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Actinorhodin Biosynthesis Terminates with an Unprecedented Biaryl Coupling Reaction
Makoto Hashimoto1,2, Susumu Watari2, Takaaki Taguchi1,3
1Research Institute of Pharmaceutical Sciences, Musashino University, 1-1-20, Shinmachi, Nishitokyo-shi, Tokyo, 202-8585, Japan.
Angewandte Chemie (International Ed. in English)
|December 2, 2022
Summary
Researchers identified two key enzymes, ActVA-ORF4 and ActVA-ORF3, crucial for the final steps in Actinorhodin (ACT) biosynthesis. These enzymes facilitate the C-C bond formation and quinone oxidation, completing the understanding of this model natural product
Area of Science:
- Biochemistry
- Natural Product Biosynthesis
- Enzymology
Background:
- Dimeric natural products are abundant, with aryl coupling often mediated by cytochrome P450 or laccase.
- Actinorhodin (ACT), a pyranonaphthoquinone, is a well-studied dimeric natural product from Streptomyces coelicolor A3(2).
- The biosynthesis of ACT involves complex enzymatic pathways, with the final dimerization step being of particular interest.
Purpose of the Study:
- To identify and characterize the enzymes responsible for the final C-C bond formation in Actinorhodin (ACT) biosynthesis.
- To elucidate the roles of ActVA-ORF4 and ActVA-ORF3 in the late stages of ACT production.
- To complete the functional assignment of all essential enzymes involved in ACT biosynthesis.
Main Methods:
- Enzyme identification and characterization.
- Biochemical assays to determine enzyme activity and substrate specificity.
- Analysis of gene clusters involved in natural product biosynthesis.
Main Results:
- Identification of ActVA-ORF4, an NmrA-family NAD(P)H-dependent dimerizing enzyme catalyzing C-C bond formation.
- Identification of ActVA-ORF3, a cofactor-independent oxidase involved in quinone formation.
- Demonstration that ActVA-ORF4 uses 8-hydroxydihydrokalafungin (DHK-OH) as the sole substrate for dimerization.
- ActVA-ORF3 produces both the coupling substrate (DHK-OH) and the final product (ACT).
Conclusions:
- The functional roles of ActVA-ORF4 and ActVA-ORF3 in the final steps of Actinorhodin biosynthesis have been elucidated.
- This study completes the functional assignment of all essential enzymes in the biosynthesis of the model natural product Actinorhodin.
- The findings provide insights into novel enzymatic mechanisms for natural product dimerization.
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