Two rings in them all: The labdane-related diterpenoids

Abstract

In his original exposition of the biogenetic isoprenoid rule, L. Ruzicka noted the structural identity between the fused A/B rings of triterpenoids/sterols and certain multicyclic diterpenoids as part of the impetus leading to that profound insight. His prescient hypothesis that this chemical structure relationship reflects similarities in the initial cyclization of these diterpenoids with that occurring in triterpenoid biosynthesis has since been verified. However, this chemical structure relationship does not continue to hold true for the additional rings found in many of these di- and tri- terpenoid natural products. This is now appreciated to arise from differences in their subsequent biogenesis, specifically further cyclization and/or rearrangement of these diterpenoids after formation of an initial bicyclic intermediate in a separately catalyzed reaction. The trivial name for the hydrocarbon skeleton of the most commonly found version of the corresponding unique intermediate forms the basis for a unifying “labdane-related” designation. This defines a large super-family of diterpenoids that contains nearly 7,000 already known natural products. Many of these are found in plants, where the requisite biosynthetic machinery for gibberellin phytohormones, particularly the relevant diterpene cyclases, provides a biosynthetic reservoir that appears to have been repeatedly drawn upon to evolve new labdane-related diterpenoids. The potent biological activity of the “ancestral” gibberellins, which has led to the independent evolution of distinct gibberellin biosynthetic pathways in plants, fungi, and bacteria, is further discussed as an archetypical example of the selective pressure driving the observed diversification of the large super-family of labdane-related diterpenoid natural products.

Expanding the Landscape of Diterpene Structural Diversity through Stereochemically Controlled Combinatorial Biosynthesis

“…The combination of TwTPS14 with SsSCS produced a compound consistent with a diTPS function new to plants and only recently reported in the bacterium Herpetosiphon aurantiacus 13. Purification and NMR analysis established the structure as kolavelool ( 26 ), from the distinct class of clerodane‐type diterpenes (Table S6) 4b. These diterpenes have been reported from a range of plant species and form the skeleton of salvinorin A, a lead drug candidate for the treatment of mental disorders and substance dependence,14 yet the biosynthetic route remains unknown.…”

“…The subsequent class I diTPS reaction completes the formation of the diterpene skeleton through dephosphorylation of the class II product and specific rearrangements, additional cyclizations, or water addition, thereby resulting in the introduction of additional chiral centers (Scheme 1). 4b …”

Discovery, Biosynthesis and Stress-Related Accumulation of Dolabradiene-Derived Defenses in Maize

“…All of these enzymes have either validated or predicted roles in GA metabolism. However, the frequently observed substrate promiscuity of characterized enzymes (Peters, 2010;Morrone et al, 2011;Zerbe and Bohlmann, 2015) also may enable roles in defense-related specialized metabolism. In the absence of mutant analyses, the maize kauralexin and zealexin metabolic pathways have remained largely unproven, with the exception of the ent-CPP synthase ZmAN2, which has been empirically demonstrated to function in kauralexin formation (Harris et al, 2005;Vaughan et al, 2015).…”

“…Plants employ variable combinations of different diTPSs and P450s to transform a few ubiquitous diterpene precursors into thousands of different diterpenoid metabolites, many of which are of limited taxonomic distribution (Peters, 2010;Zerbe and Bohlmann, 2015). Modular enzyme networks largely determine the variations of diterpene profiles in closely and distantly related plant species (Peters, 2010;Hamberger and Bak, 2013;Zerbe and Bohlmann, 2015). Naturally occurring modularity in diterpenoid biosynthesis further enables the engineering of combinatorial diTPS and P450 expression systems in microbial and plant host systems to accelerate the discovery of terpenoid pathways (Brückner and Tissier, 2013;Lange and Ahkami, 2013;Kitaoka et al, 2015;Zerbe and Bohlmann, 2015).…”

“…Plants employ variable combinations of different diTPSs and P450s to transform a few ubiquitous diterpene precursors into thousands of different diterpenoid metabolites, many of which are of limited taxonomic distribution (Peters, 2010;Zerbe and Bohlmann, 2015). Modular enzyme networks largely determine the variations of diterpene profiles in closely and distantly related plant species (Peters, 2010;Hamberger and Bak, 2013;Zerbe and Bohlmann, 2015).…”