CYP76B74 Catalyzes the 3′′-Hydroxylation of Geranylhydroquinone in Shikonin Biosynthesis

Wang, Sheng; Wang, Ruishan; Liu, Tan; Lv, Chaogeng; Liang, Jiu-Wen; Kang, Chuan-Zhi; Zhou, Liang-Yun; Guo, Juan; Cui, Guanghong; Zhang, Yan; Werck‐Reichhart, Danièle; Guo, Lan-Ping; Huang, Luqi

doi:10.1104/pp.18.01056

Cited by 39 publications

(44 citation statements)

References 54 publications

(66 reference statements)

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“…euchroma 34 and CYP76B100/101 in L. erythrorhizon (Fig. 1), have already been implicated in oxidative reactions in shikonin biosynthesis, but the evolutionary relationships between these genes has been unclear.…”

Section: Shikonin Pathway Gene Candidates Provide Insights Into Specialized Metabolic Innovation In the Boraginaceaementioning

confidence: 99%

Integrative analysis of the shikonin metabolic network identifies new gene connections and reveals evolutionary insight into shikonin biosynthesis

Suttiyut

Auber

Ghaste

et al. 2021

Preprint

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SummaryPlant specialized 1,4-naphthoquinones present a remarkable case of convergent evolution. Species across multiple discrete orders of vascular plants produce diverse 1,4-naphthoquinones via one of several pathways using different metabolic precursors. Evolution of these pathways was preceded by events of metabolic innovation and many appear to share connections with biosynthesis of photosynthetic or respiratory quinones. Here, we sought to shed light on the metabolic connections linking shikonin biosynthesis with its precursor pathways and on the origins of shiknoin metabolic genes. Downregulation of Lithospermum erythrorhizon geranyl diphosphate synthase (LeGPPS), recently shown to have been recruited from a cytoplasmic farnesyl diphosphate synthase (FPPS), resulted in reduced shikonin production and a decrease in expression of mevalonic acid and phenylpropanoid pathway genes. Next, we used LeGPPS and other known shikonin pathway genes to build a coexpression network model for identifying new gene connections to shikonin metabolism. Integrative in silico analyses of network genes revealed candidates for biochemical steps in the shikonin pathway arising from Boraginales-specific gene family expansion. Multiple genes in the shikonin coexpression network were also discovered to have originated from duplication of ubiquinone pathway genes. Taken together, our study provides evidence for transcriptional crosstalk between shikonin biosynthesis and its precursor pathways, identifies several shikonin pathway gene candidates and their evolutionary histories, and establishes additional evolutionary links between shikonin and ubiquinone metabolism. Moreover, we demonstrate that global coexpression analysis using limited transcriptomic data obtained from targeted experiments is effective for identifying gene connections within a defined metabolic network.

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Section: Shikonin Pathway Gene Candidates Provide Insights Into Specialized Metabolic Innovation In the Boraginaceaementioning

confidence: 99%

Integrative analysis of the shikonin metabolic network identifies new gene connections and reveals evolutionary insight into shikonin biosynthesis

Suttiyut

Auber

Ghaste

et al. 2021

Preprint

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“…1B ). Since then, several studies have further corroborated the existence of different 1,4-naphthoquinone pathways across plants and provided insight into their metabolic evolution ( McCoy et al , 2018 ; Rajniak et al , 2018 ; S. Wang et al , 2019 ; Auber et al , 2020 ; Song et al , 2020 ; Ueoka et al , 2020 ) ( Box 1 ). Moreover, genome assemblies from 1,4-naphthoquinone-producing species also revealed potential glimpses into the metabolic innovation that facilitated 1,4-naphthoquinone pathway evolution.…”

Section: Convergent Evolution Of Plant 14-naphthoquinone Biosynthesimentioning

confidence: 99%

“… S. Wang et al (2019) showed that CYP76B74, which localizes to the endoplasmic reticulum membrane, catalyzes the hydroxylation of the shikonin pathway intermediate geranylhydroquinone in Arnebia euchroma . Song et al (2020) more recently demonstrated that A. euchroma CYP76B100 is also capable of hydroxylating geranylhydroquinone, while CYP76B101 catalyzes the three-step oxidation of geranylhydroquinone to form a 3''-carboxylic acid derivative of geranylhydroquinone.…”

Section: Convergent Evolution Of Plant 14-naphthoquinone Biosynthesimentioning

confidence: 99%

Convergent evolution of plant specialized 1,4-naphthoquinones: metabolism, trafficking, and resistance to their allelopathic effects

Meyer

Naranjo

Widhalm

2020

Journal of Experimental Botany

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Plant 1,4-naphthoquinones encompass a class of specialized metabolites known to mediate numerous plant–biotic interactions. This class of compounds also presents a remarkable case of convergent evolution. The 1,4-naphthoquinones are synthesized by species belonging to nearly 20 disparate orders spread throughout vascular plants, and their production occurs via one of four known biochemically distinct pathways. Recent developments from large-scale biology and genetic studies corroborate the existence of multiple pathways to synthesize plant 1,4-naphthoquinones and indicate that extraordinary events of metabolic innovation and links to respiratory and photosynthetic quinone metabolism probably contributed to their independent evolution. Moreover, because many 1,4-naphthoquinones are excreted into the rhizosphere and they are highly reactive in biological systems, plants that synthesize these compounds also needed to independently evolve strategies to deploy them and to resist their effects. In this review, we highlight new progress made in understanding specialized 1,4-naphthoquinone biosynthesis and trafficking with a focus on how these discoveries have shed light on the convergent evolution and diversification of this class of compounds in plants. We also discuss how emerging themes in metabolism-based herbicide resistance may provide clues to mechanisms plants employ to tolerate allelopathic 1,4-naphthoquinones.

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“…Current efforts have extended to include synthetic chemistry for producing shikonin, alkannin, and derivatives with higher specificity and potency 12,13 . Moreover, the use of comparative transcriptomics (e.g., [14][15][16] ) and proteomics 17 approaches for elucidating the shikonin/alkannin pathway has uncovered several gene candidates and led to the identification of the geranylhydroquinone hydroxylase (GHQH; CYP76B74) 18 . Comparatively less attention has focused on the evolutionary origin of shikonin/alkannin pathway genes 16,19 and on the ecological significance of producing the compounds 3 .…”

Section: Introductionmentioning

confidence: 99%

Hybrid de novo genome assembly of red gromwell (Lithospermum erythrorhizon) reveals evolutionary insight into shikonin biosynthesis

et al. 2020

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Lithospermum erythrorhizon (red gromwell; zicao) is a medicinal and economically valuable plant belonging to the Boraginaceae family. Roots from L. erythrorhizon have been used for centuries based on the antiviral and woundhealing properties produced from the bioactive compound shikonin and its derivatives. More recently, shikonin, its enantiomer alkannin, and several other shikonin/alkannin derivatives have collectively emerged as valuable natural colorants and as novel drug scaffolds. Despite several transcriptomes and proteomes having been generated from L. erythrorhizon, a reference genome is still unavailable. This has limited investigations into elucidating the shikonin/ alkannin pathway and understanding its evolutionary and ecological significance. In this study, we obtained a de novo genome assembly for L. erythrorhizon using a combination of Oxford Nanopore long-read and Illumina short-read sequencing technologies. The resulting genome is ∼367.41 Mb long, with a contig N50 size of 314.31 kb and 27,720 predicted protein-coding genes. Using the L. erythrorhizon genome, we identified several additional phydroxybenzoate:geranyltransferase (PGT) homologs and provide insight into their evolutionary history. Phylogenetic analysis of prenyltransferases suggests that PGTs originated in a common ancestor of modern shikonin/alkanninproducing Boraginaceous species, likely from a retrotransposition-derived duplication event of an ancestral prenyltransferase gene. Furthermore, knocking down expression of LePGT1 in L. erythrorhizon hairy root lines revealed that LePGT1 is predominantly responsible for shikonin production early in culture establishment. Taken together, the reference genome reported in this study and the provided analysis on the evolutionary origin of shikonin/alkannin biosynthesis will guide elucidation of the remainder of the pathway.

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CYP76B74 Catalyzes the 3′′-Hydroxylation of Geranylhydroquinone in Shikonin Biosynthesis

Cited by 39 publications

References 54 publications

Integrative analysis of the shikonin metabolic network identifies new gene connections and reveals evolutionary insight into shikonin biosynthesis

Integrative analysis of the shikonin metabolic network identifies new gene connections and reveals evolutionary insight into shikonin biosynthesis

Convergent evolution of plant specialized 1,4-naphthoquinones: metabolism, trafficking, and resistance to their allelopathic effects

Hybrid de novo genome assembly of red gromwell (Lithospermum erythrorhizon) reveals evolutionary insight into shikonin biosynthesis

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