Biosynthesis of Fungal Natural Products Involving Two Separate Pathway Crosstalk

Abstract

Fungal natural products (NPs) usually possess complicated structures, exhibit satisfactory bioactivities, and are an outstanding source of drug leads, such as the cholesterol-lowering drug lovastatin and the immunosuppressive drug mycophenolic acid. The fungal NPs biosynthetic genes are always arranged within one single biosynthetic gene cluster (BGC). However, a rare but fascinating phenomenon that a crosstalk between two separate BGCs is indispensable to some fungal dimeric NPs biosynthesis has attracted increasing attention. The hybridization of two separate BGCs not only increases the structural complexity and chemical diversity of fungal NPs, but also expands the scope of bioactivities. More importantly, the underlying mechanism for this hybridization process is poorly understood and needs further exploration, especially the determination of BGCs for each building block construction and the identification of enzyme(s) catalyzing the two biosynthetic precursors coupling processes such as Diels-Alder cycloaddition and Michael addition. In this review, we summarized the fungal NPs produced by functional crosstalk of two discrete BGCs, and highlighted their biosynthetic processes, which might shed new light on genome mining for fungal NPs with unprecedented frameworks, and provide valuable insights into the investigation of mysterious biosynthetic mechanisms of fungal dimeric NPs which are constructed by collaboration of two separate BGCs.

Keywords: bioactivity; biosynthetic gene cluster; biosynthetic pathway crosstalk; fungi; natural product; polyketide.

Figure 1

The biosynthetic pathway of fungal polyketides penilactones A (1) and B (2). The Michael addition that triggers the coupling of cla and tra BGCs is nonenzymatic.

Figure 2

The biosynthetic pathway of fungal polyketides dalmanol A (12) and acetodalmanol A (13).

Figure 3

The biosynthetic pathway of fungal polyketide azasperpyranone A (18).

Figure 4

The biosynthetic pathway of fungal meroterpenoids austinol (23) and dehydroaustinol (24) in A. nidulans LO2026.

Figure 5

The biosynthetic pathway of fungal non-ribosomal peptide spirotryprostatin A (32). The FMO FqzB from the fqz BGC catalyzes the formation of spiro-carbon in spirotryprostatin A.

Figure 6

The biosynthetic pathway of fungal non-ribosomal peptide echinocandin B (34). The separate hty BGC is responsible for the L-homotyrosine moiety formation.

Figure 7

The proposed biosynthetic pathway of delitschiapyrone A (40).

Figure 8

The proposed biosynthetic pathway of herpotrichone A (41).

Figure 9

The proposed biosynthetic pathway of citrifuran A (42).

Figure 10

The proposed biosynthetic pathway of acautalide A (43).