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 (>50,000 already known), with the 20-carbon diterpenoids targeted here forming a significant fraction of these (>12,000 known). The extensive diversification of diterpenoids indicates that the manifold hydrocarbon skeletons that can be formed from this C20 backbone, particularly the decalin core ring structure found in the labdane-related diterpenoids (>7,000 known), provide privileged scaffolds for derivation of biological activity. Indeed, a number of these labdane-related diterpenoids are used as pharmaceuticals (e.g., the antibiotic mutilins) or are being investigated for such use (e.g., the tanshinones, triptolide, andrographolide, etc.). Moreover, we have contributed to the discovery that the human pathogen Mycobacterium tuberculosis utilizes labdane-related diterpenoid metabolism in construction of an immune- modulatory factor. In order to continue our productive work on the biosynthetic enzymes required to produce bioactive diterpenoids, we are requesting a Supplemental Equipment award to replace the GC- MS that represents the key instrument for our studies.
The diterpenoids form a very large class of natural products (>12,000 known), which includes a number of realized (e.g., pleuromutilin) or potential (e.g., triptolide) pharmaceutical use, as well as an immuno-modulatory factor produced by the human pathogen Mycobacterium tuberculosis. Here we propose to continue our fruitful investigations of the enzymes that produce these natural products. This will not only increase our understanding of the relevant enzymatic mechanisms, but also enable engineering of such biosynthesis to increase access to these often-scarce natural products.
