Open AccessIterative Catalysis in the Biosynthesis of Mitochondrial Complex II Inhibitors Harzianopyridone and Atpenin B
Author(s) -
Undramaa Bat-Erdene,
Daiki Kanayama,
Dan Tan,
W. C. Turner,
K. N. Houk,
M. Ohashi,
Yi Tang
Publication year - 2020
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.0c03438
Subject(s) - chemistry , biosynthesis , enzyme , stereochemistry , methyltransferase , pyridine , flavin group , monooxygenase , reactivity (psychology) , biochemistry , combinatorial chemistry , organic chemistry , methylation , cytochrome p450 , gene , medicine , alternative medicine , pathology
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.