Metabolic Engineering of Plant Secondary Metabolism

Peters, Reuben J.; Croteau, Rodney

doi:10.1002/0470869143.kc029

Cited by 7 publications

(6 citation statements)

References 77 publications

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“…Based on their biogenetic origin, plant secondary metabolites can be roughly grouped into three major classes: phenylpropanoids, alkaloids, and terpenoids (Peters and Crouteau, 2004). Heterologous production of plant secondary metabolites from all three classes was recently reviewed elsewhere (Marienhagen and Bott, 2013; Miralpeix et al, 2013; Zhou et al, 2014).…”

Section: Approaches For Resupply Of Pharmacologically Active Plantmentioning

confidence: 99%

Discovery and resupply of pharmacologically active plant-derived natural products: A review

Atanasov

Waltenberger

Pferschy‐Wenzig

et al. 2015

Biotechnology Advances

2,189

1,385

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Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a “screening hit” through a “drug lead” to a “marketed drug” is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis.While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

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Section: Approaches For Resupply Of Pharmacologically Active Plantmentioning

confidence: 99%

Discovery and resupply of pharmacologically active plant-derived natural products: A review

Atanasov

Waltenberger

Pferschy‐Wenzig

et al. 2015

Biotechnology Advances

2,189

1,385

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“…OsDTS2) provides a logical point for controlling the production of these specific labdanerelated diterpenoid natural products. Previous review of the relevant literature has been used to suggest that plant secondary metabolism is most often regulated at the level of transcription (Peters and Croteau, 2004). This has been demonstrated for the preceding enzyme OsCPS syn , where the corresponding mRNA increases prior to syn-labdane-related diterpenoid phytochemical accumulation in UV-irradiated rice leaves (Xu et al, 2004).…”

Section: Expression Pattern Of Osdts2 Mrnamentioning

confidence: 99%

Identification of Syn-Pimara-7,15-Diene Synthase Reveals Functional Clustering of Terpene Synthases Involved in Rice Phytoalexin/Allelochemical Biosynthesis

et al. 2004

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Rice (Oryza sativa) produces momilactone diterpenoids as both phytoalexins and allelochemicals. Accordingly, the committed step in biosynthesis of these natural products is catalyzed by the class I terpene synthase that converts syn-copalyl diphosphate to the corresponding polycyclic hydrocarbon intermediate syn-pimara-7,15-diene. Here, a functional genomics approach was utilized to identify a syn-copalyl diphosphate specific 9b-pimara-7,15-diene synthase (OsDTS2). To our knowledge, this is the first identified terpene synthase with this particular substrate stereoselectivity and, by comparison with the previously described and closely related ent-copalyl diphosphate specific cassa-12,15-diene synthase (OsDTC1), provides a model system for investigating the enzymatic determinants underlying the observed difference in substrate specificity. Further, OsDTS2 mRNA in leaves is up-regulated by conditions that stimulate phytoalexin biosynthesis but is constitutively expressed in roots, where momilactones are constantly synthesized as allelochemicals. Therefore, transcription of OsDTS2 seems to be an important regulatory point for controlling production of these defensive compounds. Finally, the gene identified here as OsDTS2 has previously been mapped at 14.3 cM on chromosome 4. The class II terpene synthase producing syn-copalyl diphosphate from the universal diterpenoid precursor geranylgeranyl diphosphate was also mapped to this same region. These genes catalyze sequential cyclization steps in momilactone biosynthesis and seem to have been evolutionarily coupled by physical linkage and resulting cosegregation. Further, the observed correlation between physical proximity and common metabolic function indicates that other such class I and class II terpene synthase gene clusters may similarly catalyze consecutive reactions in shared biosynthetic pathways.Plants produce a vast and diverse array of low-molecular weight organic compounds, the overwhelming majority of which are secondary metabolites with nonessential, yet important, functions such as defense . For example, phytoalexins are produced in response to microbial infections and exhibit antimicrobial activity (VanEtten et al., 1994), while allelochemicals are secreted to the rhizosphere and suppress the growth of neighboring plants (Bais et al., 2004). Often found serving in such roles are terpenoids, which are particularly abundant in plant metabolism and form the largest class of natural products, exhibiting wide diversity in chemical structure and biological function . Much of the structural variation within this class arises from the diverse carbon backbones formed by terpene synthases (cyclases). These divalent metal dependent enzymes carry out complex electrophilic cyclizations/ rearrangements to create these diverse skeletal structures from relatively simple acyclic precursors (Davis and Croteau, 2000). Notably, production of a specific backbone structure either dictates, or at least severely restricts, the metabolic fate of that particular molecule. Thus,...

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“…Previous review of the relevant literature has been used to suggest that plant secondary metabolism is most often regulated at the level of transcription (Peters and Croteau, 2004). Transcriptional control is manifested by up-regulation of enzymatic mRNA levels, with subsequent phytochemical accumulation, in response to the appropriate environmental conditions.…”

Section: Oscps1 Ent and Oscps2 Ent Have Distinct Metabolic Functionsmentioning

confidence: 99%

Rice Contains Two Disparate ent-Copalyl Diphosphate Synthases with Distinct Metabolic Functions

et al. 2004

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Rice (Oryza sativa) produces ent-copalyl diphosphate for both gibberellin (GA) phytohormone and defensive phytoalexin biosynthesis, raising the question of how this initial biosynthetic step is carried out for these distinct metabolic processes. Here, a functional genomics approach has been utilized to identify two disparate ent-copalyl diphosphate synthases from rice (OsCPS1 ent and OsCPS2 ent ). Notably, it was very recently demonstrated that only one of these (OsCPS1 ent ) normally operates in GA biosynthesis as mutations in this gene result in severely impaired growth. Evidence is presented here strongly indicating that the other (OsCPS2 ent ) is involved in related secondary metabolism producing defensive phytochemicals. In particular, under appropriate conditions, OsCPS2 ent mRNA is specifically induced in leaves prior to production of the corresponding phytoalexins. Thus, transcriptional control of OsCPS2 ent seems to be an important means of regulating defensive phytochemical biosynthesis. Finally, OsCPS1 ent is significantly more similar to the likewise GA-specific gene An1/ZmCPS1 ent in maize (Zea mays) than its class II terpene synthase paralogs involved in rice secondary metabolism. Hence, we speculate that this crossspecies conservation by biosynthetic process reflects derivation of related secondary metabolism from the GA primary biosynthetic pathway prior to the early divergence between the separate lineages within the cereal/grass family (Poaceae) resulting in modern rice and maize.Plants produce a vast and diverse array of low-M r organic compounds. A small number of these are primary metabolites, which are common to all plant species as they are directly required for growth and development. The remaining, overwhelming majority of these natural products are considered secondary metabolites, although many have important ecological roles, particularly in plant defense (Dixon, 2001). Terpenoids, which comprise the largest class of natural products, are particularly abundant in plants and can be found in both primary and secondary metabolism . Notably, a substantial fraction of the known terpenoids can be classified as labdanerelated diterpenoids (20 carbon). These are defined here as minimally containing the bicyclic hydrocarbon structure found in the labdane class of diterpenoids, although this core structure can be further cyclized and/or rearranged, as in the related/derived structural classes (e.g. kauranes, abietanes, and [iso] pimaranes). Significantly, this includes the GA growth hormones as primary metabolites. Nevertheless, the vast majority of the .5,000 labdane-related diterpenoids are secondary metabolites.Biosynthesis of labdane-related diterpenoids is initiated by class II terpene synthases, which catalyze formation of the characteristic bicyclic backbone in producing specific stereoisomers of labdadienyl/ copalyl diphosphate (CPP) from the universal diterpenoid precursor (E,E,E)-geranylgeranyl diphosphate (GGPP). This protonation-initiated cyclization is fundamentally different than ...

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Metabolic Engineering of Plant Secondary Metabolism

Cited by 7 publications

References 77 publications

Discovery and resupply of pharmacologically active plant-derived natural products: A review

Discovery and resupply of pharmacologically active plant-derived natural products: A review

Identification of Syn-Pimara-7,15-Diene Synthase Reveals Functional Clustering of Terpene Synthases Involved in Rice Phytoalexin/Allelochemical Biosynthesis

Rice Contains Two Disparate ent-Copalyl Diphosphate Synthases with Distinct Metabolic Functions

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