Genomic Comparisons Revealed the Key Genotypes of <i>Streptomyces</i> sp. CB03234-GS26 to Optimize Its Growth and Relevant Production of Tiancimycins
Strain robustness and titer improvement are major challenges faced in the industrial development of natural products from <i>Streptomyces</i>. Tiancimycins (TNMs) produced by <i>Streptomyces</i> sp. CB03234 are promising anticancer payloads for antibody-drug conjugates, but f...
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MDPI AG
2024-11-01
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| author | Huiming Liu Jing Lin Yong Huang Yanwen Duan Xiangcheng Zhu |
| author_facet | Huiming Liu Jing Lin Yong Huang Yanwen Duan Xiangcheng Zhu |
| author_sort | Huiming Liu |
| collection | DOAJ |
| description | Strain robustness and titer improvement are major challenges faced in the industrial development of natural products from <i>Streptomyces</i>. Tiancimycins (TNMs) produced by <i>Streptomyces</i> sp. CB03234 are promising anticancer payloads for antibody-drug conjugates, but further development is severely limited by the low titer of TNMs. Despite many efforts to generate various TNMs overproducers, the mechanisms underlying high TNMs production remain to be explored. Herein, genome resequencing and genomic comparisons of different TNMs overproducers were conducted to explore the unique genotypes in CB03234-GS26. Four target genes were selected for further bioinformatic analyses and genetic validations. The results indicated that the inactivation of histidine ammonia-lyase (HAL) showed the most significant effect by blocking the intracellular degradation of histidine to facilitate relevant enzymatic catalysis and thus improve the production of TNMs. Additionally, the potassium/proton antiporter (P/PA) was crucial for intracellular pH homeostasis, and its deficiency severely impaired the alkaline tolerance of the cells. Subsequent pan-genomic analysis suggested that HAL and P/PA are core enzymes that are highly conserved in <i>Streptomyces</i>. Therefore, HAL and P/PA represented novel targets to regulate secondary metabolism and enhance strain robustness and could become potential synthetic biological modules to facilitate development of natural products and strain improvement in <i>Streptomyces</i>. |
| format | Article |
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| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
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| spelling | doaj-art-583b52dd607d4da78e15e5683788e2312025-08-20T02:08:12ZengMDPI AGBioengineering2306-53542024-11-011111112810.3390/bioengineering11111128Genomic Comparisons Revealed the Key Genotypes of <i>Streptomyces</i> sp. CB03234-GS26 to Optimize Its Growth and Relevant Production of TiancimycinsHuiming Liu0Jing Lin1Yong Huang2Yanwen Duan3Xiangcheng Zhu4Xiangya International Academy of Translational Medicine, Central South University, Changsha 410013, ChinaXiangya International Academy of Translational Medicine, Central South University, Changsha 410013, ChinaXiangya International Academy of Translational Medicine, Central South University, Changsha 410013, ChinaXiangya International Academy of Translational Medicine, Central South University, Changsha 410013, ChinaXiangya International Academy of Translational Medicine, Central South University, Changsha 410013, ChinaStrain robustness and titer improvement are major challenges faced in the industrial development of natural products from <i>Streptomyces</i>. Tiancimycins (TNMs) produced by <i>Streptomyces</i> sp. CB03234 are promising anticancer payloads for antibody-drug conjugates, but further development is severely limited by the low titer of TNMs. Despite many efforts to generate various TNMs overproducers, the mechanisms underlying high TNMs production remain to be explored. Herein, genome resequencing and genomic comparisons of different TNMs overproducers were conducted to explore the unique genotypes in CB03234-GS26. Four target genes were selected for further bioinformatic analyses and genetic validations. The results indicated that the inactivation of histidine ammonia-lyase (HAL) showed the most significant effect by blocking the intracellular degradation of histidine to facilitate relevant enzymatic catalysis and thus improve the production of TNMs. Additionally, the potassium/proton antiporter (P/PA) was crucial for intracellular pH homeostasis, and its deficiency severely impaired the alkaline tolerance of the cells. Subsequent pan-genomic analysis suggested that HAL and P/PA are core enzymes that are highly conserved in <i>Streptomyces</i>. Therefore, HAL and P/PA represented novel targets to regulate secondary metabolism and enhance strain robustness and could become potential synthetic biological modules to facilitate development of natural products and strain improvement in <i>Streptomyces</i>.https://www.mdpi.com/2306-5354/11/11/1128<i>Streptomyces</i>tiancimycinsgenome resequencinggenotypesbioinformatics analysisalkaline tolerance |
| spellingShingle | Huiming Liu Jing Lin Yong Huang Yanwen Duan Xiangcheng Zhu Genomic Comparisons Revealed the Key Genotypes of <i>Streptomyces</i> sp. CB03234-GS26 to Optimize Its Growth and Relevant Production of Tiancimycins Bioengineering <i>Streptomyces</i> tiancimycins genome resequencing genotypes bioinformatics analysis alkaline tolerance |
| title | Genomic Comparisons Revealed the Key Genotypes of <i>Streptomyces</i> sp. CB03234-GS26 to Optimize Its Growth and Relevant Production of Tiancimycins |
| title_full | Genomic Comparisons Revealed the Key Genotypes of <i>Streptomyces</i> sp. CB03234-GS26 to Optimize Its Growth and Relevant Production of Tiancimycins |
| title_fullStr | Genomic Comparisons Revealed the Key Genotypes of <i>Streptomyces</i> sp. CB03234-GS26 to Optimize Its Growth and Relevant Production of Tiancimycins |
| title_full_unstemmed | Genomic Comparisons Revealed the Key Genotypes of <i>Streptomyces</i> sp. CB03234-GS26 to Optimize Its Growth and Relevant Production of Tiancimycins |
| title_short | Genomic Comparisons Revealed the Key Genotypes of <i>Streptomyces</i> sp. CB03234-GS26 to Optimize Its Growth and Relevant Production of Tiancimycins |
| title_sort | genomic comparisons revealed the key genotypes of i streptomyces i sp cb03234 gs26 to optimize its growth and relevant production of tiancimycins |
| topic | <i>Streptomyces</i> tiancimycins genome resequencing genotypes bioinformatics analysis alkaline tolerance |
| url | https://www.mdpi.com/2306-5354/11/11/1128 |
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