Genomic loci for this biosynthetic pathway

Cluster Type From To
The following clusters are from record BGC0001072.1:
Cluster 1Polyketide / Saccharide / Other175379

BGC0001072, simocyclinone biosynthetic gene cluster from Streptomyces antibioticus. Locus 1. Full MIBiG entry.

Chemical compounds

Compound: Simocyclinone D8
PubChem ID: 54736483
ChEMBL ID: 1235969
SMILES string: Copy to clipboard
Molecular formula: C46H42ClNO18
Average molecular mass: 932.281 Da
Molecular activity: Antibacterial, Cytotoxic
Molecular target: bacterial DNA gyrase, inhibitor of human topoisomerases I and II

Class-specific details

Biosynthetic class(es):
Polyketide / Saccharide / Other
Polyketide subclass:
Other (cyclic)
Polyketide synthase subclass:
Modular type I / Type II
Starter unit:
Unknown
Polyketide synthase / ketosynthase-encoding genes:
AAK06784.1,AAK06785.1,AAK06786.1
AAK06783.1, AAK06788.1
Thioesterase type:
Unknown
Release / cyclization type:
Unknown

Modular polyketide synthases:
AEU17897.1,AEU17898.1,AEU17899.1
Module 0
AT specificity: Malonyl-CoA
Evidence for specificity: Unknown
Module 1
AT specificity: Malonyl-CoA
Evidence for specificity: Unknown
KR stereochemistry: Unknown
Module 2
AT specificity: Malonyl-CoA
Evidence for specificity: Unknown
KR stereochemistry: Unknown
Module 3
AT specificity: Malonyl-CoA
Evidence for specificity: Unknown
KR stereochemistry: Unknown
Module 4
AT specificity: Malonyl-CoA
Evidence for specificity: Unknown

Saccharide subclass:
other
Glycosyltransferases:
AEU17886.1:
Specificity: D-olivose
Evidence for specificity: Unknown
Sugar biosynthesis subcluster: AEU17887.1, AEU17888.1, AAK06810.1,
Other biosynthetic class:
Aminocoumarin

Gene cluster description

simocyclinone (BGC0001072). Gene Cluster 1. Biosynthetic class = Polyketide/Saccharide/Other. GenBank AF324838. 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:Knock-out studies, Sequence-based prediction
MIxS-compliance:Unknown
Contact for this cluster:Andreas Bechthold & Mark Buttner (Albert-Ludwigs-Universitaet Freiburg / John Innes Centre, Norwich)

Literature references

1. Hearnshaw SJ et al. (2014) A new crystal structure of the bifunctional antibiotic simocyclinone D8 bound to DNA gyrase gives fresh insight into the mechanism of inhibition. J Mol Biol 426(10):2023-33. doi: 10.1016/j.jmb.2014.02.017. Epub
2. Oppegard LM et al. (2012) Inhibition of human topoisomerases I and II by simocyclinone D8. J Nat Prod 75(8):1485-9. doi: 10.1021/np300299y. Epub 2012 Aug 6.
3. Horbal L et al. (2012) SimReg1 is a master switch for biosynthesis and export of simocyclinone D8 and its precursors. AMB Express 2(1):1. doi: 10.1186/2191-0855-2-1.
4. Boll B et al. (2011) Role of MbtH-like proteins in the adenylation of tyrosine during aminocoumarin and vancomycin biosynthesis. J Biol Chem 286(42):36281-90. doi: 10.1074/jbc.M111.288092. Epub
5. Le TB et al. (2011) The crystal structure of the TetR family transcriptional repressor SimR bound to DNA and the role of a flexible N-terminal extension in minor groove binding. Nucleic Acids Res 39(21):9433-47. doi: 10.1093/nar/gkr640. Epub 2011
6. Flatman RH et al. (2005) Simocyclinone D8, an inhibitor of DNA gyrase with a novel mode of action. Antimicrob Agents Chemother 49(3):1093-100. doi:
7. Galm U et al. (2002) Cloning and analysis of the simocyclinone biosynthetic gene cluster of Streptomyces antibioticus Tu 6040. Arch Microbiol 178(2):102-14. doi: 10.1007/s00203-002-0429-z. Epub 2002
8. Holzenkampfer M, Zeeck A. (2002) Biosynthesis of simocyclinone D8 in an 18O2-rich atmosphere. J Antibiot (Tokyo) 55(3):341-2.
9. Holzenkampfer M et al. (2002) Simocyclinones, novel cytostatic angucyclinone antibiotics produced by Streptomyces antibioticus Tu 6040 II. Structure elucidation and biosynthesis. J Antibiot (Tokyo) 55(3):301-7.
10. Trefzer A et al. (2002) Biosynthetic gene cluster of simocyclinone, a natural multihybrid antibiotic. Antimicrob Agents Chemother 46(5):1174-82.
11. Schimana J et al. (2001) Simocyclinones: diversity of metabolites is dependent on fermentation conditions. J Ind Microbiol Biotechnol 27(3):144-8.
12. Le TB et al. (2011) Structures of the TetR-like simocyclinone efflux pump repressor, SimR, and the mechanism of ligand-mediated derepression. J Mol Biol 408(1):40-56. doi: 10.1016/j.jmb.2011.02.035. Epub 2011
13. Boll B et al. (2011) Role of MbtH-like proteins in the adenylation of tyrosine during aminocoumarin and vancomycin biosynthesis. J Biol Chem 286(42):36281-90. doi: 10.1074/jbc.M111.288092. Epub
14. Le TB et al. (2011) The crystal structure of the TetR family transcriptional repressor SimR bound to DNA and the role of a flexible N-terminal extension in minor groove binding. Nucleic Acids Res 39(21):9433-47. doi: 10.1093/nar/gkr640. Epub 2011
15. Le TB et al. (2009) Coupling of the biosynthesis and export of the DNA gyrase inhibitor simocyclinone in Streptomyces antibioticus. Mol Microbiol 72(6):1462-74. doi: 10.1111/j.1365-2958.2009.06735.x.
16. Edwards MJ et al. (2009) A crystal structure of the bifunctional antibiotic simocyclinone D8, bound to DNA gyrase. Science 326(5958):1415-8. doi: 10.1126/science.1179123.
17. Sissi C et al. (2010) Mapping simocyclinone D8 interaction with DNA gyrase: evidence for a new binding site on GyrB. Antimicrob Agents Chemother 54(1):213-20. doi: 10.1128/AAC.00972-09.
18. Edwards MJ et al. (2009) Crystallization and preliminary X-ray analysis of a complex formed between the antibiotic simocyclinone D8 and the DNA breakage-reunion domain of Escherichia coli DNA gyrase. Acta Crystallogr Sect F Struct Biol Cryst Commun 65(Pt 8):846-8. doi:
19. Oppegard LM et al. (2009) In vivo and in vitro patterns of the activity of simocyclinone D8, an angucyclinone antibiotic from Streptomyces antibioticus. Antimicrob Agents Chemother 53(5):2110-9. doi: 10.1128/AAC.01440-08.
20. Sadiq AA et al. (2010) Anti-proliferative effects of simocyclinone D8 (SD8), a novel catalytic inhibitor of topoisomerase II. Invest New Drugs 28(1):20-5. doi: 10.1007/s10637-008-9209-1. Epub 2009
21. Luft T et al. (2005) Overexpression, purification and characterization of SimL, an amide synthetase involved in simocyclinone biosynthesis. Arch Microbiol 183(4):277-85. doi: 10.1007/s00203-005-0770-0. Epub 2005
22. Schimana J et al. (2000) Simocyclinones, novel cytostatic angucyclinone antibiotics produced by Streptomyces antibioticus Tu 6040. I. Taxonomy, fermentation, isolation and biological activities. J Antibiot (Tokyo) 53(8):779-87.
23. Pacholec M et al. (2005) Characterization of the aminocoumarin ligase SimL from the simocyclinone pathway and tandem incubation with NovM,P,N from the novobiocin pathway. Biochemistry 44(12):4949-56. doi: 10.1021/bi047303g.
24. Schafer M et al. (2015) SimC7 Is a Novel NAD(P)H-Dependent Ketoreductase Essential for the Antibiotic Activity of the DNA Gyrase Inhibitor Simocyclinone. J Mol Biol 427(12):2192-204. doi: 10.1016/j.jmb.2015.03.019. Epub