Dalmanol biosyntheses require coupling of two separate polyketide gene clusters

Area of Science:

• Natural Product Biosynthesis
• Mycology
• Biochemistry

Background:

• Polyketide-polyketide hybrids are complex natural products with significant bioactivity.
• The mechanisms underlying their formation, particularly hybridization processes, are not well understood.
• Understanding these pathways is crucial for discovering novel bioactive compounds.

Purpose of the Study:

• To elucidate the biosynthetic pathways of the immunosuppressants dalmanol A and acetodalmanol A.
• To investigate the role of unspecific monooxygenase-triggered hybridization in polyketide synthesis.
• To explore the fungal generation of diverse phytochemicals, including chromanes and phloroglucinols.

Main Methods:

• Analysis of distinct polyketide (naphthalene and chromane) biosynthetic gene clusters.
• Investigation of the ketoreductase (KR) domain (ChrA KR) and its partner (ChrB) in the bioassembly line.
• Study of simultaneous fungal biosynthesis of tetrahydroxynaphthalenes.

Main Results:

• Dalmanol A and acetodalmanol A result from hybridization of naphthalene and chromane gene clusters, mediated by an unspecific monooxygenase.
• Functional dimorphism of the ChrA KR domain and its interaction with ChrB enhance polyketide diversity.
• Fungal strains generate plant chromanes (e.g., noreugenin) and phloroglucinols (e.g., 2,4,6-trihydroxyacetophenone), alongside specific tetrahydroxynaphthalenes.

Conclusions:

• This study advances the understanding of natural product biosynthesis involving multiple gene clusters.
• It highlights the fungal capability to produce diverse chromane- and phloroglucinol-based phytochemicals.
• The findings provide insights into the enzymatic mechanisms driving polyketide-polyketide hybrid formation.