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Rational Reprogramming of O-Methylation Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol Lactone Scaffolds
[Image: see text] O-Methylation modulates the pharmacokinetic and pharmacodynamic (PK/PD) properties of small-molecule natural products, affecting their bioavailability, stability, and binding to targets. Diversity-oriented combinatorial biosynthesis of new chemical entities for drug discovery and o...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical
Society
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416077/ https://www.ncbi.nlm.nih.gov/pubmed/30767524 http://dx.doi.org/10.1021/jacs.8b12967 |
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author | Wang, Xiaojing Wang, Chen Duan, Lixin Zhang, Liwen Liu, Hang Xu, Ya-ming Liu, Qingpei Mao, Tonglin Zhang, Wei Chen, Ming Lin, Min Gunatilaka, A. A. Leslie Xu, Yuquan Molnár, István |
author_facet | Wang, Xiaojing Wang, Chen Duan, Lixin Zhang, Liwen Liu, Hang Xu, Ya-ming Liu, Qingpei Mao, Tonglin Zhang, Wei Chen, Ming Lin, Min Gunatilaka, A. A. Leslie Xu, Yuquan Molnár, István |
author_sort | Wang, Xiaojing |
collection | PubMed |
description | [Image: see text] O-Methylation modulates the pharmacokinetic and pharmacodynamic (PK/PD) properties of small-molecule natural products, affecting their bioavailability, stability, and binding to targets. Diversity-oriented combinatorial biosynthesis of new chemical entities for drug discovery and optimization of known bioactive scaffolds during drug development both demand efficient O-methyltransferase (OMT) biocatalysts with considerable substrate promiscuity and tunable regioselectivity that can be deployed in a scalable and sustainable manner. Here we demonstrate efficient total biosynthetic and biocatalytic platforms that use a pair of fungal OMTs with orthogonal regiospecificity to produce unnatural O-methylated benzenediol lactone polyketides. We show that rational, structure-guided active-site cavity engineering can reprogram the regioselectivity of these enzymes. We also characterize the interplay of engineered regioselectivity with substrate plasticity. These findings will guide combinatorial biosynthetic tailoring of unnatural products toward the generation of diverse chemical matter for drug discovery and the PK/PD optimization of bioactive scaffolds for drug development. |
format | Online Article Text |
id | pubmed-6416077 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Chemical
Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-64160772019-03-13 Rational Reprogramming of O-Methylation Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol Lactone Scaffolds Wang, Xiaojing Wang, Chen Duan, Lixin Zhang, Liwen Liu, Hang Xu, Ya-ming Liu, Qingpei Mao, Tonglin Zhang, Wei Chen, Ming Lin, Min Gunatilaka, A. A. Leslie Xu, Yuquan Molnár, István J Am Chem Soc [Image: see text] O-Methylation modulates the pharmacokinetic and pharmacodynamic (PK/PD) properties of small-molecule natural products, affecting their bioavailability, stability, and binding to targets. Diversity-oriented combinatorial biosynthesis of new chemical entities for drug discovery and optimization of known bioactive scaffolds during drug development both demand efficient O-methyltransferase (OMT) biocatalysts with considerable substrate promiscuity and tunable regioselectivity that can be deployed in a scalable and sustainable manner. Here we demonstrate efficient total biosynthetic and biocatalytic platforms that use a pair of fungal OMTs with orthogonal regiospecificity to produce unnatural O-methylated benzenediol lactone polyketides. We show that rational, structure-guided active-site cavity engineering can reprogram the regioselectivity of these enzymes. We also characterize the interplay of engineered regioselectivity with substrate plasticity. These findings will guide combinatorial biosynthetic tailoring of unnatural products toward the generation of diverse chemical matter for drug discovery and the PK/PD optimization of bioactive scaffolds for drug development. American Chemical Society 2019-02-15 2019-03-13 /pmc/articles/PMC6416077/ /pubmed/30767524 http://dx.doi.org/10.1021/jacs.8b12967 Text en Copyright © 2019 American Chemical Society This is an open access article published under a Creative Commons Non-Commercial No Derivative Works (CC-BY-NC-ND) Attribution License (http://pubs.acs.org/page/policy/authorchoice_ccbyncnd_termsofuse.html) , which permits copying and redistribution of the article, and creation of adaptations, all for non-commercial purposes. |
spellingShingle | Wang, Xiaojing Wang, Chen Duan, Lixin Zhang, Liwen Liu, Hang Xu, Ya-ming Liu, Qingpei Mao, Tonglin Zhang, Wei Chen, Ming Lin, Min Gunatilaka, A. A. Leslie Xu, Yuquan Molnár, István Rational Reprogramming of O-Methylation Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol Lactone Scaffolds |
title | Rational
Reprogramming of O-Methylation
Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol
Lactone Scaffolds |
title_full | Rational
Reprogramming of O-Methylation
Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol
Lactone Scaffolds |
title_fullStr | Rational
Reprogramming of O-Methylation
Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol
Lactone Scaffolds |
title_full_unstemmed | Rational
Reprogramming of O-Methylation
Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol
Lactone Scaffolds |
title_short | Rational
Reprogramming of O-Methylation
Regioselectivity for Combinatorial Biosynthetic Tailoring of Benzenediol
Lactone Scaffolds |
title_sort | rational
reprogramming of o-methylation
regioselectivity for combinatorial biosynthetic tailoring of benzenediol
lactone scaffolds |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416077/ https://www.ncbi.nlm.nih.gov/pubmed/30767524 http://dx.doi.org/10.1021/jacs.8b12967 |
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