Terretonin Biosynthesis Requires Methylation as Essential Step for Cyclization

Abstract

Unexpected methylation: Terretonin is a fungal meroterpenoid derived from 3,5‐dimethylorsellinic acid (DMOA). Trt1 is a terpene cyclase involved in terretonin biosynthesis and only accepts the methylated compound as a substrate to produce the cyclized product. Methylation is a common requirement for the cyclization steps in DMOA‐derived meroterpenoid biosynthesis.

Biosynthesis of Terpenoid Natural Products in Fungi

“…Yet another group of isoprenyl-chain cyclizing enzymes acts on the farnesyland geranylgeranyl-chains attached to the polyketide and indole moieties during meroterpenoid [57][58][59]75, 76] and indole-diterpene [47,54,56,72,74,[89][90][91] natural products biosynthesis (see also Sect. 2.5).…”

“…1) catalyzes the transfer of FPP to the polyketide-derived aromatic core in the biosynthesis of numerous bioactive meroterpenoids. Prenyl transferases (Trt2, Pyr6, AusN, and MpaA) have been identified in biosynthetic gene clusters for terretonin, pyripyropene, austinol, and mycophenolic acid synthesis [57][58][59][75][76][77]. These enzymes are integral membrane proteins and belong to the UbiA/Coq2 quinone prenyl transferase group, which also includes enzymes involved in the secondary metabolite biosynthetic pathways of various plants [78].…”

“…2.1.2) catalyze transfer of a prenyl-chain to either a polyketide or indole precursor. UbiA-type prenyl transferases catalyze FPP transfer in the biosynthesis of meroterpenoids such as terretonin, pyripyropene, austinol, and mycophenolic acid [57][58][59][75][76][77]. IPPS-type prenyl transferases catalyze the transfer of GGPP in the biosynthesis of a large group of structurally diverse indole-diterpenoids, such as the lolitrems made by Sequences were aligned by ClustalW (Gonnet) and subsequently subjected to phylogenetic analysis using the minimum evolution method in MEGA6 [114].…”

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).…”

Meroterpenoids

“…The biosynthetic pathway toward 23 was subsequently confi rmed through the biosynthetic study on terretonin ( 17 ), using a reconstitution approach [ 19 ] ( Fig. 13.3a ).…”