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Publication Abstract from PubMed

Curacin A is a polyketide synthase (PKS)-non-ribosomal peptide synthetase (NRPS) derived natural product with potent anticancer properties generated by the marine cyanobacterium Lyngbya majuscula. Type I modular PKS assembly lines typically employ a thioesterase (TE) domain to offload carboxylic acid or macrolactone products from an adjacent acyl carrier protein (ACP) domain. In a striking departure from this scheme the curacin A PKS employs tandem sulfotransferase (ST) and TE domains to form a terminal alkene moiety. ST sulfonation of beta-hydroxy-acyl-ACP is followed by TE hydrolysis, decarboxylation and sulfate elimination (Gu, 2009, J. Amer. Chem. Soc. 131, 16033). With low sequence identity to other PKS TEs (<15%), the curacin TE represents a new thioesterase sub-family. The 1.7-A curacin TE crystal structure reveals how the familiar alpha/beta hydrolase architecture is adapted to specificity for beta-sulfated substrates. A Ser-His-Glu catalytic triad is centered in an open active-site cleft between the core domain and a lid sub-domain. Unlike TEs from other PKSs, the lid is fixed in an open conformation on one side by dimer contacts of a protruding helix and on the other side by an arginine anchor from the lid into the core. Adjacent to the catalytic triad, another arginine residue is positioned to recognize the substrate beta-sulfate group. The essential features of the curacin TE are conserved in sequences of five other putative bacterial ACP-ST-TE tridomains. Formation of a sulfate leaving group as a biosynthetic strategy to facilitate acyl chain decarboxylation is of potential value as a route to hydrocarbon biofuels.

Terminal alkene formation by the thioesterase of curacin a biosynthesis: Structure of a decarboxylating thioesterase.,Gehret JJ, Gu L, Gerwick WH, Wipf P, Sherman DH, Smith JL J Biol Chem. 2011 Feb 27. PMID:21357626^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.