TABLE 3.

Selected examples of domain or module exchange of modular PKS.

Exchange unit	Target	Engineering strategy (substrate change/donor unit/fusion point)	Rationale for engineering	Product	References
AT-PAL1	AT domain in module 1 of DEBS PKS	Methylmalonyl to malonyl CoA specific/rapamycin AT domain in module 2 exchange/N,C-term RE site splicing	Domain sequence alignment	Two novel triketide lactones	Oliynyk et al., 1996
AT-PAL1-PAL2	AT domain in module 6 of DEBS PKS	Methylmalonyl to methylmalonyl or malonyl CoA specific/RAPS AT2, DEBS AT4, DEBS AT5 exchange/interdomain region RE site splicing	Domain sequence alignment	Triketide lactones derivatives	Hans et al., 2003
AT-PAL1	AT domain in module 4 of DEBS PKS	Methylmalonyl to malonyl CoA specific/rapamycin AT domain in module 2 exchange/N,C-term RE site splicing	Domain sequence alignment	6-desmethyl erythromycin D	Petkovic et al., 2003
AT-PAL1	AT domain in module 4 of DEBS PKS	Methylmalonyl to ethylmalonyl CoA specific/niddamycin AT domain in module 5 exchange/N,C-term RE site splicing	Domain sequence alignment	6-desmethyl-6-ethylerythromycin A	Stassi et al., 1998
AT-PAL1-PAL2	AT domain in module 1-5,7 of geldanamycin PKS	Methylmalonyl or methoxymalonyl to malonyl CoA specific/rapamycin AT domain in module 2,14 exchange/N,C-term RE site splicing	Domain sequence alignment	Geldanamycin derivatives	Patel et al., 2004
AT-ACP	LM (AT-ACP) of DEBS PKS	Methylmalonyl or malonyl CoA to 40 carboxylic acids specific/AVES LM (AT-ACP) exchange/ACP C-term region splicing	Domain sequence alignment	Novel antibiotic erythromycins	Marsden et al., 1998
KSQ-AT-ACP	LM (KSQ-AT-ACP) of tylactone PKS	Malonyl to Methylmalonyl CoA specific/Platenolide LM (KSQ-AT-ACP) exchange/ACP-KS RE site splicing, synthetic linker connect	Domain sequence alignment	16-methyl platenollde I	Kuhstoss et al., 1996
KAL-AT-PAL1	AT domain in module 6 of DEBS PKS, AT domain in module 1 of β-lipomycin PKS	Methylmalonyl to methylmalonyl or malonyl CoA specific/epothilone AT domain in module 4 exchange, other various AT domains exchange/KAL-AT-PAL1	Domain sequence alignment and structure-based selection	3-hydroxycarboxylic Acid, short-chain ketones	Yuzawa et al., 2017b
KS-AT-KR-ACP	Insertion between module 1,2 (KS-AT-KR-ACP) of DEBS PKS	Methylmalonyl, malonyl CoA specific added/rapamycin module 2,5 (KS-AT-KR-ACP, AT-KR-ACP-KS) insertion/KS N-term, C-term RE site splicing	Domain sequence alignment	Novel octaketide macrolactones	Rowe et al., 2001
KS-AT-ACP, multi-modules	Modules of DEBS PKS	Same specificity/M1-M3, M1-M6, M1-RifM5, M2 to RifM5/Native RE site, conserved region of interpolypeptide linker	Domain sequence alignment	Triketide lactones derivatives	Gokhale et al., 1999
KS-AT-ACP	Modules of DEBS, soraphen, epothilone, geldanamycin, rifamycin, rapamycin, pikromycin, leptomycin PKS	Two module combinatorial biosynthesis of 14 module of 8 PKS/Conserved region of KS N-term and ACP C-term RE spicing	Domain sequence alignment	Triketide lactones derivatives	Menzella et al., 2005
KS-AT-ACP	Modules of DEBS 1,2,3 PKS	Methylmalonyl to propionyl, methylmalonyl, malonyl CoA specific/3 module combinatorial biosynthesis/conserved region of interpolypeptide linker	Domain sequence alignment	Triketide lactones derivatives	Klaus et al., 2016
AT-DH-KR-ACP-KS	Module 2 of neoaureothin PKS	Deletion of methylmalonyl CoA specific module 2/KS-AT linker conserved region and docking domain of ACP RE splicing	Domain sequence alignment	Homoaureothin	Sugimoto et al., 2015
KS-AT-ACP, KS-AT	Module 6 of DEBS PKS	Methylmalonyl-CoA to methylmalonyl or malonyl CoA specific/module 2,3,5 of DEBS PKS exchange/docking domain exchange to SYNZIP	Domain sequence alignment and structure-based selection	Triketide lactones derivatives	Klaus et al., 2019