Stereospecificity of ketoreductase domains of the 6-deoxyerythronolide B synthase

Journal of the American Chemical Society

Volumn 129, Issue 44, 2007, Pages 13758-13769

  Castonguay, Roselyne ^a   He, Weiguo ^a   Chen, Alice Y ^c   Khosla, Chaitan ^b,c   Cane, David E ^a  

^a BROWN UNIVERSITY   (United States)

^b Stanford University   (United States)

^c STANFORD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6-DEOXYERYTHRONOLIDE B SYNTHASE (DEBS); ACYL TRANSFERASE (AT); KETOREDUCTASE (KR) DOMAINS; POLYKETIDE SYNTHASE (PKS);

ANTIBIOTICS; BIOSYNTHESIS; CATALYST ACTIVITY; CHEMICAL MODIFICATION; HYDROLYSIS; STEREOCHEMISTRY;

ENZYMES;

2 METHYL 3 HYDROXYPENTANOIC ACID N ACETYLCYSTEAMINE THIOESTER; 2 METHYL 3 KETOACYL TRIKETIDE; 3,5 DIHYDROXY 2,4 DIMETHYL N HEPTANOIC ACID DELTA LACTONE; 6 DEOXYERYTHRONOLIDE B SYNTHASE; ACYL CARRIER PROTEIN; ACYLTRANSFERASE; AGLYCONE; CYSTEAMINE DERIVATIVE; ERYTHROMYCIN; HEPTANOIC ACID DERIVATIVE; KETOREDUCTASE; LACTONE DERIVATIVE; MACROLIDE; OXIDOREDUCTASE; POLYKETIDE; POLYKETIDE SYNTHASE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; SODIUM BOROHYDRIDE; THIOL ESTER HYDROLASE; UNCLASSIFIED DRUG; VALERIC ACID DERIVATIVE;

ARTICLE; BIOSYNTHESIS; CATALYSIS; CHEMICAL MODIFICATION; CHIMERA; CYCLIZATION; HYDROLYSIS; PROTEIN DOMAIN; STEREOCHEMISTRY; STEREOSPECIFICITY;

BINDING SITES; LACTONES; MASS SPECTROMETRY; MOLECULAR CONFORMATION; OXIDOREDUCTASES; POLYKETIDE SYNTHASES; PROTEIN STRUCTURE, TERTIARY; STEREOISOMERISM; SUBSTRATE SPECIFICITY;

EID: 36048958284     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja0753290     Document Type: Article

References (64)

1. (a) Walsh, C. T. ChemBioChem 2002, 3, 125-134.
2. Cane, D. E.; Walsh, C. T.; Khosla, C. Science 1998, 282, 63-68.
3. Walsh, C. T. Science 2004, 303, 1805-1810.
4. (b) For a comprehensive review of PKS and NRPS biochemistry and molecular biology as of 1997, see the thematic issue of Chem. Rev. 1997, 97, 2463-2706.
5. (c) Khosla, C.; Gokhale, R. S.; Jacobsen, J. R.; Cane, D. E. Annu. Rev. Biochem. 1999, 68, 219-253.
6. (a) Khosla, C.; Tang, Y.; Chen, A. Y.; Schnarr, N. A.; Cane, D. E. Annu. Rev. Biochem. 76, 195-221.
7. (b) Staunton, J.; Wilkinson, B. In Comprehensive Natural Products Chemistry, Polyketides and Other Secondary metabolites Including Fatty Acids and Their Derivatives; Sankawa, U., Ed.; Elsevier: Oxford, 1999; Vol. 1, p 495-532.
8. Kumar, P.; Khosla, C.; Tang, Y. Methods Enzymol. 2004, 388, 269-293.
9. Wu, N.; Kudo, F.; Cane, D. E.; Khosla, C. J. Am. Chem. Soc. 2000, 122, 4847-4852.
10. Gokhale, R. S.; Tsuji, S. Y.; Cane, D. E.; Khosla, C. Science 1999, 284, 482-485.
11. Kim, C. Y.; Alekseyev, V. Y.; Chen, A. Y.; Tang, Y.; Cane, D. E.; Khosla, C. Biochemistry 2004, 43, 13892-13898.
12. Chen, A. Y.; Schnarr, N. A.; Kim, C. Y.; Cane, D. E.; Khosla, C. J. Am. Chem. Soc. 2006, 128, 3067-3074.
13. Chen, A. Y.; Cane, D. E.; Khosla, C. Chem. Biol. 2007, 14, 784-792.
14. (a) Gokhale, R. S.; Hunziker, D.; Cane, D. E.; Khosla, C. Chem. Biol. 1999, 6, 117-125.
15. (b) Lu, H.; Tsai, S. C.; Khosla, C.; Cane, D. E. Biochemistry 2002, 41, 12590-12597.
16. (c) Schnarr, N.; Cronin, T.; Khosla, C.; Cane, D. E. Unpublished observations.
17. Hans, M.; Hornung, A.; Dziarnowski, A.; Cane, D. E.; Khosla, C. J. Am. Chem. Soc. 2003, 125, 5366-5374.
18. Walsh, C. T.; Gehring, A. M.; Weinreb, P. H.; Quadri, L. E.; Flügel, R. S. Curr. Opin. Chem. Biol. 1997, 1, 309-315.
19. Celmer, W. D. J. Am. Chem. Soc. 1965, 87, 1801-1802.
20. (a) McPherson, M.; Khosla, C.; Cane, D. E. J. Am. Chem. Soc. 1998, 120, 3267-3268.
21. (b) Yin, Y.; Gokhale, R.; Khosla, C.; Cane, D. E. Bioorg. Med. Chem. Lett. 2001, 11, 1477-1479.
22. Kao, C. M.; McPherson, M.; McDaniel, R. N.; Fu, H.; Cane, D. E.; Khosla, C. J. Am. Chem. Soc. 1998, 120, 2478-2479.
23. (a) Reid, R.; Piagentini, M.; Rodriguez, E.; Ashley, G.; Viswanathan, N.; Carney, J.; Santi, D. V.; Hutchinson, C. R.; McDaniel, R. Biochemistry 2003, 42, 72-79.
24. (b) Caffrey, P. ChemBioChem 2003, 4, 654-657.
25. Wu, J.; Zaleski, T. J.; Valenzano, C.; Khosla, C.; Cane, D. E. J. Am. Chem. Soc. 2005, 127, 17393-17404.
26. (a) Keatinge-Clay, A. T.; Stroud, R. M. Structure 2006, 14, 737-748.
27. (b) Baerga-Ortiz, A.; Popovic, B.; Siskos, A. P.; O'Hare, H. M.; Spiteller, D.; Williams, M. G.; Campillo, N.; Spencer, J. B.; Leadlay, P. F. Chem. Biol. 2006, 13, 277-285.
28. (c) Based on the determination of the crystal structure of the tylosin KR1 domain and comparison with that of the DEBS KR1 domain, Keatinge-Clay has proposed a binding model to account for the ketone facial stereospecificity of ketoreductases, as well as their preference for unepimerized or epimerized 2-methyl-3-ketoacyl-ACP substrates. Cf. Keatinge-Clay, A. Nat. Chem. Biol. 2007, 14, 898-908.
29. Marsden, A. F.; Caffrey, P.; Aparicio, J. F.; Loughran, M. S.; Staunton, J.; Leadlay, P. F. Science 1994, 263, 378-380.
30. Wiesmann, K. E.; Cortes, J.; Brown, M. J.; Cutter, A. L.; Staunton, J.; Leadlay, P. F. Chem. Biol. 1995, 2, 583-589.
31. (a) Weissman, K. J.; Timoney, M.; Bycroft, M.; Grice, P.; Hanefeld, U.; Staunton, J.; Leadlay, P. F. Biochemistry 1997, 36, 13849-13855.
32. (b) Cane, D. E.; Liang, T. C.; Taylor, P. B.; Chang, C.; Yang, C. C. J. Am. Chem. Soc 1986, 108, 4957-4964.
33. Note on stereochemical conventions: Although strictly speaking it is incorrect to mix Fischer D/L designations with the more rigorous Cahn, Ingold, Prelog R/S nomenclature, it is often convenient to retain the D- and L-labels when discussing a homologous series of polyketides, for which the specific R or S designation for the same absolute configuration at a given site might vary in response to the substitution pattern on neighboring carbons. We have there mixed the two stereochemical conventions in the interests of greater clarity.
34. (a) Evans, D. A.; Ennis, M. D.; Le, T.; Mandel, N.; Mandel, G. J. Am. Chem. Soc. 1984, 106, 1154-1156.
35. (b) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J. J. Am. Chem. Soc. 1998, 120, 5921-5942.
36. (c) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987, 28, 6141-6144.
37. (d) Beck, B. J.; Aldrich, C. C.; Fecik, R. A.; Reynolds, K. A.; Sherman, D. H. J. Am. Chem. Soc 2003, 125, 12551-12557.
38. (a) Kao, C. M.; Luo, G.; Katz, L.; Cane, D. E.; Khosla, C. J. Am. Chem. Soc. 1994, 116, 11612-11613.
39. (b) Jacobsen, J. R.; Cane, D. E.; Khosla, C. Biochemistry 1998, 37, 4928-4934.
40. Luo, G.; Pieper, R.; Rosa, A.; Khosla, C.; Cane, D. E. Bioorg. Med. Chem. 1996, 4, 995-999.
41. Donadio, S.; Staver, M. J.; Mcalpine, J. B.; Swanson, S. J.; Katz, L. Science 1991, 252, 675-679.
42. (a) Siskos, A. P.; Baerga-Ortiz, A.; Bali, S.; Stein, V.; Mamdani, H.; Spiteller, D.; Popovic, B.; Spencer, J. B.; Staunton, J.; Weissman, K. J.; Leadlay, P. F. Chem. Biol. 2005, 12, 1145-1153.
43. (b) Bali, S.; O'Hare, H. M.; Weissman, K. J. ChemBioChem 2006, 7, 478-484.
44. Tang, Y.; Kim, C. Y.; Mathews, I. I; Cane, D. E.; Khosla, C. Proc. Natl. Acad. Sci. U.S.A. 2006.
45. (a) Hicks, L. M.; Mazur, M. T.; Miller, L. M.; Dorrestein, P. C.; Schnarr, N. A.; Khosla, C.; Kelleher, N. L. ChemBioChem 2006, 7, 904-907.
46. (b) Chan, Y. A.; Boyne, M. T., II.; Podevels, A. M.; Klimowicz, A. K.; Handelsman, J.; Kelleher, N. L.; Thomas, M. G. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 14349-14354.
47. Although GC-MS has previously been used to characterize tetrasubstituted polyketide δ-lactones, the diastereomers cannot be differentiated on the basis of their MS fragmentation patterns. Cf. Weissman, K. J.; Kearney, G. C.; Leadlay, P. F.; Staunton, J. Rapid Commun. Mass. Spectrom. 1999, 13, 2103-2108.
48. Ostergaard, L. H.; Kellenberger, L.; Cortes, J.; Roddis, M. P.; Deacon, M.; Staunton, J.; Leadlay, P. F. Biochemistry 2002, 41, 2719-2726.
49. Holzbaur, I. E.; Harris, R. C.; Bycroft, M.; Cortes, J.; Bisang, C.; Staunton, J.; Rudd, B. A.; Leadlay, P. F. Chem. Biol. 1999, 6, 189-195.
50. L loading didomain and KS1, has been reported to generate a mixture of the expected triketide lactone and a diastereomer of unknown absolute configuration whose mechanism of formation has not yet been satisfactorily explained. Cf. Holzbaur, I. E.; Ranganathan, A.; Thomas, I. P.; Kearney, D. J.; Reather, J. A.; Rudd, B. A.; Staunton, J.; Leadlay, P. F. Chem. Biol. 2001, 8, 329-340.
51. Zhang, Y. M.; Wu, B.; Zheng, J.; Rock, C. O. J. Biol. Chem. 2003, 278, 52935-52943.
52. Bohm, I.; Holzbaur, I. E.; Hanefeld, U.; Cortes, J.; Staunton, J.; Leadlay, P. F. Chem. Biol. 1998, 5, 407-412.
53. Starcevic, A.; Jaspars, M.; Cullum, J.; Hranueli, D.; Long, P. F. ChemBioChem 2007, 8, 28-31. The specific mechanism suggested for enoyl-ACP reduction is unlikely, since it posits nucleophilic attack of NADPH on a carbon bearing a negatively-charged enolate oxygen. It is also implausible that different KR domains would reduce 2-methyl-3-ketoacyl-ACP substrates by two distinct mechanisms, depending on the reaction stereospecificity.
54. Tang, Y.; Kim, C. Y.; Chen, A. Y.; Cane, D. E.; Khosla, C. Chem. Biol. 2007, 14, 931-943.
55. (a) Leibundgut, M.; Jenni, S.; Frick, C.; Ban, N. Science 2007, 316, 288-290.
56. (b) Jenni, S.; Leibundgut, M.; Boehringer, D.; Frick, C.; Mikolasek, B.; Ban, N. Science 2007, 316, 254-261.
57. Alekseyev, V. Y.; Liu, C. W.; Cane, D. E.; Puglisi, J. D.; Khosla, C. Protein Sci. 2007, 16, 2093-2107.
58. Aromatic polyketide synthases generate long-chain, poly-β-ketoacyl- ACP intermediates that do not undergo premature aldol cylizations, in contrast to the highly reactive protein-free substrates which rapidly cyclize at the triketide or tetraketide stage unless prevented by masking of the ketone groups. Cf. Harris, T. M.; Harris, C. M.; Hindley, K. B. Fortschr. Chem. Org. Naturst. 1974, 31, 217-282.
59. The Evans β-ketoimides 5 and 9 are widely used for alkylation due to their high enantiomeric purity and configurational stability which due to conformational constraints that suppress epimerization of the C-2 methyl group; cf. ref 21.
60. Roujeinikova, A.; Simon, W. J.; Gilroy, J.; Rice, D. W.; Rafferty, J. B.; Slabas, A. R. J. Mol. Biol. 2007, 365, 135-145.
61. Cane, D. E.; Kudo, F.; Kinoshita, K.; Khosla, C. Chem. Biol. 2002, 9, 131-142.
62. Sambrook, J.; Fritsch, E. F.; Maniatis, T. Molecular Cloning, A Laboratory Manual, Second Edition; Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY, 1989.
63. Bradford, M. Anal. Biochem. 1976, 72, 248-254.
64. Pfeifer, B. A.; Admiraal, S. J.; Gramajo, H.; Cane, D. E.; Khosla, C. Science 2001, 291, 1790-1792.