Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase
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 <i>Pinus Sylvestris</i>, which can accept various non-physiological substrates to form unnatu...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-05-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/5/738 |
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| author | Kamal Adhikari I-Wen Lo Chun-Liang Chen Yung-Lin Wang Kuan-Hung Lin Saeid Malek Zadeh Rajesh Rattinam Yi-Shan Li Chang-Jer Wu Tsung-Lin Li |
| author_facet | Kamal Adhikari I-Wen Lo Chun-Liang Chen Yung-Lin Wang Kuan-Hung Lin Saeid Malek Zadeh Rajesh Rattinam Yi-Shan Li Chang-Jer Wu Tsung-Lin Li |
| author_sort | Kamal Adhikari |
| collection | DOAJ |
| description | 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 <i>Pinus Sylvestris</i>, 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 <i>Rhodopseudomonas palustris</i> in an <i>apo</i> 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. |
| first_indexed | 2024-03-10T19:56:19Z |
| format | Article |
| id | doaj.art-527c7db3907c42df8e7724ef76886220 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T19:56:19Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-527c7db3907c42df8e7724ef768862202023-11-19T23:55:09ZengMDPI AGBiomolecules2218-273X2020-05-0110573810.3390/biom10050738Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide SynthaseKamal Adhikari0I-Wen Lo1Chun-Liang Chen2Yung-Lin Wang3Kuan-Hung Lin4Saeid Malek Zadeh5Rajesh Rattinam6Yi-Shan Li7Chang-Jer Wu8Tsung-Lin Li9Genomics Research Center, Academia Sinica, Taipei 11529, TaiwanGenomics Research Center, Academia Sinica, Taipei 11529, TaiwanGenomics Research Center, Academia Sinica, Taipei 11529, TaiwanGenomics Research Center, Academia Sinica, Taipei 11529, TaiwanGenomics Research Center, Academia Sinica, Taipei 11529, TaiwanGenomics Research Center, Academia Sinica, Taipei 11529, TaiwanGenomics Research Center, Academia Sinica, Taipei 11529, TaiwanGenomics Research Center, Academia Sinica, Taipei 11529, TaiwanDepartment of Food Science, National Taiwan Ocean University, Keelung 20224, TaiwanGenomics Research Center, Academia Sinica, Taipei 11529, TaiwanPlant 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 <i>Pinus Sylvestris</i>, 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 <i>Rhodopseudomonas palustris</i> in an <i>apo</i> 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.https://www.mdpi.com/2218-273X/10/5/738polyketide synthasebenzoate coenzyme A ligaseprotein engineeringapoptosiscytotoxicity |
| spellingShingle | Kamal Adhikari I-Wen Lo Chun-Liang Chen Yung-Lin Wang Kuan-Hung Lin Saeid Malek Zadeh Rajesh Rattinam Yi-Shan Li Chang-Jer Wu Tsung-Lin Li Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase Biomolecules polyketide synthase benzoate coenzyme A ligase protein engineering apoptosis cytotoxicity |
| title | Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase |
| title_full | Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase |
| title_fullStr | Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase |
| title_full_unstemmed | Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase |
| title_short | Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase |
| title_sort | chemoenzymatic synthesis and biological evaluation for bioactive molecules derived from bacterial benzoyl coenzyme a ligase and plant type iii polyketide synthase |
| topic | polyketide synthase benzoate coenzyme A ligase protein engineering apoptosis cytotoxicity |
| url | https://www.mdpi.com/2218-273X/10/5/738 |
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