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Discovery of Highly Active Kynureninases for Cancer Immunotherapy through Protein Language Model
Open accessPreprint — published as 10.1093/nar/gkae1245 · Paper page
Abstract
Overcoming the immunosuppressive tumor microenvironment is a promising strategy in anticancer therapy. L-kynurenine, a strong immunosuppressive metabolite can be degraded through kynureninases. Through homology searches and protein language models, we identified and then experimentally determined the efficacy of four top-ranked kynureninases. The catalytically most active one nearly doubles turnover number over the prior best, reducing tumor weight by 3.42 times in mouse model comparisons, and thus, presenting substantial therapeutic potential.
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Metadata
- Authors
- Eom, H., Cho, K. S., Lee, J., Kim, S., Park, S., Kim, H., Yang, J., Han, Y.-H., Lee, J., Seok, C., Lee, M. S., Song, W. J., & Steinegger, M.
- Affiliations
- Seoul National University (KR)
- Asan Medical Center (KR)
- Corresponding author
- Lee, Myeong Sup
- Song, Woon Ju
- Steinegger, Martin
- ORCID
- Venue
- Nucleic Acids Research
- Publisher
- openRxiv
- Published
- 2024-01-20
- Volume
- 53
- Issue
- 1
- ISSN
- 0305-1048 (ISSN-L)
- PMC
- PMC11704957
- OpenAlex
- W4406149659
- Cited by
- 10
- References
- 1
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 1
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Nucleic Acids Research (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Research Foundation
- National Research Foundation of Korea (2020M3‐A9G7‐103933, 2020M3A9G7103934)
- Ministry of Science and ICT, South Korea
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme Catalysis and Immobilization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- kynureninase, enzyme discovery, protein language models, homology modeling, enzyme kinetic parameters, tumor immunosuppression, cancer immunotherapy, tumor microenvironment, enzyme activity prediction
- MeSH terms
- Animals, Humans, Hydrolases, Immunotherapy, Kinetics, Kynurenine, Models, Molecular, Neoplasms, Cell Line, Tumor, Mice, Tumor Microenvironment
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