Curacin A
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| Systematic (IUPAC) name | |
|---|---|
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(4R)-4-[(1Z,5E,7E,11R)-11-Methoxy-8-methyl-1,5,7,13-tetradecatetraen-1-yl]-2-[(1R,2S)-2-methylcyclopropyl]-4,5-dihydro-1,3-thiazol | |
| Identifiers | |
| PubChem | CID 5281967 |
| ChemSpider | 4445239 |
| Chemical data | |
| Formula | C23H35NOS |
| Molar mass | 373.60 g·mol−1 |
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| (verify) | |
Curacin A is a hybrid Polyketide Synthase(PKS) Non-Ribosomal Peptide Synthase(NRPS) derived natural product produced by and isolated from the cyanobacterium Lyngbya majuscula.[1] 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.[1][2] Curacin A has been characterized as potent antiproliferative cytotoxic compound with notable anticancer activity for several cancer lines including renal, colon, and breast cancer.[2][3] 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.[1][4]
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.[1] 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.[1] CurA contains a unique GCN5-related N-acetyltransferase(GNAT) loading domain and an associated acyl carrier protein (ACP).[2] 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.[1][2][5] 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.[5] subsequent enzymes, including a unique heme independent halogenase (HaI) catalyze the formation of a cyclopropyl ring.[1][5][6] 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.[1][5][6] Seven standalone PKS modules follow to extend the growing polyketide chain with S-adenosyl methionine (SAM) dependent methylations occurring at positions 10 and 13.[1] 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.[7]
Cyclopropyl ring formation
The Cur B(ACP), Cur C (ketosynthase), and Cur D(HMG-CoA Reductase) are responsible for the formation of (S)HMG-ACP3.[6] HaI, from the Cur A gene, is a unique non-heme halogenase that goes through a purported Fe(IV)=O intermediate to add a chlorine atom onto an unactivated carbon atom.[6] After chlorination, ECH1 acting as a dehydratates HMG-ACP3 to 3-methylgultaconyl-ACP3 and ECH2 performs the required decarboxylation.[6] Finally,an unusual ER catalyzed cyclization reaction, purported to go through a substitution like mechanism, forms the cyclopropane ring.[6] The added chlorine atom assists in the decarboxylation step and likely serves as the leaving group during cyclopropane ring formation.[6]
References
- 1 2 3 4 5 6 7 8 9 Chang, Zunxue; Sitachitta, Namthip; Rossi, James V.; Roberts, Mary Ann; Flatt, Patricia M.; Jia, Junyong; Sherman, David H.; Gerwick, William H. (August 2004). "Biosynthetic Pathway and Gene Cluster Analysis of Curacin A, an Antitubulin Natural Product from the Tropical Marine Cyanobacterium". Journal of Natural Products 67 (8): 1356–1367. doi:10.1021/np0499261.
- 1 2 3 4 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).
- ↑ 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).
- 1 2 3 4 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).
- 1 2 3 4 5 6 7 L. Gu et al., Metamorphic enzyme assembly in polyketide diversification. Nature 459, 731 (06/04/print, 2009)
- ↑ 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).