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Curacin A
Curacin A is a hybrid Polyketide Synthase(PKS) Non-Ribosomal Peptide Synthase(NRPS) derived natural product produced by and isolated from the cyanobacterium ''Lyngya Majuscula''.〔Z. Chang et al., Biosynthetic Pathway and Gene Cluster Analysis of Curacin A, an Antitubulin Natural Product from the Tropical Marine Cyanobacterium Lyngbya majuscula†. Journal of Natural Products 67, 1356 (2004/08/01, 2004).〕 Curacin A belongs to a family of natural products including jamaicamide, mupriocin, and pederin that have an unusual terminal alkene. Additionally, Curacin A contains a notable thiazoline ring and a unique cyclopropyl moiety, which is essential to the compound's biological activity.〔〔 Curacin A has been characterized as potent antiproliferative cytotoxic compound with notable anticancer activity for several cancer lines including renal, colon, and breast cancer.〔L. Gu et al., GNAT-Like Strategy for Polyketide Chain Initiation. Science 318, 970 (2007).〕〔P. Verdier-Pinard et al., Structure-Activity Analysis of the Interaction of Curacin A, the Potent Colchicine Site Antimitotic Agent, with Tubulin and Effects of Analogs on the Growth of MCF-7 Breast Cancer Cells. Molecular Pharmacology 53, 62 (1998).〕 Curacin A has been shown to interact with colchicine binding sites on tubulin, which inhibits microtubule polymerization, an essential process for cell division and proliferation.〔〔A. V. Blokhin et al., Characterization of the interaction of the marine cyanobacterial natural product curacin A with the colchicine site of tubulin and initial structure-activity studies with analogues. Molecular Pharmacology 48, 523 (1995).〕
== Biosynthesis ==
The synthetic enzymes for Curacin A are found in a gene cluster with 14 open reading frames (ORFs) with the nomenclature CurA through CurN.〔 Analysis of the pathway demonstrated the presence of one NRPS/PKS hybrid module located on CurF, one HMG-coa synthase casette located on CurD, and seven monomodular PKS modules.〔 CurA contains a unique GCN5-related N-acetyltransferase(GNAT) loading domain and an associated acyl carrier protein (ACP).〔 The loading module tethers an acetyl group to the ACP that then condenses with one of three tandem ACPs present in the adjacent module of CurA.〔〔〔 An hydroxymethylglutaryl-CoA synthase casette (mevalonate pathway) catlyzes the formation of hydroxymethylglutaryl acid by the addition of an malonyl-CoA unit to the terminal ketide of the aceto-acetyl-ACP moiety of ACP1,ACP2, or ACP3.〔L. Gu et al., Tandem Acyl Carrier Proteins in the Curacin Biosynthetic Pathway Promote Consecutive Multienzyme Reactions with a Synergistic Effect. Angewandte Chemie International Edition 50, 2795 (2011).〕 subsequent enzymes, including a unique heme independent halogenase (HaI) catalyze the formation of a cyclopropyl ring.〔〔〔L. Gu et al., Metamorphic enzyme assembly in polyketide diversification. Nature 459, 731 (06/04/print, 2009)〕 A cysteine specific NRPS module located on Cur F follows after cyclopropyl ring formation, and due to the activity of a cyclizing condensation domain, forms a thiazole ring attached to the cylcopropyl moiety from previous reactions in the pathway.〔〔〔 Seven standalone PKS modules follow to extend the growing polyketide chain with S-adenosyl methionine (SAM) dependent methylations occuring at positions 10 and 13.〔 A rare offloading strategy involving a sulfotransferase is employed by the final curacin synthase module. The sulfotransferase sulfates the hydroxyl group of carbon 15, which activates the molecule for decarboxylation and terminal alkene formation.〔J. G. McCarthy et al., Structural Basis of Functional Group Activation by Sulfotransferases in Complex Metabolic Pathways. ACS Chemical Biology 7, 1994 (2012/12/21, 2012).〕
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