Evolution of (S)-2-Aminobutanol Synthesis from Chemical Resolution to Biomanufacturing
- 1School of Materials Science and Engineering, Pingdingshan University, Pingdingshan 467000, China
- 2School of Environmental and Chemical Engineering, Xi’an Polytechnic University, Xi’an 710048, China
- 3The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China
Abstract
As a pivotal chiral precursor for the synthesis of the antituberculosis drug ethambutol and antiepileptic drugs such as levetiracetam, Chiral (S)-2-aminobutanol requires high optical purity for clinical safety. This review systematically summarizes the evolution and recent advances in its synthetic routes. Traditional chemical methods, including the 1-nitropropane and 1-butene epoxidation routes, suffer from severe safety hazards and heavily rely on downstream chiral resolution. However, both chemical crystallization and enzymatic kinetic resolution are constrained by a 50% theoretical yield ceiling and incur heavy environmental burdens. To break this bottleneck, in vitro multienzyme cascades utilizing amine dehydrogenases (AmDHs) and ω-transaminases (ω-TAs) have emerged, achieving 100% theoretical yield from prochiral precursors and >99% enantiomeric excess (ee) driven by a distinct dual-pocket active site model. Furthermore, synthetic biology has enabled de novo biosynthesis via whole-cell cell factories. It should be noted that the recently reported 45.3 g·L−1 titer refers to the upstream amino acid precursor L-2-aminobutyric acid (L-2-ABA), not to the final (S)-2-aminobutanol product. To overcome bottlenecks like the intracellular toxicity of the intermediate 2-ketobutyrate (2-OBA), strategies including efflux pump engineering (e.g., rhtA) and quorum sensing-based dynamic regulation have successfully boosted the fermentation titer to 45.3 g·L−1. Finally, the industrialization potential of these generations of technologies is evaluated, highlighting that the transition toward in vitro continuous-flow microreactors and a hybrid whole-cell + cell-free architecture, combined with the integration of AI into whole-cell factories, represents a future trend for green and low-carbon manufacturing.
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BibTeX
@article{wang2026evolution,
title = {{Evolution of (S)-2-Aminobutanol Synthesis from Chemical Resolution to Biomanufacturing}},
author = {Bing-Bing Wang and Chang-Dong Chen and Yong-Jun Han and Wei-Shuang Tong and Hua-Shan Gao and Wei Ma and Jun-Yang Liu and Jian-Zhong Xu},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209203},
url = {https://www.mdpi.com/1422-0067/27/20/9203},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Evolution of (S)-2-Aminobutanol Synthesis from Chemical Resolution to Biomanufacturing
AU - Bing-Bing Wang
AU - Chang-Dong Chen
AU - Yong-Jun Han
AU - Wei-Shuang Tong
AU - Hua-Shan Gao
AU - Wei Ma
AU - Jun-Yang Liu
AU - Jian-Zhong Xu
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209203
UR - https://www.mdpi.com/1422-0067/27/20/9203
AB - As a pivotal chiral precursor for the synthesis of the antituberculosis drug ethambutol and antiepileptic drugs such as levetiracetam, Chiral (S)-2-aminobutanol requires high optical purity for clinical safety. This review systematically summarizes the evolution and recent advances in its synthetic routes. Traditional chemical methods, including the 1-nitropropane and 1-butene epoxidation routes, suffer from severe safety hazards and heavily rely on downstream chiral resolution. However, both chemical crystallization and enzymatic kinetic resolution are constrained by a 50% theoretical yield ceiling and incur heavy environmental burdens. To break this bottleneck, in vitro multienzyme cascades utilizing amine dehydrogenases (AmDHs) and ω-transaminases (ω-TAs) have emerged, achieving 100% theoretical yield from prochiral precursors and >99% enantiomeric excess (ee) driven by a distinct dual-pocket active site model. Furthermore, synthetic biology has enabled de novo biosynthesis via whole-cell cell factories. It should be noted that the recently reported 45.3 g·L−1 titer refers to the upstream amino acid precursor L-2-aminobutyric acid (L-2-ABA), not to the final (S)-2-aminobutanol product. To overcome bottlenecks like the intracellular toxicity of the intermediate 2-ketobutyrate (2-OBA), strategies including efflux pump engineering (e.g., rhtA) and quorum sensing-based dynamic regulation have successfully boosted the fermentation titer to 45.3 g·L−1. Finally, the industrialization potential of these generations of technologies is evaluated, highlighting that the transition toward in vitro continuous-flow microreactors and a hybrid whole-cell + cell-free architecture, combined with the integration of AI into whole-cell factories, represents a future trend for green and low-carbon manufacturing.
SN - 1422-0067
ER -