Pathway engineering in yeast for synthesizing the complex polyketide bikaverin.

Abstract:

:Fungal polyketides display remarkable structural diversity and bioactivity, and therefore the biosynthesis and engineering of this large class of molecules is therapeutically significant. Here, we successfully recode, construct and characterize the biosynthetic pathway of bikaverin, a tetracyclic polyketide with antibiotic, antifungal and anticancer properties, in S. cerevisiae. We use a green fluorescent protein (GFP) mapping strategy to identify the low expression of Bik1 (polyketide synthase) as a major bottleneck step in the pathway, and a promoter exchange strategy is used to increase expression of Bik1 and bikaverin titer. Then, we use an enzyme-fusion strategy to directly couple the monooxygenase (Bik2) and methyltransferase (Bik3) to efficiently channel intermediates between modifying enzymes, leading to an improved titer of bikaverin at 202.75 mg/L with flask fermentation (273-fold higher than the initial titer). This study demonstrates that the biosynthesis of complex fungal polyketides can be established and efficiently engineered in S. cerevisiae, highlighting the potential for natural product synthesis and large-scale fermentation in yeast.

journal_name

Nat Commun

journal_title

Nature communications

authors

Zhao M,Zhao Y,Yao M,Iqbal H,Hu Q,Liu H,Qiao B,Li C,Skovbjerg CAS,Nielsen JC,Nielsen J,Frandsen RJN,Yuan Y,Boeke JD

doi

10.1038/s41467-020-19984-3

subject

Has Abstract

pub_date

2020-12-03 00:00:00

pages

6197

issue

1

issn

2041-1723

pii

10.1038/s41467-020-19984-3

journal_volume

11

pub_type

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