2RER

Crystal structure of the aromatase/cyclase domain of TcmN from Streptomyces glaucescens

2RER の概要

• エントリーDOI: 10.2210/pdb2rer/pdb
• 関連するPDBエントリー: 2RES 2REZ
• 分子名称: Multifunctional cyclase-dehydratase-3-O-methyl transferase tcmN (2 entities in total)
• 機能のキーワード: cyclase, aromatase, polyketide, helix-grip, dehydratase, anticancer, antibiotic, antibiotic biosynthesis, methyltransferase, multifunctional enzyme, transferase, biosynthetic protein
• 由来する生物種: Streptomyces glaucescens
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19938.34

構造登録者

Ames, B.D.,Korman, T.P.,Vu, T.N.,Tsai, S.C. (登録日: 2007-09-26, 公開日: 2008-04-22, 最終更新日: 2024-02-21)

主引用文献

Ames, B.D.,Korman, T.P.,Zhang, W.,Smith, P.,Vu, T.,Tang, Y.,Tsai, S.C.
Crystal structure and functional analysis of tetracenomycin ARO/CYC: implications for cyclization specificity of aromatic polyketides.
Proc.Natl.Acad.Sci.Usa, 105:5349-5354, 2008

PubMed Abstract: Polyketides are a class of natural products with highly diverse chemical structures and pharmaceutical activities. Polyketide cyclization, promoted by the aromatase/cyclase (ARO/CYC), helps diversify aromatic polyketides. How the ARO/CYC promotes highly specific cyclization is not well understood because of the lack of a first-ring ARO/CYC structure. The 1.9 A crystal structure of Tcm ARO/CYC reveals that the enzyme belongs to the Bet v1-like superfamily (or STAR domain family) with a helix-grip fold, and contains a highly conserved interior pocket. Docking, mutagenesis, and an in vivo assay show that the size, shape, and composition of the pocket are important to orient and specifically fold the polyketide chain for C9-C14 first-ring and C7-C16 second-ring cyclizations. Two pocket residues, R69 and Y35, were found to be essential for promoting first- and second-ring cyclization specificity. Different pocket residue mutations affected the polyketide product distribution. A mechanism is proposed based on the structure-mutation-docking results. These results strongly suggest that the regiospecific cyclizations of the first two rings and subsequent aromatizations take place in the interior pocket. The chemical insights gleaned from this work pave the foundation toward defining the molecular rules for the ARO/CYC cyclization specificity, whose rational control will be important for future endeavors in the engineered biosynthesis of novel anticancer and antibiotic aromatic polyketides.

PubMed: 18388203
DOI: 10.1073/pnas.0709223105

実験手法

X-RAY DIFFRACTION (1.9 Å)