9W6X

Crystal Structure of YtkW in Complex with SAM

Summary for 9W6X

• Entry DOI: 10.2210/pdb9w6x/pdb
• Descriptor: YtkW, S-ADENOSYLMETHIONINE (3 entities in total)
• Functional Keywords: ytkw, sam, transferase
• Biological source: Streptomyces sp. TP-A2060
• Total number of polymer chains: 1
• Total formula weight: 21896.77

Authors

Wang, S.C.,Pan, L.F. (deposition date: 2025-08-05, release date: 2026-07-15)

Primary citation

Feng, J.,Wang, S.,Yang, X.,Tian, T.,Huang, W.,Teng, X.,Pan, H.X.,Sun, A.,Pu, J.,Pan, L.,Tang, G.L.
S-Methyl Thioester Formation Uncovers Early Biosynthetic Steps of Yatakemycin.
Angew.Chem.Int.Ed.Engl., 65:e22109-e22109, 2026

PubMed Abstract: Sulfur-containing natural products are widely distributed in nature. Yatakemycin (YTM) is a complex antitumor and antifungal antibiotic featuring a typical cyclopropane moiety as the pharmacophore and containing an S-methyl thioester moiety. In this study, functional characterization of three genes (ytkG/F/W) within the biosynthetic gene cluster (BGC) revealed their roles in sulfur transfer and subsequent S-methylation to form the S-methyl thioester moiety. Identification of the sulfur source further suggests that the S-methyl thioester formation is an intersection between primary and secondary metabolic pathways. Additionally, we demonstrate that a key O-methylation step, catalyzed by a catechol-O-methyltransferase (MT)-like MT encoded by a gene outside the BGC, is the prerequisite of the S-methyl thioester formation. Notably, the catalytic mechanism of YtkW, an unprecedented thiocarboxylic acid S-MT, was elucidated via crystal structure determination, molecular docking, and relevant mutagenesis-based analyses. Based on these findings, a plausible early-stage biosynthetic pathway for YTM involving S-methyl thioester formation is proposed, which not only advances the biosynthetic understanding of YTM but also provides promising tools for exploring structural diversification of this antibiotic.

PubMed: 41761722
DOI: 10.1002/anie.202522109

Experimental method

X-RAY DIFFRACTION (2.38 Å)