Chemistry:Curacin A
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| Formula | C23H35NOS |
| Molar mass | 373.60 g·mol−1 |
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Curacin A is a hybrid polyketide synthase (PKS)/nonribosomal peptide synthase (NRPS) derived natural product produced isolated from the cyanobacterium Lyngbya majuscula.[1] Curacin A belongs to a family of natural products including jamaicamide, mupirocin, 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 cassette 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 cassette (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 CurF 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 CurB (ACP), CurC (ketosynthase), and CurD (HMG-CoA reductase) are responsible for the formation of (S)HMG-ACP3.[6] HaI, from the CurA 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
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "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 (8): 1356–67. August 2004. doi:10.1021/np0499261. PMID 15332855.
- ↑ 2.0 2.1 2.2 2.3 "GNAT-like strategy for polyketide chain initiation". Science 318 (5852): 970–4. November 2007. doi:10.1126/science.1148790. PMID 17991863. Bibcode: 2007Sci...318..970G.
- ↑ "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 (1): 62–76. January 1998. doi:10.1124/mol.53.1.62. PMID 9443933.
- ↑ "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 (3): 523–31. September 1995. PMID 7565634.
- ↑ 5.0 5.1 5.2 5.3 "Tandem acyl carrier proteins in the curacin biosynthetic pathway promote consecutive multienzyme reactions with a synergistic effect". Angewandte Chemie 50 (12): 2795–8. March 2011. doi:10.1002/anie.201005280. PMID 21387490.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 "Metamorphic enzyme assembly in polyketide diversification". Nature 459 (7247): 731–5. June 2009. doi:10.1038/nature07870. PMID 19494914. Bibcode: 2009Natur.459..731G.
- ↑ "Structural basis of functional group activation by sulfotransferases in complex metabolic pathways". ACS Chemical Biology 7 (12): 1994–2003. December 2012. doi:10.1021/cb300385m. PMID 22991895.
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