Genomic loci for this biosynthetic pathway

Cluster Type From To
The following clusters are from record BGC0000976.1:
Cluster 1NRP / Polyketide165189

BGC0000976, curacin biosynthetic gene cluster from Moorea producens. Locus 1. Full MIBiG entry.

Chemical compounds

Compound: Curacin A
PubChem ID: 6438908
ChEBI ID: 3961
ChEMBL ID: 89138
ChemSpider ID: 4445239
SMILES string: Copy to clipboard
Molecular formula: C23H35NOS
Average molecular mass: 373.599 Da
Molecular activity: Other
Molecular target: Colchicine site of tubulin

Class-specific details

Biosynthetic class(es):
NRP / Polyketide
None (linear)
Thioesterase type:
None
Release / cyclization type:
None

Nonribosomal peptide synthetases:
No gene ID (AEE88284.1)
Module 4
A specificity: Cysteine
Evidence for specificity: Structure-based inference
C domain subtype: Other
Polyketide subclass:
None (linear)
Polyketide synthase subclass:
Modular type I
Starter unit:
Malonyl-CoA
Thioesterase type:
Other
Release / cyclization type:
Other

Modular polyketide synthases:
No gene ID (AEE88289.1)
Module 0
AT specificity: Malonyl-CoA
Evidence for specificity: Activity assay
Scaffold-modifying domain: None
Module 1
AT specificity: Malonyl-CoA
Evidence for specificity: Activity assay
Scaffold-modifying domain: Other

No gene ID (AEE88288.1)
Module X
Scaffold-modifying domain: None

No gene ID (AEE88287.1)
Module X
Scaffold-modifying domain: Beta-branching

No gene ID (AEE88285.1)
Module X
Scaffold-modifying domain: Other

No gene ID (AEE88284.1)
Module 2
Scaffold-modifying domain: Other
Module 3
AT specificity: Malonyl-CoA
Evidence for specificity: Structure-based inference
Scaffold-modifying domain: None

No gene ID (AEE88283.1)
Module 5
AT specificity: Malonyl-CoA
Evidence for specificity: Structure-based inference
KR stereochemistry: A-group
Scaffold-modifying domain: None

No gene ID (AEE88282.1)
Module 6
AT specificity: Malonyl-CoA
Evidence for specificity: Structure-based inference
KR stereochemistry: B-group
Scaffold-modifying domain: None

No gene ID (AEE88281.1)
Module 7
AT specificity: Malonyl-CoA
Evidence for specificity: Structure-based inference
KR stereochemistry: B-group
Scaffold-modifying domain: None

No gene ID (AEE88280.1)
Module 8
AT specificity: Malonyl-CoA
Evidence for specificity: Structure-based inference
KR stereochemistry: B-group
Scaffold-modifying domain: Methylation

No gene ID (AEE88279.1)
Module 9
AT specificity: Malonyl-CoA
Evidence for specificity: Structure-based inference
KR stereochemistry: B-group
Scaffold-modifying domain: None

No gene ID (AEE88278.1)
Module 10
AT specificity: Malonyl-CoA
Evidence for specificity: Structure-based inference
KR stereochemistry: B-group
Scaffold-modifying domain: Methylation

No gene ID (AEE88277.1)
Module 11
AT specificity: Malonyl-CoA
Evidence for specificity: Activity assay
KR stereochemistry: B-group
Scaffold-modifying domain: None

Gene cluster description

curacin (BGC0000976). Gene Cluster 1. Biosynthetic class = NRP/Polyketide. GenBank HQ696500, positions 1-65189. Click on genes for more information.

Legend:

biosynthetic genes
transport-related genes
regulatory genes
other genes

Domain annotation

Homologous known gene clusters

General MIBiG information on this cluster

Complete gene cluster sequence?complete
Evidence for cluster-compound connection:Enzymatic assays, Gene expression correlated with compound production, Sequence-based prediction
MIxS-compliance:Unknown
Comments:Thioesterase results in decarboxylation and desulfonation of the compound.
Contact for this cluster:Nathan Moss (Scripps Institution of Oceanography)

Literature references

1. Chang Z et al. (2004) Biosynthetic pathway and gene cluster analysis of curacin A, an antitubulin natural product from the tropical marine cyanobacterium Lyngbya majuscula. J Nat Prod 67(8):1356-67. doi: 10.1021/np0499261.
2. Berman FW et al. (1999) Antillatoxin and kalkitoxin, ichthyotoxins from the tropical cyanobacterium Lyngbya majuscula, induce distinct temporal patterns of NMDA receptor-mediated neurotoxicity. Toxicon 37(11):1645-8.
3. Verdier-Pinard P et al. (1999) Biosynthesis of radiolabeled curacin A and its rapid and apparently irreversible binding to the colchicine site of tubulin. Arch Biochem Biophys 370(1):51-8. doi: 10.1006/abbi.1999.1363.
4. Verdier-Pinard P et al. (1998) 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. Mol Pharmacol 53(1):62-76.
5. Blokhin AV et al. (1995) 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. Mol Pharmacol 48(3):523-31.
6. Gu L et al. (2006) Metabolic coupling of dehydration and decarboxylation in the curacin A pathway: functional identification of a mechanistically diverse enzyme pair. J Am Chem Soc 128(28):9014-5. doi: 10.1021/ja0626382.
7. Geders TW et al. (2007) Crystal structure of the ECH2 catalytic domain of CurF from Lyngbya majuscula. Insights into a decarboxylase involved in polyketide chain beta-branching. J Biol Chem 282(49):35954-63. doi: 10.1074/jbc.M703921200. Epub 2007
8. Gu L et al. (2009) Polyketide decarboxylative chain termination preceded by o-sulfonation in curacin a biosynthesis. J Am Chem Soc 131(44):16033-5. doi: 10.1021/ja9071578.
9. Khare D et al. (2010) Conformational switch triggered by alpha-ketoglutarate in a halogenase of curacin A biosynthesis. Proc Natl Acad Sci U S A 107(32):14099-104. doi:
10. Gu L et al. (2011) Tandem acyl carrier proteins in the curacin biosynthetic pathway promote consecutive multienzyme reactions with a synergistic effect. Angew Chem Int Ed Engl 50(12):2795-8. doi: 10.1002/anie.201005280.
11. Gehret JJ et al. (2011) Terminal alkene formation by the thioesterase of curacin A biosynthesis: structure of a decarboxylating thioesterase. J Biol Chem 286(16):14445-54. doi: 10.1074/jbc.M110.214635. Epub
12. Busche A et al. (2012) Characterization of molecular interactions between ACP and halogenase domains in the Curacin A polyketide synthase. ACS Chem Biol 7(2):378-86. doi: 10.1021/cb200352q. Epub 2011 Dec 15.
13. McCarthy JG et al. (2012) Structural basis of functional group activation by sulfotransferases in complex metabolic pathways. ACS Chem Biol 7(12):1994-2003. doi: 10.1021/cb300385m. Epub 2012 Sep