A Permissive Amide N-Methyltransferase for Dithiolopyrrolones
Xiaoyan Chen1, Rachel M Johnson1, Bo Li2
1Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
ACS Catalysis
|December 18, 2023
Summary
Researchers identified DtpM, an enzyme crucial for synthesizing the antifungal compound thiolutin by adding an N-methyl group. This discovery aids in understanding natural product biosynthesis and developing new therapeutics.
Area of Science:
- Biochemistry
- Natural Product Biosynthesis
- Enzymology
Background:
- Amide N-methylation is vital for bioactive compound efficacy but difficult to achieve selectively.
- Thiolutin and holomycin, differing by a single N-methyl group, exhibit distinct antimicrobial activities, with only thiolutin possessing antifungal properties.
- The enzyme catalyzing N-methylation in thiolutin biosynthesis remained unidentified.
Purpose of the Study:
- To identify and characterize the enzyme responsible for the N-methylation of holomycin to thiolutin.
- To explore the substrate scope and properties of the identified enzyme.
- To provide insights into the biosynthesis of dithiolopyrrolone natural products.
Main Methods:
- Gene identification and characterization of the amide N-methyltransferase DtpM.
- Enzymatic assays to confirm DtpM's catalytic activity.
- Sequence similarity network analysis to infer evolutionary relationships.
Main Results:
- DtpM was identified as the enzyme catalyzing the conversion of holomycin to thiolutin.
- DtpM demonstrated efficient N-methylation activity and broad substrate specificity for dithiolopyrrolones.
- DtpM exhibited high thermal stability.
- Sequence analysis suggested DtpM is evolutionarily closer to O-methyltransferases than some known amide methyltransferases.
Conclusions:
- The identification of DtpM expands the known repertoire of amide N-methyltransferases.
- DtpM's properties suggest its potential utility in the chemoenzymatic synthesis of novel dithiolopyrrolone derivatives.
- This work facilitates the development of new therapeutic agents based on dithiolopyrrolone scaffolds.
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