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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 Pinus Sylvestris, which can accept various non-physiological substrates to form unnatural polyketide prod...

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Autores principales: Adhikari, Kamal, Lo, I-Wen, Chen, Chun-Liang, Wang, Yung-Lin, Lin, Kuan-Hung, Zadeh, Saeid Malek, Rattinam, Rajesh, Li, Yi-Shan, Wu, Chang-Jer, Li, Tsung-Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277991/
https://www.ncbi.nlm.nih.gov/pubmed/32397467
http://dx.doi.org/10.3390/biom10050738
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author Adhikari, Kamal
Lo, I-Wen
Chen, Chun-Liang
Wang, Yung-Lin
Lin, Kuan-Hung
Zadeh, Saeid Malek
Rattinam, Rajesh
Li, Yi-Shan
Wu, Chang-Jer
Li, Tsung-Lin
author_facet Adhikari, Kamal
Lo, I-Wen
Chen, Chun-Liang
Wang, Yung-Lin
Lin, Kuan-Hung
Zadeh, Saeid Malek
Rattinam, Rajesh
Li, Yi-Shan
Wu, Chang-Jer
Li, Tsung-Lin
author_sort Adhikari, Kamal
collection PubMed
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 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.
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spelling pubmed-72779912020-06-12 Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase Adhikari, Kamal Lo, I-Wen Chen, Chun-Liang Wang, Yung-Lin Lin, Kuan-Hung Zadeh, Saeid Malek Rattinam, Rajesh Li, Yi-Shan Wu, Chang-Jer Li, Tsung-Lin Biomolecules Article 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. MDPI 2020-05-09 /pmc/articles/PMC7277991/ /pubmed/32397467 http://dx.doi.org/10.3390/biom10050738 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Adhikari, Kamal
Lo, I-Wen
Chen, Chun-Liang
Wang, Yung-Lin
Lin, Kuan-Hung
Zadeh, Saeid Malek
Rattinam, Rajesh
Li, Yi-Shan
Wu, Chang-Jer
Li, Tsung-Lin
Chemoenzymatic Synthesis and Biological Evaluation for Bioactive Molecules Derived from Bacterial Benzoyl Coenzyme A Ligase and Plant Type III Polyketide Synthase
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277991/
https://www.ncbi.nlm.nih.gov/pubmed/32397467
http://dx.doi.org/10.3390/biom10050738
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