A unifying paradigm for naphthoquinone-based meroterpenoid (bio)synthesis

Area of Science:

• Biochemistry
• Natural Product Chemistry
• Enzymology

Background:

• Bacterial meroterpenoids are natural products with significant therapeutic potential.
• Their biosynthetic pathways remain largely unknown, challenging classical biochemical models.
• Specific substitution patterns in naphthoquinone meroterpenoids contradict known reactivity rules.

Purpose of the Study:

• To elucidate the unknown biosynthetic logic of bacterial meroterpenoids.
• To explain the unusual substitution patterns observed in certain meroterpenoid classes.
• To identify the enzymatic mechanisms responsible for these biosynthetic discrepancies.

Main Methods:

• Discovery and characterization of a novel enzyme-promoted α-hydroxyketone rearrangement.
• Utilizing vanadium-dependent haloperoxidases as catalysts for the rearrangement.
• Application of the biosynthetic rearrangement in the total synthesis of naphthomevalin.

Main Results:

• Identified an unprecedented α-hydroxyketone rearrangement catalyzed by vanadium-dependent haloperoxidases.
• Demonstrated this rearrangement as a potentially conserved biosynthetic reaction in merochlorin and napyradiomycin antibiotics.
• Successfully applied the rearrangement in a concise total synthesis of naphthomevalin.

Conclusions:

• The α-hydroxyketone rearrangement provides a biochemical explanation for previously unexplained meroterpenoid structures.
• This enzymatic transformation is potentially a conserved mechanism in the biosynthesis of this important class of natural products.
• The findings open new avenues for understanding and synthesizing complex meroterpenoid antibiotics.