Tropolone is biosynthesized through a highly unusual polyketide-derived pathway involving multiple key enzymatic steps. Here's a simplified overview of the pathway:
1. Activation of Shikimate Pathway Metabolites:
The process starts with the activation of two intermediates from the shikimate pathway, dihydroxybenzoate (DHB) and tetrahydroxynaphthalene (THN). Enzymes known as non-reducing polyketide synthases (NR-PKSs) are responsible for this activation.
2. Generation of Triacetic Acid Lactone Intermediate:
NR-PKSs, specifically TplA and TplB, utilize the activated DHB and THN to generate a triacetic acid lactone intermediate.
3. Ring Contraction and Cyclization:
An enzyme called TplC initiates a cascade of rearrangements. It modifies the triacetic acid lactone to induce ring contraction. Subsequent steps catalyzed by other enzymes promote cyclization to form the tropolone ring system.
4. Aromatic Hydroxylation:
Finally, enzymes such as cytochrome P450 monooxygenases perform hydroxylation reactions on the tropolone scaffold to produce hydroxylated tropolones.
In summary, the complex biosynthesis of tropolones in fungi involves the activation of shikimate pathway metabolites, triacetic acid lactone formation, ring contraction/cyclization, and aromatic hydroxylation. The research team responsible for this discovery conducted extensive genetic analysis, biochemistry, and chemical synthesis to unravel the detailed pathway. Their findings shed light on the intricate biochemistry of tropolone biosynthesis and have opened new avenues for the exploration of related natural products with potential pharmacological significance.
