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

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

Fingerprint Dive into the research topics of 'Characterization of TnmH as an O-Methyltransferase Revealing Insights into Tiancimycin Biosynthesis and Enabling a Biocatalytic Strategy To Prepare Antibody-Tiancimycin Conjugates'. Together they form a unique fingerprint.

Cite this