Molecular basis for the unusual ring reconstruction in fungal meroterpenoid biogenesis

Abstract

Trt14 from Aspergillus terreus is involved in unusual skeletal reconstruction during the biosynthesis of the fungal meroterpenoid terretonin. Detailed in vitro characterization revealed that this novel multifunctional enzyme catalyzes not only the D-ring expansion via intramolecular methoxy rearrangement, but also the hydrolysis of the expanded D-ring. The X-ray crystal structures of Trt14, in complex with substrate or product, and two Trt14 homologs, AusH and PrhC from Aspergillus nidulans and Penicillium brasilianum, respectively, indicated similar overall structures to those of the NTF2-like superfamily of enzymes, despite lacking sequence and functional similarities. Moreover, we gained structural insight into the mechanism of the Trt14-catalyzed ring reconstruction from the in-crystal enzyme reaction and site-directed mutagenesis to show that this reaction involves sequential ester bond cleavage and formation. Structural comparison of Trt14 and its homologs suggests that the enzymes in this new superfamily employ similar acid-base chemistry to diversify the molecular architecture of fungal meroterpenoids.

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

“…Next, the C-9 alcohol attacks the aldehyde to form e/h, and the hemiacetal alcohol attacks the carbonyl group of the methyl ester to give f/i. Subsequently, the methoxide ion released by the lactonization initiates the C-10/C-11 retro-Claisen cleavage in a way similar to that proposed in the terretonin biosynthesis [28,31] to give 1/j. Lactone hydrolyzation and dehydration of j affords 2.…”

Marine natural products

“…Biochemical and crystallographic analyses have revealed that one multifunctional enzyme is involved in unusual skeletal reconstruction in terretonin biosynthesis, catalysing both a ring expansion and a hydrolysis reaction. 284…”

Enzyme-catalysed [6+4] cycloadditions in the biosynthesis of natural products

“…3a). A structural homologues search 25 indicated that these enzymes belong to a dimeric α+β barrel superfamily (Pfam CL0032), enzymes of which are evolutionarily conserved with diverse functions [26][27][28][29][30] .…”