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울산대학교 의과대학, 갤럭스 주식회사

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Nucleic Acids Res., Jan 07 2025, 53 (1) gkae1245 | https://doi.org/10.1093/nar/gkae1245 Discovery of highly active kynureninases for cancer immunotherapy through protein language model

Hyunuk Eom¹, Sukhwan Park², Kye Soo Cho³, Jihyeon Lee¹, Hyunbin Kim², Stephanie Kim², Jinsol Yang³, Young-Hyun Han³, Juyong Lee^4,5,6, Chaok Seok^7,8,1,3, Myeong Sup Lee^9,3,*, Woon Ju Song^1,* and Martin Steinegger^2,7,8,*

¹Department of Chemistry, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
²School of Biological Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
³Galux Inc, 1837 Nambusunhwan-ro, Gwanak-gu, Seoul 08738, Republic of Korea
⁴Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
⁵School of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
⁶Arontier Co., 241 Gangnam-daero, Seocho-gu, Seoul 06735, Republic of Korea
⁷Artificial Intelligence Institute, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
⁸Institute of Molecular Biology and Genetics, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea
⁹Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea

^*To whom correspondence should be addressed.: Martin Steinegger
Correspondence may also be addressed to Myeong Sup Lee.
Correspondence may also be addressed to Woon Ju Song.

Abstract

Tailor-made enzymes empower a wide range of versatile applications, although searching for the desirable enzymes often requires high throughput screening and thus poses significant challenges. In this study, we employed homology searches and protein language models to discover and prioritize enzymes by their kinetic parameters. We aimed to discover kynureninases as a potentially versatile therapeutic enzyme, which hydrolyses L-kynurenine, a potent immunosuppressive metabolite, to overcome the immunosuppressive tumor microenvironment in anticancer therapy. Subsequently, we experimentally validated the efficacy of four top-ranked kynureninases under in vitro and in vivo conditions. Our findings revealed a catalytically most active one with a nearly twofold increase in turnover number over the prior best and a 3.4-fold reduction in tumor weight in mouse model comparisons. Consequently, our approach holds promise for the targeted quantitative enzyme discovery and selection suitable for specific applications with higher accuracy, significantly broadening the scope of enzyme utilization. A web-executable version of our workflow is available at seekrank.steineggerlab.com and our code is available as free open-source software at github.com/steineggerlab/SeekRank.

논문정보

형식Research article
게재일2025년 01월 (BRIC 등록일 2025-01-10)
연구진국내 연구진
분야 생명과학 > 유전학

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