PDBsum entry 4xrt

Lyase

PDB id: 4xrt

Contents

Protein chains

302 a.a.

Ligands

FMT ×2

Waters ×635

References listed in PDB file

Key reference

• Title: Structural and functional analysis of two di-Domain aromatase/cyclases from type ii polyketide synthases.
• Authors: G.Caldara-Festin, D.R.Jackson, J.F.Barajas, T.R.Valentic, A.B.Patel, S.Aguilar, M.Nguyen, M.Vo, A.Khanna, E.Sasaki, H.W.Liu, S.C.Tsai.
• Ref.: Proc Natl Acad Sci U S A, 2015, 112, E6844. [DOI no: 10.1073/pnas.1512976112]
• PubMed id: 26631750

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.