Complete Biosynthetic Pathway of Anditomin: Nature’s Sophisticated Synthetic Route to a Complex Fungal Meroterpenoid

Abstract

Anditomin and its precursors, andilesins, are fungal meroterpenoids isolated from Aspergillus variecolor and have unique, highly oxygenated chemical structures with a complex bridged-ring system. Previous isotope-feeding studies revealed their origins as 3,5-dimethylorsellinic acid and farnesyl pyrophosphate and suggested the possible involvement of a Diels-Alder reaction to afford the congested bicyclo[2.2.2]octane core structure of andilesins. Here we report the first identification of the biosynthetic gene cluster of anditomin and the determination of the complete biosynthetic pathway by characterizing the functions of 12 dedicated enzymes. The anditomin pathway actually does not employ a Diels-Alder reaction, but involves the nonheme iron-dependent dioxygenase AndA to synthesize the bridged-ring by an unprecedented skeletal reconstruction. Another dioxygenase, AndF, is also responsible for the structural complexification, generating the end product anditomin by an oxidative rearrangement.

3,5‐Dimethylorsellinic Acid Derived Meroterpenoids from Eupenicillium sp. 6A‐9, a Fungus Isolated from the Marine Sponge Plakortis simplex

“…The biosynthesis of intriguing meroterpenoids metabolized by Aspergillus and Penicillium has been investigated for decades, and recently the molecular bases (biosynthetic genes/enzymes) for five 3,5-dimethylorsellinic acid (DMOA) and farnesyl pyrophosphate derived meroterpenoids, andrastin A, austinol, terretonin, anditomin, and berkeleydione, have been reported [20][21][22][23][24][25][26][27][28][29] and thoroughly reviewed. [30] Notably, the completely elucidated pathways for austinol [21,22,27] and berkeleydione, [29] for which the known compounds preaustinoid A1 (7) and preaustinoid A3 (10) acquired here are biosynthetic intermediates, enabled us to propose detailed mechanisms for the biosynthesis of the five related new meroterpenoids 1-5 (Scheme 1).…”

Heterologous expression of highly reducing polyketide synthase involved in betaenone biosynthesis

“…Representative examples are found in the total biosynthesis of tenellin, 11 aphidicolin, 12 paxilline, 13 aspyridone, 14 aflatrem, 15 and anditomin (11 + 1 genes). 16 For skeletal construction of 1 in A. oryzae, bet1 and bet3 genes were subcloned into fungal expression vectors, pUARA2 (argB marker) and pUSA2 (sC marker), 15 to construct pUARA2-bet1 and pUSA2-bet3, which were then introduced into A. oryzae NSAR1 to construct both a bet1 single transformant and a bet1/3 double transformant ( The 1 H-NMR spectrum of the product completely agreed with that of 4, 9 allowing us to determine the structure of the observed metabolite as 5. These results showed that the collaborative action of Bet1 and Bet3 plays a key role in the skeletal construction of 5 in betaenone biosynthesis.…”

A chemocentric view of the natural product inventory

“…The mononuclear nonheme iron oxygenases are likewise an important family of oxidative catalysts, as illustrated by AndA and AndF, which have recently been characterized for their roles in the generation of complexity, including the bicyclo [2,2,2] core of the anditomin meroterpenoids in fungi (Fig. 1b) 4 . Also important for particular natural product classes are flavin coenzyme-linked oxygenases 5 and even oxygen-linked halogenases, as seen in the generation of the trichloromethyl group in barbamide formation (Fig.…”