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Outline
Recombinant human arginase 1 (rhArg1) has significant therapeutic potential for the treatment of arginase 1 deficiency (ARG1-D) and arginine-auxotrophic cancers. However, its relatively low catalytic efficiency and limited in vivo stability restrict its clinical application. To enhance the catalytic performance of rhArg1, we employed the protein language model SaProt to perform zero-shot global mutational effect prediction across the entire rhArg1 sequence. Based on the predicted scores, the top 37 candidate variants were selected for experimental validation. Enzyme activity assays revealed that 16 of the 37 variants exhibited higher activity than the wild-type (WT) enzyme. Among them, the V30A, C45F, A56V, and H312P variants showed the most pronounced improvements, with catalytic activities increased by 33%, 23%, 22%, and 90%, respectively, compared with WT. Further kinetic characterization demonstrated that the H312P variant increased by 131% in catalytic efficiency (kcat/KM) relative to WT. These results indicate that the protein language model SaProt can effectively guide the rational engineering of arginase. The high-activity variants identified in this study provide promising candidate molecules for the treatment of ARG1-D and arginine-auxotrophic cancers.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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