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Details for Patent: 6,753,173

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Details for Patent: 6,753,173

Title: Methods to mediate polyketide synthase module effectiveness
Abstract:Linking sequences that modulate cross-talk between modules of Type I polyketide synthases have been identified and methods for their use are described. Arbitrarily chosen modules can be mixed and matched by supplying the appropriate linkers to facilitate transfer of a growing polyketide chain between modules. Employing these techniques, new polyketide end products may be obtained.
Inventor(s): Gokhale; Rajesh S. (Delhi, IN), Tsuji; Stuart (Stanford, CA), Khosla; Chaitan (Palo Alto, CA)
Assignee: Board of Trustees of the Leland Stanford Junior University (Palo Alto, CA)
Filing Date:Feb 09, 2000
Application Number:09/500,747
Claims:1. A hybrid modular polyketide synthase (PKS) comprising at least a first extender module and a second extender module of a different PKS from said first module, wherein said extender modules are defined as consisting of the amino acid sequence from the N-terminus of the ketosynthase (KS) domain through the C-terminus of the acyl transferase protein (ACP) domain: wherein the C-terminus of said first module is covalently linked to the N-terminus of a intra-molecular linker (RAL) and the N-terminus of the second module is covalently linked to the C-terminus of said RAL, and wherein said RAL is defined as the amino acid sequence between the C-terminus of an upstream ACP domain and the N-terminus of an adjacent downstream KS domain; said ACP and KS domains occupying adjacent modules in the same reading frame; wherein either said first module or second module is not covalently linked to said RAL in a naturally occurring polyketide synthase; whereby the RAL effects the transfer of a nascent polyketide chain from said first module to said second module.

2. The hybrid modular PKS of claim 1 wherein said RAL is selected from the group consisting of M2 ery, M4 ery, M6 ery, M2 rif, M3 rif, M5 rif, M3 rap, M4 rap, and M7 rap intra-module linkers (SEQ. ID. NO's: 3-11, respectively).

3. The hybrid modular PKS of claim 1 which contains ery modules 1 and 3 through 6 inclusive and tylosin module 2, and wherein said polyketide chain is transferred from ery module 1 to ery module 2 and then to ery modules 3 through 6 inclusive.

4. The hybrid modular PKS of claim 1 which contains ery modules 1 through 5 inclusive and narbomycin module 6, wherein said polyketide chain is transferred from ery modules 1 through 5 inclusive to nar module 6.

5. The hybrid modular PKS of claim 1 which contains modules 1 and 3 through 6 inclusive of ery and modules 2-3 of tylosin, spiramycin or niddamycin, wherein said polyketide chain is transferred from ery module 1 to modules 2-3 of tylosin, spiramycin or niddamycin and then to ery modules 3 through 6 inclusive.

6. The hybrid modular PKS of claim 1 which contains modules 1 through 3 inclusive of tylosin, spiramycin or niddamycin and modules 3 through 6 inclusive of ery, and wherein said polyketide chain is transferred from modules 1 through 3 inclusive of said tylosin, spiramycin or niddamycin to ery modules 3 through 6 inclusive.

7. The hybrid modular PKS of claim 1 which contains a module of tylosin, spiramycin or niddamycin and modules 1-2 and 3 through 6 inclusive of ery, wherein said polyketide chain is transferred from ery modules 1-2 to the tylosin, spiramycin or niddamycin module and then to ery modules 3 through 6 inclusive.

8. The hybrid modular PKS of claim 1 which contains modules 1 and 3 through 6 inclusive of ery and module 5 of tylosin, spiramycin or niddamycin having the enoyl reductase catalytic activity inactivated, wherein said polyketide chain is transferred from ery module 1 to module 5 of tylosin, spiramycin or niddamycin and then to ery modules 3 through 6 inclusive.

9. The hybrid modular PKS of claim 1 which contains ery modules 1 through 4 inclusive and 6 and module 6 of spiramycin or niddamycin, wherein said polyketide chain is transferred from ery modules 1 through 4 inclusive to module 6 of spiramycin or niddamycin and then to ery module 6.

10. The hybrid modular PKS of claim 1 which contains module 1 of FK-506 or 520 and modules 2 through 14 inclusive of rapamycin, wherein said polyketide chain is transferred from module 1 of FK-506 or 520 and then to modules 2 through 14 inclusive of rapamycin.

11. The hybrid modular PKS of claim 1 which contains module 1 and 11 through 14 inclusive of rapamycin and modules 2 through 6 inclusive of FK-506 or 520 wherein said polyketide chain is transferred from module 1 of rapamycin to modules 2 through 6 inclusive of FK-506 or 520 and then to modules 11 through 14 inclusive of rapamycin.

12. The hybrid modular PKS of claim 1 which contains module 1 of rapamycin, modules 2 through 7 inclusive of FK-506 or 520 and modules 12 through 14 inclusive of rapamycin, wherein said polyketide chain is transferred from module 1 of rapamycin to modules 2 through 7 inclusive of FK-506 or 520 and then to modules 12 through 14 inclusive of rapamycin.

13. The hybrid modular PKS of claim 1 which contains module 1 of rapamycin, modules 2 through 8 inclusive of FK-506 or 520 and modules 13-14 of rapamycin, wherein said polyketide chain is transferred from module 1 of rapamycin to modules 2 through 8 inclusive of FK-506 or 520 and then to modules 13-14 of rapamycin.

14. The hybrid modular PKS of claim 1 which contains modules 1 through 10 inclusive of rapamycin and modules 7 through 10 inclusive of FK-506 or 520, wherein said polyketide chain is transferred from modules 1 through 10 inclusive of rapamycin to modules 7 through 10 inclusive of FK-506 or 520.

15. A hybrid modular polyketide synthase (PKS) comprising at least a first extender module and a second extender module of a different PKS from said first module, wherein said extender modules are defined as consisting of the amino acid, sequence from the N-terminus of the ketosynthase (KS) domain through the C-terminus of the acyl transferase protein (ACP) domain: wherein the C-terminus of said first module is covalently linked to the N-terminus of a inter-molecular linker (ERL) and the N-terminus of the second module is covalently linked to the C-terminus of said ERL, and wherein said ERL is defined as a contiguous polypeptide comprising, in order, (1) the amino acid sequence beginning at the C-terminus of the ACP domain of the most downstream module of a first open reading frame and (2) the amino acid sequence upstream of the N-terminus of the most upstream KS domain of a second open reading frame, which second open reading frame is immediately adjacent to and downstream of said first open reading frame; and wherein either said first module or second module is not covalently linked to said ERL in a naturally occurring polyketide synthase; whereby the ERL effects the transfer of a nascent polyketide chain from said first module to said second module.

16. The hybrid modular PKS of claim 15 wherein the portion of the ERL at the N-terminus of the second module is selected from the group consisting of SEQ. ID. NO's: 12-19, respectively.

17. The hybrid modular PKS of claim 15 which contains ery modules 1 and 3 through 6 inclusive and tylosin module 2, and wherein said polyketide chain is transferred from ery module 1 to tyl module 2 and then to ery modules 3 through 6 inclusive.

18. The hybrid modular PKS of claim 15 which contains ery modules 1 through 5 inclusive and narbomycin module 6, wherein said polyketide chain is transferred from ery modules 1 through 5 inclusive to nar module 6.

19. The hybrid modular PKS of claim 15 which contains modules 1 and 3 through 6 inclusive of ery and modules 2-3 of tylosin, spiramycin or niddamnycin, wherein said polyketide chain is transferred from ery module 1 to modules 2-3 of tylosin, spiramycin or niddamycin and then to ery modules 3 through 6 inclusive.

20. The hybrid modular PKS of claim 15 which contains modules 1 through 3 inclusive of tylosin, spiramycin or niddamycin and modules 3 through 6 inclusive of ery, and wherein said polyketide chain is transferred from modules 1 through 3 inclusive of tylosin, spiramycin or niddamycin to ery modules 3 through 6 inclusive.

21. The hybrid modular PKS of claim 15 which contains a module of tylosin, spiramycin or niddamycin and modules 1-2 and 3 through 6 inclusive of ery, wherein said polyketide chain is transferred from ery modules 1-2 to the tylosin, spiramycin or niddamycin module and then to ery modules 3 through 6 inclusive.

22. The hybrid modular PKS of claim 15 which contains modules 1 and 3 through 6 inclusive of ery and module 5 of tylosin, spiramycin or niddamycin having the enoyl reductase catalytic activity inactivated, wherein said polyketide chain is transferred from ery module 1 to module 5 of tylosin, spiramycin or niddamycin and then to ery modules 3 through 6 inclusive.

23. The hybrid modular PKS of claim 15 which contains ery modules 1 through 4 inclusive and 6 and module 6 of spiramycin or niddamycin, wherein said polyketide chain is transferred from ery modules 1 through 4 inclusive to module 6 of spiramycin or niddamycin and then to ery module 6.

24. The hybrid modular PKS of claim 15 which contains module 1 of FK-506 or 520 and modules 2 through 14 inclusive of rapamycin, wherein said polyketide chain is transferred from module 1 of FK-506 or 520 and then to modules 2 through 14 inclusive of rapamycin.

25. The hybrid modular PKS of claim 15 which contains module 1 and 11 through 14 inclusive of rapamycin and modules 2 through 6 inclusive of FK-506 or 520 wherein said polyketide chain is transferred from module 1 of rapamycin to modules 2 through 6 inclusive of FK-506 or 520 and then to modules 11 through 14 inclusive of rapamycin.

26. The hybrid modular PKS of claim 15 which contains module 1 of rapamycin, modules 2 through 7 inclusive of FK-506 or 520 and modules 12 through 14 inclusive of rapamycin, wherein said polyketide chain is transferred from module 1 of rapamycin to modules 2 through 7 inclusive of FK-506 or 520 and then to modules 12 through 14 inclusive of rapamycin.

27. The hybrid modular PKS of claim 15 which contains module 1 of rapamycin, modules 2 through 8 inclusive of FK-506 or 520 and modules 13-14 of rapamycin, wherein said polyketide chain is transferred from module 1 of rapamycin to modules 2 through 8 inclusive of FK-506 or 520 and then to modules 13-14 of rapamycin.

28. The hybrid modular PKS of claim 15 which contains modules 1 through 10 inclusive of rapamycin and modules 7 through 10 inclusive of FK-506 or 520, wherein said polyketide chain is transferred from modules 1 through 10 inclusive of rapamycin to modules 7 through 10 inclusive of FK-506 or 520.
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