New insights into the formation of fungal aromatic polyketides

Abstract

Fungal aromatic polyketides constitute a large family of bioactive natural products and are synthesized by the non-reducing group of iterative polyketide synthases (NR-PKSs). Their diverse structures arise from selective enzymatic modifications of reactive enzyme-bound poly-β-keto intermediates. How iterative PKSs control starter unit selection, polyketide chain initiation and elongation, intermediate folding and cyclization, selective redox or modification reactions during assembly, and product release are central mechanistic questions underlying iterative catalysis. This review highlights recent insights into these questions, with a particular focus on the biosynthetic programming of fungal aromatic polyketides, and draws comparisons to the allied biosynthetic processes in bacteria.

Rational reprogramming of fungal polyketide first-ring cyclization

“…2). The success of this experiment contrasts previous in trans domain complementation attempts that did not yield observable products in vivo (1,29) and emphasizes that appropriate protein-protein docking, substrate recognition, and processing still can take place with dissected domains expressed in heterologous hosts. Taken together, these experiments show that the PT-less nrPKSs and the freestanding PT domains are all catalytically active.…”

“…This change would require radical rerouting of the polyketide substrate chain to expose a carbon to the catalytic base that is distal (S type) or proximal (F type) to the phosphopantetheine thioester. As shown above and observed previously by others (1,29,36), in trans reconstitution of iPKSs from dissected domains incurs a penalty for catalysis in terms of product yield and/or fidelity. Thus, we elected to conduct these experiments with nrPKSs where the heterologous PT domains replace their native equivalents in cis (29).…”

“…CD spectra were acquired with a JASCO J-810 instrument using a path length of 1 cm. 1 H, 13 C, and 2D NMR [homonuclear correlation spectroscopy (COSY), heteronuclear single-quantum correlation spectroscopy (HSQC), heteronuclear multiple-bond correlation spectroscopy (HMBC), and rotating frame nuclear Overhauser effect spectroscopy (ROESY)] spectra were recorded in DMSO-d 6 , CD 3 OD, or C 5 D 5 N on a JEOL ECX-300 Spectrometer. ESI-MS data were collected on an Agilent 6130 Single Quad LC-MS. SI Materials and Methods has details.…”

“…F-type firstring cyclizations typically result from aldol condensations in the C2-C7 (as in 1), C4-C9, or C6-C11 register. In contrast, bacterial polyketide cyclase/aromatase enzymes (parts of type II PKS multienzyme complexes) typically direct an S-type folding event, whereby the carbons of the benzene ring are derived from three intact malonate-derived C 2 units (1,28). Nevertheless, a select few fungal polyketides, including DALs like 2, feature a first-ring connectivity that is analogous to the S-type folding mode, resulting from an unorthodox C8-C3 aldol cyclization event (20).…”

“…Importantly, they also provide lead compounds and inspiration for pharmaceutical drug discovery, which is evidenced by the statin cholesterol-lowering agents (1,2). Fungal polyketides are biosynthesized by multidomain megasynthases [type I iterative polyketide synthases (iPKSs)] that use ketoacyl synthase, acyl transferase, and acyl carrier protein (ACP) domains to catalyze recursive thioClaisen condensations using malonyl-CoA extender units.…”