Chemoenzymatic synthesis of the polyketide macrolactone 10-deoxymethynolide.
The polyketide synthase-derived pikromycin thioesterase (Pik TE) is unique in its ability to catalyze the cyclization of 12- and 14-membered macrolactones. In this investigation, the total synthesis of the natural hexaketide chain elongation intermediate as its N-acetyl cysteamine (NAC) thioester has been achieved, and its reaction with Pik TE demonstrated the ability of Pik TE to catalyze its macrolactonization to the natural product 10-deoxymethynolide. A steady-state kinetic analysis of the hexaketide chain intermediate with Pik TE was done. A preliminary substrate specificity study with unnatural hexaketide analogues was accomplished, demonstrating the importance of total synthesis in obtaining access to advanced polyketide intermediates. The results show the sensitivity of Pik TE to minor substrate modifications, and illustrate the potential use of thioesterases as versatile macrolactonization catalysts.
Aldrich
Courtney C
CC
University of Michigan Life Sciences Institute, Department of Medicinal Chemistry, 210 Washtenaw Avenue, Ann Arbor, Michigan 48109-2216, USA.
Venkatraman
Lakshmanan
L
Sherman
David H
DH
Fecik
Robert A
RA
D002384:Catalysis; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000737:chemistry*; D013869:Thiolester Hydrolases / Q000737:chemistry*
D007783:Lactones; D018942:Macrolides; D009097:Multienzyme Complexes; C079477:10-deoxymethynolide; D013869:Thiolester Hydrolases