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Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):E6844-51. doi: 10.1073/pnas.1512976112. Epub 2015 Dec 2.

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

Author information

1
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697; Department of Chemistry, University of California, Irvine, CA 92697; Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697;
2
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697; Department of Chemistry, University of California, Irvine, CA 92697; Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697; drjackso@uci.edu sctsai@uci.edu.
3
Division of Medicinal Chemistry, College of Pharmacy, University of Texas, Austin, TX 78712; Department of Chemistry, University of Texas, Austin, TX 78712.

Abstract

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 di-domain ARO/CYCs in bacterial type II polyketide synthases and lays the groundwork for engineered biosynthesis of new bioactive polyketides.

KEYWORDS:

aromatase/cyclase; polyketide biosynthesis; structural biology

PMID:
26631750
PMCID:
PMC4687605
DOI:
10.1073/pnas.1512976112
[Indexed for MEDLINE]
Free PMC Article

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