Characterization of a novel natural tetracenomycin reveals crucial role of 4-hydroxy group in ribosome binding

Vera A Alferova; Tinashe P Maviza; Mikhail V Biryukov; Yuliya V Zakalyukina; Vladimir I Polshakov; Petr V Sergiev; Vladimir A Korshun; Ilya A Osterman

doi:10.1016/j.biochi.2022.10.016

Characterization of a novel natural tetracenomycin reveals crucial role of 4-hydroxy group in ribosome binding

Biochimie. 2023 Mar:206:150-153. doi: 10.1016/j.biochi.2022.10.016. Epub 2022 Oct 29.

Authors

Vera A Alferova¹, Tinashe P Maviza², Mikhail V Biryukov³, Yuliya V Zakalyukina⁴, Vladimir I Polshakov⁵, Petr V Sergiev⁶, Vladimir A Korshun¹, Ilya A Osterman⁷

Affiliations

¹ Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, Moscow, 117997, Russia; Gause Institute of New Antibiotics, Bolshaya Pirogovskaya 11, Moscow, 119021, Russia.
² Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, 143028, Russia.
³ Gause Institute of New Antibiotics, Bolshaya Pirogovskaya 11, Moscow, 119021, Russia; Department of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia; Genetics and Life Sciences Research Center, Sirius University of Science and Technology, Sochi, 354340, Russia.
⁴ Genetics and Life Sciences Research Center, Sirius University of Science and Technology, Sochi, 354340, Russia; Department of Soil Science, Lomonosov Moscow State University, Moscow, 119234, Russia.
⁵ Center for Magnetic Tomography and Spectroscopy, Faculty of Fundamental Medicine, Lomonosov Moscow State University, Moscow, 119991, Russia.
⁶ Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, 143028, Russia; Department of Chemistry, Lomonosov Moscow State University, Moscow, 119992, Russia.
⁷ Center of Life Sciences, Skolkovo Institute of Science and Technology, Skolkovo, 143028, Russia; Genetics and Life Sciences Research Center, Sirius University of Science and Technology, Sochi, 354340, Russia; Department of Chemistry, Lomonosov Moscow State University, Moscow, 119992, Russia. Electronic address: i.osterman@skoltech.ru.

PMID: 36346253
DOI: 10.1016/j.biochi.2022.10.016

Abstract

The aromatic polyketides tetracenomycins were recently found to be potent inhibitors of protein synthesis. Their binding site is located in a unique locus within the tunnel of the large ribosomal subunit. Here we report the isolation and structure elucidation of a novel natural tetracenomycin congener - O⁴-Me-tetracenomycin C (O⁴-Me-TcmC). This compound is isomeric to tetracenomycin X (TcmX), however, in contrast to TcmX, O⁴-Me-TcmC exhibited no antimicrobial activity and was unable to inhibit protein synthesis in vitro. Structural alignment of tetracenomycins to the binding locus from cryo-EM TcmX-70S ribosome data revealed the crucial role of the 4-hydroxyl group. These findings are important for further development of semi-synthetic tetracenomycins as potential antibacterials.

Keywords: Polyketide antibiotics; Ribosome; Structure-activity relationship; Tetracenomycins.

MeSH terms

Anti-Bacterial Agents* / chemistry
Anti-Bacterial Agents* / pharmacology
Binding Sites
Protein Biosynthesis*
Ribosomes

Substances

5838 DNI
tetracenomycin X
Anti-Bacterial Agents