Curacin A

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]

Curacin A

Identifiers
IUPAC name (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
CAS Number	155233-30-0 Y
PubChem CID	5281967
ChemSpider	4445239
UNII	S9C9YBJ48Q
KEGG	C11689
ChEBI	CHEBI:3961
ChEMBL	ChEMBL89138
CompTox Dashboard (EPA)	DTXSID001032406
Chemical and physical data
Formula	C23H35NOS
Molar mass	373.60 g·mol−1
3D model (JSmol)	Interactive image
SMILES C[C@H]1C[C@H]1C2=N[C@@H](CS2)/C=C\CC/C=C/C=C(\C)/CC[C@H](CC=C)OC
InChI InChI=1S/C23H35NOS/c1-5-11-21(25-4)15-14-18(2)12-9-7-6-8-10-13-20-17-26-23(24-20)22-16-19(22)3/h5,7,9-10,12-13,19-22H,1,6,8,11,14-17H2,2-4H3/b9-7+,13-10-,18-12+/t19-,20+,21-,22+/m0/s1 Key:LUEYTMPPCOCKBX-KWYHTCOPSA-N
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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]