ArticleBiotechnology and bioengineering2026
Evolution and Active Learning Identify Terminal and Distal Determinants for Improved TAL in P-Coumaric Acid Production.
Article in Biotechnology and bioengineering, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
p-Coumaric acid (p-CA) is a phenylpropanoid-derived platform molecule widely used in food, cosmetic, and nutraceutical products, and microbial biosynthesis represents a sustainable alternative to plant extraction. Tyrosine ammonia-lyase (TAL) catalyzes the single-step, cofactor-independent conversion of l-tyrosine to p-CA; however, natural TALs often suffer from low efficiency and limited robustness. Here, we established an "evolution-to-design" workflow integrating evolutionary analysis, terminal-region engineering, and active learning-guided semi-rational design to optimize TAL from Rhodotorula glutinis (RglTAL). Selection pressure analysis revealed strong positive selection at both termini. N-terminal truncation (28 residues) increased whole-cell activity by 31.0% and raised Tm by 1.0°C, while N-terminal replacements further enhanced activity, indicating an N-terminal conformational constraint. AI-assisted screening identified three distal substitutions (G30N, Q387A, L609A); the triple variant improved specific activity by 63.7% (0.31 U/mg) and raised Tm by 3.4°C. Combining these mutations with N-terminal truncation further increased activity to 0.36 U/mg. Molecular dynamics simulations suggest these gains arise from synergistic stabilization, active-site pocket tuning, and truncation-like N-terminal remodeling by G30N. This work provides an improved TAL biocatalyst and a generalizable framework bridging evolutionary insights and data-driven design for bioprocess-oriented enzyme optimization.
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