2026-10-06 北海道大学
5-アザシチジンの生合成に見出した生合成経路と新規反応
＜関連情報＞
- https://www.hokudai.ac.jp/news/2026/10/5-135–1.html
- https://www.nature.com/articles/s41929-026-01611-x
抗がん性ヌクレオシドアナログ5-アザシチジンの生合成において1,3,5-トリアジン骨格を形成する酵素的骨格編集反応 Enzymatic skeletal editing reaction forming the 1,3,5-triazine core during biosynthesis of the anticancer nucleoside analogue 5-azacytidine
Akari Umezawa, Takeshi Tsunoda, Yu Nakashima, Yung-Lin Wang, Tomoki Yoneda, Chitose Maruyama, Ning-Shian Hsu, Taro Matsuyama, Kazunori Miyamoto, Hajime Sato, Asuha Shimose, Reo Takazawa, Yoshimitsu Hamano, Tsung-Lin Li, Yasuhide Inokuma, Masanobu Uchiyama, Yasushi Ogasawara, Hiroyuki Morita & Tohru Dairi
Nature Catalysis Published:07 September 2026
DOI:https://doi.org/10.1038/s41929-026-01611-x
Abstract
5-Azacytidine is a cytidine-mimic nucleoside containing the 1,3,5-triazine base 5-azacytosine and is currently used to treat myelodysplastic syndrome, a group of blood cancers. 5-Azacytidine was initially reported as a synthetic cytidine analogue before its isolation as a natural product in 1966. Since then, its biosynthesis has remained unexplored, probably because it was regarded as a synthetic analogue. Here we identified the 5-azacytidine biosynthetic gene cluster and revealed unusual catalytic reactions underlying 5-azacytosine biosynthesis through biochemical, structural and density functional theory analyses. AzcE, a guanosine triphosphate (GTP) cyclohydrolase, converts GTP to 2,5,6-triaminopyrimidin-4(1H)-one; AzcA, a cupin domain-containing enzyme, remodels the carbon–nitrogen framework of the pyrimidine into 6-amino-4-oxo-1,4-dihydro-1,3,5-triazine-2-carboxylic acid through selective cleavage and reassembly of the heterocyclic skeleton; and AzcB/C catalyses an unusual thiamine pyrophosphate-dependent decarboxylation at the α‑imino carboxylic acid moiety of the AzcA product to complete 5‑azacytosine biosynthesis. This work uncovers intriguing enzymatic chemistry in the biosynthesis of a long-known therapeutic natural product, highlighting opportunities for discovering enzymatic diversity.
