posted on 2021-04-23, 17:04authored byXingxing Wei, Xiaoxuan Chen, Lin Chen, Dexiu Yan, Wei-Guang Wang, Yudai Matsuda
Tetrahydroxanthone dimers are fungal
products, among which secalonic
acid D (1) is one of the most studied compounds because
of its potent biological activity. Because the biosynthetic gene cluster
of 1 has been previously identified, we sought to heterologously
produce 1 in Aspergillus oryzae by expressing
the relevant biosynthetic genes. However, our initial attempt of the
total biosynthesis of 1 failed; instead, it produced
four isomers of 1 due to the activity of an endogenous
enzyme of A. oryzae. Subsequent overexpression of
the Baeyer–Villiger monooxygenase, AacuH, which competes with
the endogenous enzyme, altered the product profile and successfully
generated 1. Characterization of the key biosynthetic
enzymes revealed the surprising substrate promiscuity of the dimerizing
enzyme, AacuE, and indicated that efficient synthesis of 1 requires highly selective preparation of the tetrahydroxanthone
monomer, which is apparently controlled by AacuH. This study facilitates
engineered biosynthesis of tetrahydroxanthone dimers both in a selective
and divergent manner.