Harvesting the biosynthetic machineries that cultivate a variety of indispensable plant natural products

Abstract

Plants are a sustainable resource for valuable natural chemicals best illustrated by large-scale farming centered on specific products. Here, we review recent discoveries of plant metabolic pathways producing natural products with unconventional biomolecular structures. Prenylation of polyketides by aromatic prenyltransferases (aPTases) ties together two of the major groups of plant specialized chemicals, terpenoids and polyketides, providing a core modification leading to new bioactivities and downstream metabolic processing. Moreover, PTases that biosynthesize Z-terpenoid precursors for small molecules such as lycosantalene have recently been found in the tomato family. Gaps in our understanding of how economically important compounds such as cannabinoids are produced are being identified using next-generation 'omics' to rapidly advance biochemical breakthroughs at an unprecedented rate. For instance, olivetolic acid cyclase, a polyketide synthase (PKS) co-factor from Cannabis sativa, directs the proper cyclization of a polyketide intermediate. Elucidations of spatial and temporal arrangements of biosynthetic enzymes into metabolons, such as those used to control the efficient production of natural polymers such as rubber and defensive small molecules such as linamarin and lotaustralin, provide blueprints for engineering streamlined production of plant products.

Figure 1

Specialized metabolites from plants. Segments of the molecules depicted are color-coded based on biosynthetic origin. Molecules in green are derived from T3PKSs, red derived from PTases, blue derived from fatty acid or amino acid anabolic and catabolic pathways, and black derived from an assortment of other biosynthetic pathways. E or Z configurations are shown for natural rubber to highlight the absolute stereochemistry of its double bonds.

Figure 2

PTases employed in plant natural product biosynthesis. (a) Aromatic PTases (aPTases) catalyze the addition of a terpenoid-derived prenyl group onto an electron-rich aromatic phenolic core, as exemplified by the prenylation of naringenin to form 6-prenylnaringenin and 8-prenylnaringenin. Notably, aPTases often exhibit relaxed substrate specificity and/or relaxed regiospecificity as shown here. As reported, when isolated from hops, the amounts of 6-prenylnaringenin and 8-prenylnaringenin are approximately equal. However, this ratio may not hold true in other plants, which may vary from plant to plant. Additionally, the ratios of each prenylated compound account for 1–2% of total prenylflavonoids in hops and vary dependent on growth conditions making accurate quantification difficult. (b) cis-PTases catalyze the formation of Z-terpenoids, thus increasing the structural diversity and potential beneficial activity of the broad family of plant terpenoids.

Figure 3

Biosynthesis of Δ⁹-tetrahydrocannabinolic acid. This biosynthetic pathway features enzymes that likely possess species-specific enzymatic activity, namely the hexanoyl-CoA ligase, tetraketide synthase and olivetolic acid cyclase that are all required for the formation of the precursor molecule olivetolic acid. In the absence of olivetolic acid cyclase, 2-pyrones (α-pyrones) form as the major products. 2-Pyrones derived from both triketide and tetraketide intermediates occur upon lactonization of extended polyketide intermediates. For clarity, the 2-pyrone derived from a fully extended tetraketide intermediate is shown. Olivetolic acid is then geranylated by CsPT1 to form cannabigerolic acid. Cannabigerolic acid then undergoes cyclization catalyzed by THCA synthase to form Δ⁹-tetrahydrocannabinolic acid. The psychotropic activity of these compounds comes about upon heating of Δ⁹-tetrahydrocannabinolic acid, which undergoes decarboxylation to Δ⁹-tetrahydrocannabinol.

Figure 4

Production of bitter acids in hops trichomes. (a) Biosynthetic pathway to α-acids and β-acids, including the enzymatic pathways discussed in the text. The oxygenase required for α-acid formation has not yet been functionally characterized to date. While both isovaleryl-CoA and isobutyryl-CoA are utilized by HlVPS, for clarity, only the isovaleryl-CoA transformation is depicted. (b) Depiction and cellular location of the metabolon that produces β-acids in hops. Many plant natural products are sequestered in specialized cells and tissues. Glandular trichomes are notable developmental innovations that have arisen during land plant evolution. Practically, they also provide an economical route to downstream processing to enrich for particular plant chemicals.