Collaborative Biosynthesis of Maleimide- and Succinimide-Containing Natural Products by Fungal Polyketide Megasynthases

Abstract

Fungal polyketide synthases (PKSs) can function collaboratively to synthesize natural products of significant structural diversity. Here we present a new mode of collaboration between a highly reducing PKS (HRPKS) and a PKS-nonribosomal peptide synthetase (PKS-NRPS) in the synthesis of oxaleimides from the Penicillium species. The HRPKS is recruited in the synthesis of an olefin-containing free amino acid, which is activated and incorporated by the adenylation domain of the PKS-NRPS. The precisely positioned olefin from the unnatural amino acid is proposed to facilitate a scaffold rearrangement of the PKS-NRPS product to forge the maleimide and succinimide cores of oxaleimides.

Highly Enantioselective, Base‐Free Synthesis of α‐Quaternary Succinimides through Catalytic Asymmetric Allylic Alkylation

“…We logically became interested in applying this strategy to the synthesis of five‐membered ring succinimides. Indeed, this heterocyclic motif is prevalent in a number of biologically active natural products such as hirsutellone A, which was isolated from the insect pathogenic fungus Hirsutella nivea BCC 2594, the haterumaimides, which are chlorinated lissoclimide‐type diterpenoids isolated from an Okinawan Lissoclinum sp , asperparaline A, which was isolated from Aspergillus japonicus JV‐23, and oxaleimide A, isolated from Penicillium oxalicum (Figure ). This motif is also present in a number of pharmaceuticals such as the anticonvulsant ethosuximide and the aldose reductase inhibitor ranirestat …”

“…[4] For the past several years, we have been focusedo ni mplementing the palladium-catalyzed asymmetric allylic alkylation (Pd-AAA)t ot he synthesis of various chiral heterocyclesi ncluding chiral isoxazolidin-5-ones, [5] b-lactams [5] butenolides, [6] furanones, [6] butyrolactones, [6,7] 4,5-dihydro pyrazoles [8] and other diversely substituted 5-, 6-, 7-, 14-and 16-memberedr ing aphosphono-oxaheterocycles [9] all bearing aq uaternary stereogenic center.W el ogicallyb ecamei nterested in applying this strategyt ot he synthesis of five-membered ring succinimides. Indeed, this heterocyclic motif is prevalent in an umber of biologicallya ctive natural products such as hirsutellone A, [10] which was isolated from the insect pathogenicf ungus Hirsutella nivea BCC 2594, the haterumaimides, [11] which are chlorinated lissoclimide-type diterpenoids isolated from an Okinawan Lissoclinum sp,a sperparalineA, [12] whichw as isolated from Aspergillus japonicus JV-23, and oxaleimide A, [13] isolated from Penicillium oxalicum (Figure 1). This motif is also presenti na number of pharmaceuticals such as the anticonvulsant ethosuximide [14] and the aldose reductase inhibitor ranirestat.…”

Late-Stage Terpene Cyclization by an Integral Membrane Cyclase in the Biosynthesis of Isoprenoid Epoxycyclohexenone Natural Products

“…We then overexpressed a putative fungal transcriptional regulator found in the gene cluster, macR , using the constitutive gpdA promoter. 21 After confirming the ecotopic integration of the overexpression cassette, the strain DH1 was cultured on TGA plates and extracted for metabolite analysis. As shown in Figure 2, several new metabolites (compounds 1–4 ) related to epoxycyclohexenone were produced (Figure 2B, ii).…”

Genome mining and biosynthesis of a polyketide from a biofertilizer fungus that can facilitate reductive iron assimilation in plant

“…1C, i). To activate this gene cluster, we use a transcription activation approach (8,9). The gene tlnI, which encodes a putative GAL4-like Zn 2 Cys 6 transcription factor, was cloned under the control of the constitutive gpdA promoter (8).…”

“…Through genome sequencing and bioinformatic analysis, it is accepted that most fungi only produce a small fraction (<10%) of natural products under laboratory conditions compared with the number of biosynthetic gene clusters encoded (7). Recent advances in fungal genome mining tools have led to the specific and global activation of biosynthetic gene clusters as a step toward realizing the biosynthetic potential (8,9). These approaches therefore hold significant promise in identifying new fungal natural products that are beneficial to plant growth, and may lead to applications in agriculture.…”