Navigating the Fungal Polyketide Chemical Space: From Genes to Molecules

Abstract

The iterative type I polyketide synthases (IPKSs) are central to the biosynthesis of an enormously diverse array of natural products in fungi. These natural products, known as polyketides, exhibit a wide range of biological activities and include clinically important drugs as well as undesirable toxins. The PKSs synthesize these structurally diverse polyketides via a series of decarboxylative condensations of malonyl-CoA extender units and β-keto modifications in a highly programmed manner. Significant progress has been made over the past few years in understanding the biosynthetic mechanism and programming of fungal PKSs. The continuously expanding fungal genome sequence data have sparked genome-directed discoveries of new fungal PKSs and associated products. The increasing number of fungal PKSs that have been linked to their products along with in-depth biochemical and structural characterizations of these large enzymes have remarkably improved our knowledge on the molecular basis for polyketide structural diversity in fungi. This perspective highlights the recent advances and examines how the newly expanded paradigm has contributed to our ability to link fungal PKS genes to chemical structures and vice versa. The knowledge will help us navigate through the logarithmically expanding seas of genomic information for polyketide compound discovery and provided opportunities to reprogram these megasynthases to generate new chemical entities.

Rational reprogramming of fungal polyketide first-ring cyclization

“…Despite catalyzing an atypical S-type folding, the PT domain of the AtCURS2 curvularin synthase nrPKS is firmly rooted in the C2-C7 clade of PTs, which yield RALs like 1 (20). This result concurs with previous observations that fungal iPKSs evolve orthogonal product specificities primarily by point mutations and not domain shuffling among distinct enzymes (2).…”

“…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.…”

“…Fungal iPKSs may be classified into three subgroups (5). Highly reducing iPKSs (hrPKSs) generate complex linear or nonaromatic cyclic products by reducing the nascent β-ketoacyl intermediates to the β-alcohol, the alkene, or the alkane after each condensation step using their ketoreductase, dehydratase, and enoyl reductase domains to execute a cryptic biosynthetic program (2,(6)(7)(8). Partially reducing iPKSs omit enoyl reduction to generate simple cyclic structures (5).…”

“…nrPKSs select different starter units by a starter unit:ACP transacylase domain (9) and mold the polyketide chains into cyclic products by regiospecific cyclizations. First-ring cyclizations are catalyzed by the product template domains (PTs) (10), whereas the polyketide chains are terminated by Claisen cyclase (11), macrolactone synthase (12) [thioesterase (TE)], or reductive release domains (2).…”

Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases

“…secondary metabolites | fungal genetics E ncompassing one of the largest classes of structurally diverse small molecule natural products, polyketides have provided multiple clinically useful drug classes that save lives (1)(2)(3). Natural polyketides from diverse microorganisms also deliver novel scaffolds that can be exploited in drug discovery programs by semisynthetic modification and combined chemical and biosynthetic approaches (4,5) and as inspiration for total synthesis and combinatorial chemistry (6,7).…”