cells did not increase the yield of the corresponding dephosphorylated products, either. Together, these findings elucidated the involvement of two class II diTPSs in clerodane biosynthesis in S. barbata, while the class I diTPS is likely not responsible for the subsequent dephosphorylation step.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Tandem duplication and sub‐functionalization of clerodane diterpene synthase originate the blooming of clerodane diterpenoids in Scutellaria barbata

Qiu

et al. 2023

The Plant Journal

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“…Several instances are reported of three or more genes comprising the same biosynthetic pathway are physically co-localized, thus genome mining can aid gene discovery [33][34][35][36] . Because the polyketidemodule biosynthesis genes clustered within HpBGC1 20 , clustering may well also be the case for the downstream genes 32,37,38 . Based on functional annotation, 405 genes were predicted to be UbiAfamily aromatic prenyltransferases.…”

Section: Genome Mining and Co-expression Analysis To Identify Aromati...mentioning

confidence: 99%

Single-cell RNA-seq based elucidation of the antidepressant hyperforin biosynthesisde novoin St. John’s wort

Wu,

Morotti,

Yang

et al. 2024

Preprint

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Hyperforin is the compound responsible for the effectiveness of St. John's wort (Hypericum perforatum) as an antidepressant, but its biosynthesis remains unknown. Gene discovery based on co-expression analysis of bulk RNA-sequencing data or genome mining failed to discover the missing steps in hyperforin biosynthesis. Here we sequenced the tetraploid H. perforatum genome. By single-cell RNA-seq, we identified a distinct type of cells, Hyper cells, wherein hyperforin biosynthesis de novo takes place. Through pathway reconstitution in yeast and tobacco, we identify and characterize four transmembrane prenyltransferases to resolve hyperforin biosynthesis. The hyperforin polycyclic scaffold is created by a reaction cascade involving an irregular isoprenoid coupling and a tandem cyclization. Our findings reveal how and where hyperforin is biosynthesized that enables synthetic-biology reconstitution of the complete pathway. These results deepen our comprehension of specialized metabolism at the cellular level, and we anticipate acceleration of pathway elucidation in plant metabolism.

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“…For example, the presence of anticancer clerodane diterpenoids serves as a chemotaxonomic marker for Scutellaria barbata , although the molecular mechanisms underlying clerodane biosynthesis remain unknown. Li et al [87] have reported a high-quality assembly of the 414.98 Mb genome of S barbata into 13 pseudochromosomes. They have also mapped the plastidial metabolism of kaurene (gibberellins), abietane, and clerodane diterpenes in 3 species of the Lamiaceae family ( S barbata , Scutellaria baicalensis , and Salvia splendens ) using phylogenomic and biochemical data.…”

Section: Biological Essence and Inspirationmentioning

confidence: 99%

Theory and scientificity of traditional Chinese medicine

Guo,

Zhang,

Huang

2023

Sci Tradit Chin Med

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The Nobel Prize for artemisinin and the COVID-19 pandemic have heightened interest in the disease prevention and treatment of traditional Chinese medicine (TCM). However, uncertainty and misinformation remain about some key issues. Herein, we discuss the current literature showing that, despite TCM gaining recognition, the theoretical systems of TCM and Western medicine rooted in different cultural backgrounds have huge differences in their theories and treatments. How to achieve accurate diagnosis in TCM, how to give scientific treatment, what is the mechanism of treatment, and what are the effect and safety of treatment, all need to be more clearly explained and require high-quality modern scientific evidence. An emerging consensus exists that, with the help of modern technology and scientific methods, it is necessary to excavate the essence of TCM that truly conforms to the laws of human life movement and disease development, realize cross-complementation with Western medicine, enhance human understanding of diseases, enrich diagnosis and treatment methods, and promote a new level in the field of life sciences.

show abstract

The genomes of medicinal skullcaps reveal the polyphyletic origins of clerodane diterpene biosynthesis in the family Lamiaceae

Cited by 21 publications

References 86 publications

Tandem duplication and sub‐functionalization of clerodane diterpene synthase originate the blooming of clerodane diterpenoids in Scutellaria barbata

Tandem duplication and sub‐functionalization of clerodane diterpene synthase originate the blooming of clerodane diterpenoids in Scutellaria barbata

Single-cell RNA-seq based elucidation of the antidepressant hyperforin biosynthesisde novoin St. John’s wort

Theory and scientificity of traditional Chinese medicine

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