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Publication Abstract from PubMed

Polyketide synthases (PKS) and non-ribosomal peptide synthetases (NRPS) are large multidomain proteins present in microorganisms that produce bioactive compounds. Curacin A is such a bioactive compound with potent anti-proliferative activity. During its biosynthesis the growing substrate is bound covalently to an acyl carrier protein (ACP) that is able to access catalytic sites of neighboring domains for chain elongation and modification. While ACP domains usually occur as monomers, the curacin A cluster codes for a triplet ACP(ACP_I-ACP_II-ACP_III) within the CurA PKS module. We have determined the structure of the isolated holo ACP_I and show that the ACPs are independent of each other within this tridomain system. In addition, we have determined the structure of the 3-hydroxyl-3-methylglutaryl-loaded holo-ACP_I, which is the substrate for the unique halogenase (Hal) domain embedded within the CurA module. We have identified the interaction surface of both proteins using mutagenesis and MALDI-based identification of product formation. Amino acids affecting product formation are located on helices II and III of ACP_I and form a contiguous surface. Since the CurA Hal accepts substrate only when presented by one of the ACPs within the ACP_I-ACP_II-ACP_III tridomain, our data provide insight into the specificity of the chlorination reaction.

Characterization of molecular interactions between ACP and halogenase domains in the curacin A polyketide synthase.,Busche AE, Gottstein D, Hein C, Ripin N, Pader I, Tufar P, Eisman EB, Gu L, Walsh CT, Loehr F, Sherman DH, Guntert P, Dotsch V ACS Chem Biol. 2011 Nov 21. PMID:22103656^[1]

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