Chemoenzymatic synthesis of the polyketide macrolactone 10-deoxymethynolide

Courtney Aldrich, Lakshmanan Venkatraman, David H. Sherman, Robert A. Fecik

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8910-8911
Number of pages2
JournalJournal of the American Chemical Society
Volume127
Issue number25
DOIs
StatePublished - Jun 29 2005

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