Cortes, J., Haydock, S. F., Roberts, G. A., Bevitt, D. J. & Leadlay, P. F. An unusually large multifunctional polypeptide in the erythromycin-producing polyketide synthase of Saccharopolyspora erythraea. Nature 348, 176–178 (1990).

Article  CAS  PubMed  Google Scholar 

Donadio, S., Staver, M. J., McAlpine, J. B., Swanson, S. J. & Katz, L. Modular organization of genes required for complex polyketide biosynthesis. Science 252, 675–679 (1991).

Article  CAS  PubMed  Google Scholar 

Hertweck, C. The biosynthetic logic of polyketide diversity. Angew. Chem. Int. Ed. Engl. 48, 4688–4716 (2009).

Article  CAS  PubMed  Google Scholar 

Nguyen, T. et al. Exploiting the mosaic structure of trans-acyltransferase polyketide synthases for natural product discovery and pathway dissection. Nat. Biotechnol. 26, 225–233 (2008).

Article  CAS  PubMed  Google Scholar 

Piel, J. Biosynthesis of polyketides by trans-AT polyketide synthases. Nat. Prod. Rep. 27, 996–1047 (2010).

Article  CAS  PubMed  Google Scholar 

Helfrich, E. J. N. & Piel, J. Biosynthesis of polyketides by trans-AT polyketide synthases. Nat. Prod. Rep. 33, 231–316 (2016).

Article  CAS  PubMed  Google Scholar 

Ray, L. et al. A crotonyl-CoA reductase-carboxylase independent pathway for assembly of unusual alkylmalonyl-CoA polyketide synthase extender units. Nat. Commun. 7, 13609 (2016).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jin, W., Tu, J., Zhang, B., Wu, X. & Chen, Y. Gene conversion-associated successive engineering of modular polyketide synthases. Commun. Chem. 8, 261 (2025).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Nivina, A., Yuet, K. P., Hsu, J. & Khosla, C. Evolution and diversity of assembly-line polyketide synthases. Chem. Rev. 119, 12524–12547 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Helfrich, E. J. N. et al. Evolution of combinatorial diversity in trans-acyltransferase polyketide synthase assembly lines across bacteria. Nat. Commun. 12, 1422 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Guzman, K. M., Yuet, K. P., Lynch, S. R., Liu, C. W. & Khosla, C. Properties of a ‘split-and-stuttering’ module of an assembly line polyketide synthase. J. Org. Chem. 86, 11100–11106 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jian, X. et al. Antibiotic skeletal diversification via differential enoylreductase recruitment and module iteration in trans-acyltransferase polyketide synthases. J. Am. Chem. Soc. 146, 6114–6124 (2024).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Di, X. et al. Recent advances in discovery, structure, bioactivity, and biosynthesis of trans-AT polyketides. J. Agric. Food Chem. 72, 21318–21343 (2024).

Article  CAS  PubMed  Google Scholar 

Mai, Z. P. et al. Insight into the role of a trans-AT polyketide synthase in the biosynthesis of lankacidin-type natural products. Nat. Synth. 3, 1255–1265 (2024).

Article  CAS  Google Scholar 

Masschelein, J. et al. A dual transacylation mechanism for polyketide synthase chain release in enacyloxin antibiotic biosynthesis. Nat. Chem. 11, 906–912 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kosol, S. et al. Structural basis for chain release from the enacyloxin polyketide synthase. Nat. Chem. 11, 913–923 (2019).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Butcher, R. A. et al. The identification of bacillaene, the product of the PksX megacomplex in Bacillus subtilis. Proc. Natl Acad. Sci. USA 104, 1506–1509 (2007).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vriens, E. et al. Polyketide synthase-mediated O-methyloxime formation in the biosynthesis of the oximidine anticancer agents. Angew. Chem. Int. Ed. Engl. 62, e202304476 (2023).

Article  CAS  PubMed  Google Scholar 

Minas, H. A. et al. Modular oxime formation by a trans-AT polyketide synthase. Angew. Chem. Int. Ed. Engl. 62, e202304481 (2023).

Article  CAS  PubMed  Google Scholar 

Al-Dhelaan, R. et al. Condensation-incompetent ketosynthase inhibits trans-acyltransferase activity. ACS Chem. Biol. 14, 304–312 (2019).

Article  CAS  PubMed  Google Scholar 

Luo, M. et al. The mechanism of dehydrating bimodules in trans-acyltransferase polyketide biosynthesis: a showcase study on hepatoprotective hangtaimycin. Angew. Chem. Int. Ed. Engl. 60, 19139–19143 (2021).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Li, X. et al. Cytochrome P450 monooxygenase for catalyzing C-42 hydroxylation of the glycine-derived fragment in hangtaimycin biosynthesis. Org. Lett. 24, 1388–1393 (2022).

Article  CAS  PubMed  Google Scholar 

Luo, M., Dong, Y., Deng, Z. & Sun, Y. Methylation in hangtaimycin biosynthesis and its antibacterial activities. Syn. Sys. Biotechnol. 8, 682–687 (2023).

Article  CAS  Google Scholar 

Mei, Q. et al. Formation of the diketopiperazine moiety by a distinct condensation-like domain in hangtaimycin biosynthesis. Angew. Chem. Int. Ed. Engl. 64, e202421950 (2025).

Article  CAS  PubMed  Google Scholar 

Song, L. et al. Discovery and biosynthesis of gladiolin: a Burkholderia gladioli antibiotic with promising activity against Mycobacterium tuberculosis. J. Am. Chem. Soc. 139, 7974–7981 (2017).

Article  CAS  PubMed  Google Scholar 

Thomas, I., Martin, C. J., Wilkinson, C. J., Staunton, J. & Leadlay, P. F. Skipping in a hybrid polyketide synthase: evidence for ACP-to-ACP chain transfer. Chem. Biol. 9, 781–787 (2002).

Article  CAS  PubMed  Google Scholar 

Zhang, Y.-M., Hurlbert, J., White, S. W. & Rock, C. O. Roles of the active site water, histidine 303, and phenylalanine 396 in the catalytic mechanism of the elongation condensing enzyme of Streptococcus pneumoniae. J. Biol. Chem. 281, 17390–17399 (2006).

Article  CAS  PubMed  Google Scholar 

Gay, D. C. et al. A close look at a ketosynthase from a trans-acyltransferase modular polyketide synthase. Structure 22, 444–451 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dutta, S. et al. Structure of a modular polyketide synthase. Nature 510, 512–517 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar 

Whicher, J. R. et al. Structural rearrangements of a polyketide synthase module during its catalytic cycle. Nature 510, 560–564 (2014).

Article  CAS  PubMed  PubMed Central  Google Scholar