[TCMN_STRGA] The N-terminal domain enhances the formation of an early, partially cyclized intermediate, while the C-terminal domain catalyzes the 3-O-methylation of one or more later intermediates in the biosynthetic pathway. Catalyzes the methylation of tetracenomycin D3 (Tcm D3) to yield Tcm B3. Catalyzes as well the following side reactions: methylation of 8-O-methyl-Tcm D3 to yield Tcm E; and of 9-carboxymethyl-Tcm B3 to yield Tcm A2.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
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.
Crystal structure and functional analysis of tetracenomycin ARO/CYC: implications for cyclization specificity of aromatic polyketides.,Ames BD, Korman TP, Zhang W, Smith P, Vu T, Tang Y, Tsai SC Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5349-54. Epub 2008 Apr 3. PMID:18388203[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
↑Ames BD, Korman TP, Zhang W, Smith P, Vu T, Tang Y, Tsai SC. Crystal structure and functional analysis of tetracenomycin ARO/CYC: implications for cyclization specificity of aromatic polyketides. Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5349-54. Epub 2008 Apr 3. PMID:18388203
