Friday, May 9, 2025
5/9/2025
Investigating labdane-related diterpenoid biosynthesis - Project Summary/Abstract Natural products have a proven record of providing a significant fraction, either directly or as lead compounds, of human medicines. Among natural products, the terpenoids (isoprenoids) stand out as being the largest class (>80,000 already known), with the labdane-related diterpenoids (LRDs) that are the focus of our studies forming a significant fraction of these (>7,000 known). Notably LRD biosynthesis further models that of all terpenoids more generally, as the relevant diterpene cyclases and diterpene synthases are phylogenetically and mechanistically related to the oxido-squalene cyclases and terpene synthases from triterpenoid and smaller (mono-, sesqui- and other di-) terpenoid biosynthesis (respectively). More concretely, the extensive diversification of LRDs indicates that the manifold hydrocarbon skeletons that can be formed around the characteristic decalin core ring provides privileged scaffolds for derivation of biological activity. Indeed, a number of these LRDs are used as pharmaceuticals (e.g., the novel mutilin antibiotics derived from pleuromutilin) or are being investigated for such use (e.g., the tanshinones), while others serve important roles in widely grown crops (e.g., rice), such that engineering their biosynthesis may enable reduced agrochemicals application and, hence, improve food and environmental safety. Accordingly, we propose here to continue our productive studies of the enzymes required to produce LRDs. Specifically, we will build on our previous work in this area, which includes investigations of enzymatic structure-function that have provided novel biosynthetic access to an array of LRD backbones, such as those relevant to production of pleuromutilin, as well as further elucidation of the complex LRD metabolism in rice, which serves as a model system for the extensive diversification of these natural products throughout cereal crop plants more generally, and which we have shown play key roles as antibiotics against microbial pathogens as well as parasitic nematodes. This MIRA renewal proposal covers our systematic studies in this general area, advancing our long-term goal of engineering enzymes and metabolic pathways for production of targeted libraries and specific individual LRD ‘natural’ products, several of which are already in medical use and the utility of which in crop engineering for improved environmental and, hence, human health is already being realized.
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