Pinoresinol–lariciresinol reductases, key to the lignan synthesis in plants

Markulin, Lucija; Corbin, Cyrielle; Renouard, Sullivan; Drouet, Samantha; Gutierrez, Laurent; Mateljak, Ivan; Auguin, Daniel; Hano, Christophe; Fuss, Elisabeth; Lainé, Éric

doi:10.1007/s00425-019-03137-y

Cited by 50 publications

(50 citation statements)

References 125 publications

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“…In addition, PLRs also display substrate stereochemical selectivity, which contributes to enantiomeric diversity of lignans [20][21][22][23] . We found this to be true for IiPLR1, which gave comparable k cat /K m values for both (±)-pinoresinol and (±)-lariciresinol in the range of 0.9-1.6 µM −1 min −1 , although no experiments with respect to the enantio-specificity of this enzyme were performed 12,18 .…”

Section: Discussionmentioning

confidence: 83%

“…Lignans biosynthesis starts with the coupling of two coniferyl alcohols by an oxidase (laccase or peroxidase) with the aid of a dirigent protein to form pinoresinol 11 . Pinoresinol/lariciresinol reductase (PLR), an NADPH-dependent reductase, converts pinoresinol to lariciresinol and subsequently secoisolariciresinol 12 . Because the reductive steps that give rise to lariciresinol and secoisolariciresinol represent entry into the biosynthesis of furano, dibenzylbutane, dibenzylbutyrolactone, and aryltetrahydronaphthalene lignan subclasses 13 , PLR is regarded as a pivotal enzyme that contributes to lignan structural diversity.…”

Section: Introductionmentioning

confidence: 99%

“…The substrate selectivity of PLRs has attracted considerable attention 12 . Most PLRs that have been characterized reduce both pinoresinol and lariciresinol efficiently to produce lariciresinol and secoisolariciresinol, respectively 12 . Known exceptions are Arabidopsis thaliana reductases that have substrate preference toward pinoresinol but only weak (AtPrR1) or no activity (AtPrR2) toward lariciresinol and are thus named pinoresinol reductases (PrR) 15 .…”

Section: Introductionmentioning

confidence: 99%

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Structure based engineering for substrate specificity of pinoresinol-lariciresinol reductases

Xiao

Shao

Zhou

et al. 2020

Preprint

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Pinoresinol–lariciresinol reductases (PLR) are enzymes involved in the lignan biosynthesis after the initial dimerization of two monolignols, which represents the entry point for the synthesis of 8-8′ lignans and contributes greatly to their structural diversity. Of particular interest has been in determining how differing substrate specificities are achieved with these enzymes. Here, we present crystal structures of IiPLR1/AtPrR1/AtPrR2 in the apo, substrate-binding and product-binding forms. Each structure contains a head-to-tail homodimer, and the catalytic pocket comprises structural elements from both monomers. A loop β4 covers the top of the pocket, and residue 98 from the loop governs catalytic specificity. Structure-guided mutagenesis could switch the substrate specificity of IiPLR1 and AtPrR2, respectively. Our study provides new insight into the molecular mechanism underlying the substrate specificity of PLR/PrRs and suggests an efficient strategy for the large-scale commercial production of the pharmaceutically valuable compound lariciresinol.

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Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure based engineering for substrate specificity of pinoresinol-lariciresinol reductases

Xiao

Shao

Zhou

et al. 2020

Preprint

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“…The early lignan biosynthetic steps have been well described in different plant species and are well accepted. Two coniferyl alcohol moieties are converted into matairesinol in five steps involving three enzymes: an oxidase (most probably a laccase) in association with a DIR, a pinoresinol-lariciresinol reductase (PLR), and a secoisolariciresinol dehydrogenase (SDH) [43]. Some steps of the downstream biosynthetic pathway from matairesinol leading to PPT are still mainly hypothetical as will be described later ( Fig.…”

Section: The Origins Of Lignansmentioning

confidence: 99%

Bioproduction of Anticancer Podophyllotoxin and Related Aryltretralin-Lignans in Hairy Root Cultures of Linum Flavum L.

Mikac

Markulin

Drouet

et al. 2020

Reference Series in Phytochemistry

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Podophyllotoxin (PPT) is the unique natural precursor of Etoposide, a topoisomerase II inhibitor drug, used in more than a dozen anticancer chemotherapy treatments. Etoposide is appearing on the list of essential medicines of the World Health Organization. PPT is still exclusively extracted from the rhizome of Podophyllum species, its main natural source. The supply of Podophyllum hexandrum plants is limited, since the occurrence of these plant species is scarce, collection is destructive, and the plants need a long regeneration period. As a consequence, this species is now endangered and listed on Appendix II of the Convention on International Trading of Endangered Species. Chemical synthesis of PPT is difficult due to the presence of four contiguous chiral centers and the presence of a base sensitive trans-lactone moiety. Alternatives are being actively searched, but so far, no wild plants have been described with similar PPT production capacity as compared to Podophyllum. However, several plants producing PPT or other related aryltetralin lignans (ATL) have been identified in recent decades, including the Linaceae. Given its high lignan accumulation capacity, Linum flavum is considered a promising alternative source of PPT and other related ATL. However, unlike the common flax L. usitatissimum, L. flavum has a low agricultural potential (e.g., slow growth and dehiscence of fruits). Therefore, in vitro cultures of plant cells and/or tissues provide an interesting alternative to whole L. flavum plants for the production of these valuable ATL. In particular, L. flavum hairy roots (HRs) accumulate high levels of ATL and it is also possible to further increase this ATL accumulation by the selection of the best genotype, optimization of cultures media and conditions and choice of carbon sources, use of plant growth regulators, elicitor treatments, or precursors' addition. To date, the ATL accumulation levels can still be perceived insufficient for L. flavum HRs before being used as a commercially viable biotechnological production system. To reach this goal, a better knowledge of the mechanisms that regulate the metabolic flux of intermediates in the different branches of the ATL metabolic pathway will be an important prerequisite to direct the biosynthesis toward the production of a high amount of the desired PPT. In the future, metabolic engineering aiming at constructing the PPT pathway in a heterologous host is very appealing, but for that approach in-depth knowledge of the biosynthetic pathway toward PPT and other related ATL is necessary.

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“…Pinoresinol is then reduced into secoisolariciresinol by a stereoselective pinoresinol-lariciresinol reductase (PLR) enzyme, via lariciresinol formation. Two PLRs with opposite stereospecificity have been cloned and characterized in flax [20][21][22][23][24][25][26][27]. In flax, lariciresinol and secoisolariciresinol are stored as glycosides obtained after the action of specific UDP-glucosyltransferases [28].…”

Section: Introductionmentioning

confidence: 99%

Feasible Production of Lignans and Neolignans in Root-Derived In Vitro Cultures of Flax (Linum usitatissimum L.)

Anjum

Komal

Drouet

et al. 2020

Plants

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Flax lignans and neolignans impart health benefits, particularly in treating different types of cancers, due to their strong phytoestrogenic and antioxidant properties. The present study enhances the comprehension on the biosynthesis of antioxidant lignans and neolignans in root-derived in vitro cultures of flax (both callus and adventitious root). The results presented here clearly showed that the adventitious root culture efficiently produced a higher amount of lignans (at day 40) and neolignans (at day 30) than callus culture of flax. High performance liquid chromatography (HPLC) analysis revealed that the accumulations of secoisolariciresinol diglucoside (SDG, 5.5 mg g−1 DW (dry weight)) and dehydrodiconiferyl alcohol glucoside (DCG, 21.6 mg/g DW) were 2-fold higher, while guaiacylglycerol-β-coniferyl alcohol ether glucoside (GGCG, 4.9 mg/g DW) and lariciresinol glucoside (LDG, 11.9 mg/g DW) contents were 1.5-fold higher in adventitious root culture than in callus culture. Furthermore, the highest level of total phenolic production (119.01 mg/L), with an antioxidant free radical scavenging activity of 91.01%, was found in adventitious root culture at day 40, while the maximum level of total flavonoid production (45.51 mg/L) was observed in callus culture at day 30 of growth dynamics. These results suggest that adventitious root culture can be a good candidate for scaling up to industrial level to commercially produce these pharmacologically and nutritionally valuable metabolites.

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Pinoresinol–lariciresinol reductases, key to the lignan synthesis in plants

Cited by 50 publications

References 125 publications

Structure based engineering for substrate specificity of pinoresinol-lariciresinol reductases

Structure based engineering for substrate specificity of pinoresinol-lariciresinol reductases

Bioproduction of Anticancer Podophyllotoxin and Related Aryltretralin-Lignans in Hairy Root Cultures of Linum Flavum L.

Feasible Production of Lignans and Neolignans in Root-Derived In Vitro Cultures of Flax (Linum usitatissimum L.)

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