Characterization of the Rifamycin-Degrading Monooxygenase From Rifamycin Producers Implicating Its Involvement in Saliniketal Biosynthesis
Rifamycin derivatives, such as rifampicin, have potent antibiotic activity and have long been used in the clinic as mainstay components for the treatment of tuberculosis, leprosy, and AIDS-associated mycobacterial infections. However, the extensive usage of these antibiotics has resulted in the rapi...
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| Format: | Article |
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Frontiers Media S.A.
2020-06-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmicb.2020.00971/full |
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| author | Xiao-Fu Zheng Xin-Qiang Liu Shu-Ya Peng Qiang Zhou Bin Xu Hua Yuan Hua Yuan Gong-Li Tang |
| author_facet | Xiao-Fu Zheng Xin-Qiang Liu Shu-Ya Peng Qiang Zhou Bin Xu Hua Yuan Hua Yuan Gong-Li Tang |
| author_sort | Xiao-Fu Zheng |
| collection | DOAJ |
| description | Rifamycin derivatives, such as rifampicin, have potent antibiotic activity and have long been used in the clinic as mainstay components for the treatment of tuberculosis, leprosy, and AIDS-associated mycobacterial infections. However, the extensive usage of these antibiotics has resulted in the rapid development of bacterial resistance. The resistance mechanisms mainly include mutations of the rifamycin target RNA polymerase of bacteria and enzymatic modifications of rifamycin antibiotics. One modification is the recently characterized rifamycin degradation catalyzed by Rox enzymes, which belong to the widely occurring flavin monooxygenases. Intriguingly, our recent sequence analysis revealed the rifamycin producers also encode Rox homologs that are not yet characterized. In this work, we expanded the study of the Rox-catalyzed rifamycin degradation. We first showed that the Rox proteins from rifamycin producers have the enzymatic rifamycin SV-degrading activity. Then we used the structurally diverse rifamycin compounds rifampicin and 16-demethylrifamycin W to probe the substrate scope and found that they each have a slightly different substrate scope. Finally, we demonstrated that Rox proteins can also catalyze the transformation of 16-demethylsalinisporamycin to 16-demethylsaliniketal A. Since 16-demethylsalinisporamycin and 16-demethylsaliniketal A are the counterpart analogs of salinisporamycin and saliniketal A, our biochemical findings not only uncover a previously uncharacterized self-resistance mechanism in the rifamycin producers, but also bridge the gap between the biosynthesis of the potential antitumor compound saliniketal A. |
| first_indexed | 2024-12-10T18:58:05Z |
| format | Article |
| id | doaj.art-2b837c1d51b44db99a28da55179e1862 |
| institution | Directory Open Access Journal |
| issn | 1664-302X |
| language | English |
| last_indexed | 2024-12-10T18:58:05Z |
| publishDate | 2020-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj.art-2b837c1d51b44db99a28da55179e18622022-12-22T01:37:06ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2020-06-011110.3389/fmicb.2020.00971536908Characterization of the Rifamycin-Degrading Monooxygenase From Rifamycin Producers Implicating Its Involvement in Saliniketal BiosynthesisXiao-Fu Zheng0Xin-Qiang Liu1Shu-Ya Peng2Qiang Zhou3Bin Xu4Hua Yuan5Hua Yuan6Gong-Li Tang7Department of Chemistry, College of Sciences, Shanghai University, Shanghai, ChinaCAS-Key Laboratory of Synthetic Biology, Shanghai Institute of Plant Physiology and Ecology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, ChinaInstitute of Microbial Pharmaceuticals, College of Life and Health Sciences, Northeastern University, Shenyang, ChinaThe Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of Chemistry, College of Sciences, Shanghai University, Shanghai, ChinaCollege of Life Sciences, Shanghai Normal University, Shanghai, ChinaState Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, ChinaState Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, ChinaRifamycin derivatives, such as rifampicin, have potent antibiotic activity and have long been used in the clinic as mainstay components for the treatment of tuberculosis, leprosy, and AIDS-associated mycobacterial infections. However, the extensive usage of these antibiotics has resulted in the rapid development of bacterial resistance. The resistance mechanisms mainly include mutations of the rifamycin target RNA polymerase of bacteria and enzymatic modifications of rifamycin antibiotics. One modification is the recently characterized rifamycin degradation catalyzed by Rox enzymes, which belong to the widely occurring flavin monooxygenases. Intriguingly, our recent sequence analysis revealed the rifamycin producers also encode Rox homologs that are not yet characterized. In this work, we expanded the study of the Rox-catalyzed rifamycin degradation. We first showed that the Rox proteins from rifamycin producers have the enzymatic rifamycin SV-degrading activity. Then we used the structurally diverse rifamycin compounds rifampicin and 16-demethylrifamycin W to probe the substrate scope and found that they each have a slightly different substrate scope. Finally, we demonstrated that Rox proteins can also catalyze the transformation of 16-demethylsalinisporamycin to 16-demethylsaliniketal A. Since 16-demethylsalinisporamycin and 16-demethylsaliniketal A are the counterpart analogs of salinisporamycin and saliniketal A, our biochemical findings not only uncover a previously uncharacterized self-resistance mechanism in the rifamycin producers, but also bridge the gap between the biosynthesis of the potential antitumor compound saliniketal A.https://www.frontiersin.org/article/10.3389/fmicb.2020.00971/fullrifamycin degradationRox enzymeflavin monooxygenaseself-resistancesaliniketal |
| spellingShingle | Xiao-Fu Zheng Xin-Qiang Liu Shu-Ya Peng Qiang Zhou Bin Xu Hua Yuan Hua Yuan Gong-Li Tang Characterization of the Rifamycin-Degrading Monooxygenase From Rifamycin Producers Implicating Its Involvement in Saliniketal Biosynthesis Frontiers in Microbiology rifamycin degradation Rox enzyme flavin monooxygenase self-resistance saliniketal |
| title | Characterization of the Rifamycin-Degrading Monooxygenase From Rifamycin Producers Implicating Its Involvement in Saliniketal Biosynthesis |
| title_full | Characterization of the Rifamycin-Degrading Monooxygenase From Rifamycin Producers Implicating Its Involvement in Saliniketal Biosynthesis |
| title_fullStr | Characterization of the Rifamycin-Degrading Monooxygenase From Rifamycin Producers Implicating Its Involvement in Saliniketal Biosynthesis |
| title_full_unstemmed | Characterization of the Rifamycin-Degrading Monooxygenase From Rifamycin Producers Implicating Its Involvement in Saliniketal Biosynthesis |
| title_short | Characterization of the Rifamycin-Degrading Monooxygenase From Rifamycin Producers Implicating Its Involvement in Saliniketal Biosynthesis |
| title_sort | characterization of the rifamycin degrading monooxygenase from rifamycin producers implicating its involvement in saliniketal biosynthesis |
| topic | rifamycin degradation Rox enzyme flavin monooxygenase self-resistance saliniketal |
| url | https://www.frontiersin.org/article/10.3389/fmicb.2020.00971/full |
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