New azodyrecins identified by a genome mining-directed reactivity-based screening

Atina Rizkiya Choirunnisa; Kuga Arima; Yo Abe; Noritaka Kagaya; Kei Kudo; Hikaru Suenaga; Junko Hashimoto; Manabu Fujie; Noriyuki Satoh; Kazuo Shin-Ya; Kenichi Matsuda; Toshiyuki Wakimoto

doi:10.3762/bjoc.18.102

New azodyrecins identified by a genome mining-directed reactivity-based screening

Beilstein J Org Chem. 2022 Aug 10:18:1017-1025. doi: 10.3762/bjoc.18.102. eCollection 2022.

Authors

Atina Rizkiya Choirunnisa^#¹, Kuga Arima^#¹, Yo Abe¹, Noritaka Kagaya², Kei Kudo³, Hikaru Suenaga³, Junko Hashimoto⁴, Manabu Fujie⁵, Noriyuki Satoh⁵, Kazuo Shin-Ya³, Kenichi Matsuda^{1

6}, Toshiyuki Wakimoto^{1

6}

Affiliations

¹ Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
² Technology Research Association for Next Generation Natural Products Chemistry, Tokyo 135-0064, Japan.
³ National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064, Japan.
⁴ Japan Biological Informatics Consortium (JBIC), Tokyo 135-0064, Japan.
⁵ Okinawa Institute of Science and Technology Graduate University, Okinawa, 904-0495, Japan.
⁶ Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo 060-0812, Japan.

^# Contributed equally.

Abstract

Only a few azoxy natural products have been identified despite their intriguing biological activities. Azodyrecins D-G, four new analogs of aliphatic azoxides, were identified from two Streptomyces species by a reactivity-based screening that targets azoxy bonds. A biological activity evaluation demonstrated that the double bond in the alkyl side chain is important for the cytotoxicity of azodyrecins. An in vitro assay elucidated the tailoring step of azodyrecin biosynthesis, which is mediated by the S-adenosylmethionine (SAM)-dependent methyltransferase Ady1. This study paves the way for the targeted isolation of aliphatic azoxy natural products through a genome-mining approach and further investigations of their biosynthetic mechanisms.

Keywords: Streptomyces; biosynthesis; methyltransferase; natural azoxides; reactivity-based screening.

Grants and funding

This work was partly supported by Hokkaido University, Global Facility Center (GFC), Pharma Science Open Unit (PSOU), funded by MEXT under "Support Program for Implementation of New Equipment Sharing System", Global Station for Biosurfaces and Drug Discovery, a project of Global Institution for Collaborative Research and Education in Hokkaido University, the Asahi Glass Foundation, the Naito Foundation, the Uehara Memorial Foundation, the Sumitomo Foundation−Grant for Basic Science Research Projects, Daiichi Sankyo Foundation of Life Science, the Japan Agency for Medical Research and Development JP19ae0101045, Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Japan Science and Technology Agency (JST Grant Numbers ACT-X JPMJAX201F and A-STEP JPMJTR20US), Japan JP16H06448, JP18H02581, JP19K16390, JP21H02635, and JP22K15302.