Improving polyketide biosynthesis by rescuing the translation of truncated mRNAs into functional polyketide synthase subunits
Abstract Modular polyketide synthases (mPKSs) are multidomain enzymes in bacteria that synthesize a variety of pharmaceutically important compounds. mPKS genes are usually longer than 10 kb and organized in operons. To understand the transcriptional and translational characteristics of these large g...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55973-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832594554550747136 |
|---|---|
| author | Yan Liu Chaoyi Song Qingwen Cui Hongluan Sun Chanjuan Jiang Ruofei Guo Ruoting He Zhen Li Ji Luan Hailong Wang |
| author_facet | Yan Liu Chaoyi Song Qingwen Cui Hongluan Sun Chanjuan Jiang Ruofei Guo Ruoting He Zhen Li Ji Luan Hailong Wang |
| author_sort | Yan Liu |
| collection | DOAJ |
| description | Abstract Modular polyketide synthases (mPKSs) are multidomain enzymes in bacteria that synthesize a variety of pharmaceutically important compounds. mPKS genes are usually longer than 10 kb and organized in operons. To understand the transcriptional and translational characteristics of these large genes, here we split the 13-kb busA gene, encoding a 456-kDa three-module PKS for butenyl-spinosyn biosynthesis, into three smaller separately translated genes encoding one PKS module in an operon. Expression of the native and split busA genes in Streptomyces albus reveals that the majority ( >93%) of PKS mRNAs are truncated, resulting in a greater abundance of and a higher synthesis rate for the proteins encoded by genes closer to the operon promoter. Splitting the large busA gene rescues translation of truncated mRNAs into functional PKS subunits, and increases the biosynthetic efficiency of butenyl-spinosyn PKS by 13-fold. The truncated mRNA translation rescue strategy will facilitate engineering of multi-domain proteins to enhance their functions. |
| format | Article |
| id | doaj-art-7cb0cee3ef5e472e830193b81cb7cb63 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-7cb0cee3ef5e472e830193b81cb7cb632025-01-19T12:31:50ZengNature PortfolioNature Communications2041-17232025-01-0116111510.1038/s41467-025-55973-0Improving polyketide biosynthesis by rescuing the translation of truncated mRNAs into functional polyketide synthase subunitsYan Liu0Chaoyi Song1Qingwen Cui2Hongluan Sun3Chanjuan Jiang4Ruofei Guo5Ruoting He6Zhen Li7Ji Luan8Hailong Wang9State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Helmholtz International Lab for Anti-infectives, Shandong University–Helmholtz Institute of Biotechnology, Shandong UniversityState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Helmholtz International Lab for Anti-infectives, Shandong University–Helmholtz Institute of Biotechnology, Shandong UniversityState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Helmholtz International Lab for Anti-infectives, Shandong University–Helmholtz Institute of Biotechnology, Shandong UniversityState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Helmholtz International Lab for Anti-infectives, Shandong University–Helmholtz Institute of Biotechnology, Shandong UniversityState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Helmholtz International Lab for Anti-infectives, Shandong University–Helmholtz Institute of Biotechnology, Shandong UniversityState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Helmholtz International Lab for Anti-infectives, Shandong University–Helmholtz Institute of Biotechnology, Shandong UniversityState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Helmholtz International Lab for Anti-infectives, Shandong University–Helmholtz Institute of Biotechnology, Shandong UniversityState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Helmholtz International Lab for Anti-infectives, Shandong University–Helmholtz Institute of Biotechnology, Shandong UniversityState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Helmholtz International Lab for Anti-infectives, Shandong University–Helmholtz Institute of Biotechnology, Shandong UniversityState Key Laboratory of Microbial Technology, Institute of Microbial Technology, Helmholtz International Lab for Anti-infectives, Shandong University–Helmholtz Institute of Biotechnology, Shandong UniversityAbstract Modular polyketide synthases (mPKSs) are multidomain enzymes in bacteria that synthesize a variety of pharmaceutically important compounds. mPKS genes are usually longer than 10 kb and organized in operons. To understand the transcriptional and translational characteristics of these large genes, here we split the 13-kb busA gene, encoding a 456-kDa three-module PKS for butenyl-spinosyn biosynthesis, into three smaller separately translated genes encoding one PKS module in an operon. Expression of the native and split busA genes in Streptomyces albus reveals that the majority ( >93%) of PKS mRNAs are truncated, resulting in a greater abundance of and a higher synthesis rate for the proteins encoded by genes closer to the operon promoter. Splitting the large busA gene rescues translation of truncated mRNAs into functional PKS subunits, and increases the biosynthetic efficiency of butenyl-spinosyn PKS by 13-fold. The truncated mRNA translation rescue strategy will facilitate engineering of multi-domain proteins to enhance their functions.https://doi.org/10.1038/s41467-025-55973-0 |
| spellingShingle | Yan Liu Chaoyi Song Qingwen Cui Hongluan Sun Chanjuan Jiang Ruofei Guo Ruoting He Zhen Li Ji Luan Hailong Wang Improving polyketide biosynthesis by rescuing the translation of truncated mRNAs into functional polyketide synthase subunits Nature Communications |
| title | Improving polyketide biosynthesis by rescuing the translation of truncated mRNAs into functional polyketide synthase subunits |
| title_full | Improving polyketide biosynthesis by rescuing the translation of truncated mRNAs into functional polyketide synthase subunits |
| title_fullStr | Improving polyketide biosynthesis by rescuing the translation of truncated mRNAs into functional polyketide synthase subunits |
| title_full_unstemmed | Improving polyketide biosynthesis by rescuing the translation of truncated mRNAs into functional polyketide synthase subunits |
| title_short | Improving polyketide biosynthesis by rescuing the translation of truncated mRNAs into functional polyketide synthase subunits |
| title_sort | improving polyketide biosynthesis by rescuing the translation of truncated mrnas into functional polyketide synthase subunits |
| url | https://doi.org/10.1038/s41467-025-55973-0 |
| work_keys_str_mv | AT yanliu improvingpolyketidebiosynthesisbyrescuingthetranslationoftruncatedmrnasintofunctionalpolyketidesynthasesubunits AT chaoyisong improvingpolyketidebiosynthesisbyrescuingthetranslationoftruncatedmrnasintofunctionalpolyketidesynthasesubunits AT qingwencui improvingpolyketidebiosynthesisbyrescuingthetranslationoftruncatedmrnasintofunctionalpolyketidesynthasesubunits AT hongluansun improvingpolyketidebiosynthesisbyrescuingthetranslationoftruncatedmrnasintofunctionalpolyketidesynthasesubunits AT chanjuanjiang improvingpolyketidebiosynthesisbyrescuingthetranslationoftruncatedmrnasintofunctionalpolyketidesynthasesubunits AT ruofeiguo improvingpolyketidebiosynthesisbyrescuingthetranslationoftruncatedmrnasintofunctionalpolyketidesynthasesubunits AT ruotinghe improvingpolyketidebiosynthesisbyrescuingthetranslationoftruncatedmrnasintofunctionalpolyketidesynthasesubunits AT zhenli improvingpolyketidebiosynthesisbyrescuingthetranslationoftruncatedmrnasintofunctionalpolyketidesynthasesubunits AT jiluan improvingpolyketidebiosynthesisbyrescuingthetranslationoftruncatedmrnasintofunctionalpolyketidesynthasesubunits AT hailongwang improvingpolyketidebiosynthesisbyrescuingthetranslationoftruncatedmrnasintofunctionalpolyketidesynthasesubunits |