Characterization of TnmH as an O-Methyltransferase Revealing Insights into Tiancimycin Biosynthesis and Enabling a Biocatalytic Strategy To Prepare Antibody-Tiancimycin Conjugates

Ajeeth Adhikari, Christiana N. Teijaro, Xiaohui Yan, Chin Yuan Chang, Chun Gui, Yu Chen Liu, Ivana Crnovcic, Dong Yang, Thibault Annaval, Christoph Rader, Ben Shen

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

The enediynes are among the most cytotoxic molecules known, and their use as anticancer drugs has been successfully demonstrated by targeted delivery. Clinical advancement of the anthraquinone-fused enediynes has been hindered by their low titers and lack of functional groups to enable the preparation of antibody-drug conjugates (ADCs). Here we report biochemical and structural characterization of TnmH from the tiancimycin (TNM) biosynthetic pathway, revealing that (i) TnmH catalyzes regiospecific methylation at the C-7 hydroxyl group, (ii) TnmH exhibits broad substrate promiscuity toward hydroxyanthraquinones and S-alkylated SAM analogues and catalyzes efficient installation of reactive alkyl handles, (iii) the X-ray crystal structure of TnmH provides the molecular basis to account for its broad substrate promiscuity, and (iv) TnmH as a biocatalyst enables the development of novel conjugation strategies to prepare antibody-TNM conjugates. These findings should greatly facilitate the construction and evaluation of antibody-TNM conjugates as next-generation ADCs for targeted chemotherapy.

Original languageEnglish
Pages (from-to)8432-8441
Number of pages10
JournalJournal of Medicinal Chemistry
Volume63
Issue number15
DOIs
StatePublished - 13 Aug 2020

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