Hybrid polyketide synthases

1. A non-naturally occurring hybrid polyketide synthase (PKS) which synthesizes adipic acid, wherein the PKS comprises:

(a) a first module that is a loading module that incorporates succinyl-CoA, wherein the first module comprises an aspartate-specific adenylation (A) domain from the non-ribosomal peptide synthetase (NRPS) from the calcium-dependent antibiotic (CPA) pathway from Saccharopolyspora erythraea linked to a peptidylcarrier protein (PCP) domain from the bleomycin pathway from Streptomyces verticillus ; wherein the A domain comprises a glutamine substitution for the conserved Asp235 residue of the substrate-binding pocket as defined in the gramicidin S synthase phenylalanine-activating domain; and

a second module comprising at least one extension module and a TE domain; or

(b) a first module that is a loading module that incorporates succinyl-CoA, wherein the first module comprises a loading domain and ACP domain of a chondrochloren PKS in which a succinyl-CoA synthetase replaces a CoA ligase domain and

a second module comprising at least one extension module and a TE domain; or

(c) an etnangien loading module which incorporates succinate using a trans-AT domain; and

(i) at least one heterologous extension module, and a TE domain: or

(ii) extension module 1 from Sorangium cellulosum PKS in which DH-ER-KR domains are inserted between the ACP2 and ACP3; and a TE domain; or

(iii) wherein the etnangien loading module has inactivated the KS domain joined to the KS domain of extension module 2 from Sorangium cellulosum PKS linked to a malonyl-specific AT domain joined to DH-ER-KR-ACP-TE domains; or

(d) a loading module and at least three extension modules as set forth in FIG. 14 , wherein the PKS produces the intermediates [a], [b], [c], and [d] set forth in FIG. 14 , wherein the 9-carbon backbone of [d] is released from the ACP by the TE domain and converted to adipic and propionic acid by an esterase, an alcohol dehydrogenase, a flavin-binding family monooxygenase, and an aldehyde dehydrogenase as set forth in FIG. 13 .

2. The non-naturally occurring hybrid PKS of claim 1 , wherein the PKS comprises the modules set forth in (a), wherein the at least one extension module comprises a KS domain joined to an AT-DH-ER-KR-ACP from nystatin module 5 or nystatin module 15 that incorporates malonyl-CoA and fully reduces a corresponding β-carbonyl group; and a TE domain fused to the ACP from the nystatin module 5 or 15.

3. The non-naturally occurring hybrid PKS of claim 2 , wherein the KS domain is from the bleomycin pathway from Streptomyces verticillus and the TE domain is from the erythromycin pathway.

4. The PKS of claim 2 , wherein the A domain is directly linked to the PCP domain.

5. The non-naturally occurring hybrid PKS of claim 1 , wherein the PKS comprises the modules set forth in (b) and wherein the at least one extension module comprises a nystatin module 5; and a TE domain.

6. The non-naturally occurring hybrid PKS of claim 1 , wherein the PKS comprises the etnangien loading module, the at least one heterologous extension module, and the TE domain as set forth in (c) (i).

7. The non-naturally occurring hybrid PKS of claim 1 , wherein the PKS comprises a loading module and three extension modules as set forth in FIG. 14 , wherein the PKS produces the intermediates [a], [b], [c], and [d] set forth in FIG. 14 , wherein the 9-carbon backbone of [d] is released from the ACP by the TE domain and converted to adipic and propionic acid by an esterase, an alcohol dehydrogenase, a flavin-binding family monooxygenase, and an aldehyde dehydrogenase as set forth in FIG. 13 .

8. The non-naturally occurring hybrid PKS of claim 1 , wherein the PKS comprises the modules set forth in FIG. 11 , and wherein the A domain is a variant of protein DhbE from Bacillus subtilis.

9. A recombinant nucleic acid encoding the non-naturally occurring hybrid polyketide synthase (PKS) of claim 1 .

10. A replicon comprising the recombinant nucleic acid of claim 9 , wherein the replicon is capable of stably maintained in a host cell.

11. The replicon of claim 10 , wherein the replicon is a plasmid or vector.

12. The replicon of claim 11 , wherein the vector is an expression vector.

13. A host cell comprising the recombinant nucleic acid of claim 9 or the replicon of claim 10 .

14. The host cell of claim 13 , wherein the host cell when cultured produces adipic acid.

15. A method of producing adipic acid comprising: culturing the host cell of claim 14 in a suitable culture medium such that adipic acid is produced.

16. The method of claim 15 , further comprising isolating the adipic acid.

17. The method of claim 16 , further comprising reacting the adipic acid with a diamine to produce a nylon.