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Article

Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase

1
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
2
Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, Academia Sinica and National Chung Hsing University, Taipei 11529, Taiwan
3
Graduate Institute of Biotechnology, National Chung Hsing University, Taichung 40227, Taiwan
4
Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Taipei 11529, Taiwan
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Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30013, Taiwan
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Department of Food Science, National Taiwan Ocean University, Keelung 20224, Taiwan
7
Biotechnology Center, National Chung Hsing University, Taichung 40227, Taiwan
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(5), 738; https://doi.org/10.3390/biom10050738
Received: 21 March 2020 / Revised: 20 April 2020 / Accepted: 27 April 2020 / Published: 9 May 2020
Plant type III polyketide synthases produce diverse bioactive molecules with a great medicinal significance to human diseases. Here, we demonstrated versatility of a stilbene synthase (STS) from Pinus Sylvestris, which can accept various non-physiological substrates to form unnatural polyketide products. Three enzymes (4-coumarate CoA ligase, malonyl-CoA synthetase and engineered benzoate CoA ligase) along with synthetic chemistry was practiced to synthesize starter and extender substrates for STS. Of these, the crystal structures of benzoate CoA ligase (BadA) from Rhodopseudomonas palustris in an apo form or in complex with a 2-chloro-1,3-thiazole-5-carboxyl-AMP or 2-methylthiazole-5-carboxyl-AMP intermediate were determined at resolutions of 1.57 Å, 1.7 Å, and 2.13 Å, respectively, which reinforces its capacity in production of unusual CoA starters. STS exhibits broad substrate promiscuity effectively affording structurally diverse polyketide products. Seven novel products showed desired cytotoxicity against a panel of cancer cell lines (A549, HCT116, Cal27). With the treatment of two selected compounds, the cancer cells underwent cell apoptosis in a dose-dependent manner. The precursor-directed biosynthesis alongside structure-guided enzyme engineering greatly expands the pharmaceutical repertoire of lead compounds with promising/enhanced biological activities. View Full-Text
Keywords: polyketide synthase; benzoate coenzyme A ligase; protein engineering; apoptosis; cytotoxicity polyketide synthase; benzoate coenzyme A ligase; protein engineering; apoptosis; cytotoxicity
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MDPI and ACS Style

Adhikari, K.; Lo, I.-W.; Chen, C.-L.; Wang, Y.-L.; Lin, K.-H.; Zadeh, S.M.; Rattinam, R.; Li, Y.-S.; Wu, C.-J.; Li, T.-L. Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase. Biomolecules 2020, 10, 738. https://doi.org/10.3390/biom10050738

AMA Style

Adhikari K, Lo I-W, Chen C-L, Wang Y-L, Lin K-H, Zadeh SM, Rattinam R, Li Y-S, Wu C-J, Li T-L. Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase. Biomolecules. 2020; 10(5):738. https://doi.org/10.3390/biom10050738

Chicago/Turabian Style

Adhikari, Kamal, I-Wen Lo, Chun-Liang Chen, Yung-Lin Wang, Kuan-Hung Lin, Saeid M. Zadeh, Rajesh Rattinam, Yi-Shan Li, Chang-Jer Wu, and Tsung-Lin Li. 2020. "Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase" Biomolecules 10, no. 5: 738. https://doi.org/10.3390/biom10050738

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