Structural and functional analysis of two di-domain aromatase/cyclases from type II polyketide synthases

Aromatic polyketides make up a large class of natural products with diverse bioactivity. During biosynthesis, linear poly-β-ketone intermediates are regiospecifically cyclized, yielding molecules with defined cyclization patterns that are crucial for polyketide bioactivity. The aromatase/cyclases (A...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2015-12, Vol.112 (50), p.E6844-E6851
Main Authors: Caldara-Festin, Grace, Jackson, David R., Barajas, Jesus F., Valentic, Timothy R., Patel, Avinash B., Aguilar, Stephanie, Nguyen, MyChi, Vo, Michael, Khanna, Avinash, Sasaki, Eita, Liu, Hung-wen, Tsai, Shiou-Chuan
Format: Article
Language:English
Subjects:
Aromatase - chemistry
Aromatase - genetics
Aromatase - metabolism
Biological activity
Biological Sciences
Biosynthesis
Metabolites
Models, Molecular
Mutagenesis
Natural products
PNAS Plus
Polyketide Synthases - chemistry
Polyketide Synthases - genetics
Polyketide Synthases - metabolism
Protein Conformation
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Summary:Aromatic polyketides make up a large class of natural products with diverse bioactivity. During biosynthesis, linear poly-β-ketone intermediates are regiospecifically cyclized, yielding molecules with defined cyclization patterns that are crucial for polyketide bioactivity. The aromatase/cyclases (ARO/CYCs) are responsible for regiospecific cyclization of bacterial polyketides. The two most common cyclization patterns are C7–C12 and C9–C14 cyclizations. We have previously characterized three monodomain ARO/CYCs: ZhuI, TcmN, and WhiE. The last remaining uncharacterized class of ARO/CYCs is the di-domain ARO/CYCs, which catalyze C7–C12 cyclization and/or aromatization. Di-domain ARO/CYCs can further be separated into two subclasses: “nonreducing” ARO/CYCs, which act on nonreduced poly-β-ketones, and “reducing” ARO/CYCs, which act on cyclized C9 reduced poly-β-ketones. For years, the functional role of each domain in cyclization and aromatization for di-domain ARO/CYCs has remained a mystery. Here we present what is to our knowledge the first structural and functional analysis, along with an in-depth comparison, of the nonreducing (StfQ) and reducing (BexL) di-domain ARO/CYCs. This work completes the structural and functional characterization of mono- and didomain ARO/CYCs in bacterial type II polyketide synthases and lays the groundwork for engineered biosynthesis of new bioactive polyketides.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1512976112