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

Grace Caldara-Festin, David R. Jackson, Jesus F. Barajas, Timothy R. Valentic, Avinash B. Patel, Stephanie Aguilar, My Chi Nguyen, Michael Vo, Avinash Khanna, Eita Sasaki, Hung Wen Liu, Shiou Chuan Tsai, Janet L. Smith

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

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

Original languageEnglish
Pages (from-to)E6844-E6851
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number50
DOIs
Publication statusPublished - 2015 Dec 15
Externally publishedYes

Keywords

  • Aromatase/cyclase
  • Polyketide biosynthesis
  • Structural biology

ASJC Scopus subject areas

  • General

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