GNAT-Like Strategy for Polyketide Chain Initiation

• DOI: 10.1126/science.1148790
• Publication Date: 2007-11-09T00:46:19Z
• Authors: Liangcai Gu; Todd W. Geders; Bo Wang; William H. Gerwick; Kristina Håkansson; Janet L. Smith; David H. Sherman
• Keywords: Decarboxylation; Acyl carrier protein; Acetyltransferases; Coenzyme A; Polyketide synthase; Phosphofructokinase 2

An unexpected biochemical strategy for chain initiation is described the loading module of polyketide synthase curacin A, an anticancer lead derived from marine cyanobacterium Lyngbya majuscula . A central GCN5-related N -acetyltransferase (GNAT) domain bears bifunctional decarboxylase/ S activity, both unprecedented GNAT superfamily. CurA tridomain, consisting adaptor domain, and acyl carrier protein, was assessed biochemically, revealing that a showing homology to (GNAT L ) catalyzes (i) decarboxylation malonyl-coenzyme (malonyl-CoA) acetyl-CoA (ii) direct -acetyl transfer load adjacent protein (ACP ). Moreover, N-terminal adapter shown facilitate acetyl-group transfer. Crystal structures were solved at 1.95 angstroms (ligand-free form) 2.75 (acyl-CoA complex), distinct substrate tunnels acyl-CoA holo-ACP binding. Modeling site-directed mutagenesis experiments demonstrated histidine-389 threonine-355, convergence CoA ACP tunnels, participate in malonyl-CoA but not Decarboxylation precedes transfer, leading acetyl-ACP as key starter unit.