Iterative Catalysis in the Biosynthesis of Mitochondrial Complex II Inhibitors Harzianopyridone and Atpenin B

The pentasubstituted pyridine natural products harzianopyridone and atpenins are potent inhibitors of mitochondrial complex II. We identified the pathways of these compounds from their fungal producers and uncovered that the biosynthetic steps require multiple iterative enzymes. In particular, a met...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2020-05, Vol.142 (19), p.8550-8554
Main Authors: Bat-Erdene, Undramaa, Kanayama, Daiki, Tan, Dan, Turner, William C, Houk, K. N, Ohashi, Masao, Tang, Yi
Format: Article
Language:English
Subjects:
Biocatalysis
Biological Products - chemistry
Biological Products - metabolism
Hypocreales - enzymology
Methyltransferases - chemistry
Methyltransferases - metabolism
Mixed Function Oxygenases - chemistry
Mixed Function Oxygenases - metabolism
Molecular Structure
Pyridones - chemistry
Pyridones - metabolism
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Summary:The pentasubstituted pyridine natural products harzianopyridone and atpenins are potent inhibitors of mitochondrial complex II. We identified the pathways of these compounds from their fungal producers and uncovered that the biosynthetic steps require multiple iterative enzymes. In particular, a methyltransferase and a flavin-dependent monooxygenase are used iteratively to introduce C5 and C6 methoxy groups. The pathway unexpectedly requires the installation and removal of an N-methoxy group, which is proposed to be a directing group that tunes the reactivity of the pyridone ring, possibly through the alpha effect.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.0c03438