BGC0001072

BGC0001072: simocyclinone D8 biosynthetic gene cluster from Streptomyces antibioticus

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Location: 1 - 75,379 nt. (total: 75,379 nt).
This entry is originally from NCBI GenBank AF324838.2.

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Gene details

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General

Compounds

Genes

Polyketide

Saccharide

History

NRPS/PKS domains

KnownClusterBlast

General information about the BGC

MIBiG accession	BGC0001072
Short description	simocyclinone D8 biosynthetic gene cluster from Streptomyces antibioticus
Status	Minimal annotation: no A minimal annotation only contains information on the BGC loci and one or more linked chemical product(s) Completeness: complete Whether the loci encodes everything needed for the pathway producing the compound(s)
Biosynthetic class(es)	Polyketide (Other) Saccharide Other (Aminocoumarin)
Loci	NCBI GenBank: AF324838.2
Compounds	simocyclinone D8
Species	Streptomyces antibioticus [taxonomy]
References	A new crystal structure of the bifunctional antibiotic simocyclinone D8 bound to DNA gyrase gives fresh insight into the mechanism of inhibition. Hearnshaw SJ et al., J Mol Biol (2014) PMID:24594357 Inhibition of human topoisomerases I and II by simocyclinone D8. Oppegard LM et al., J Nat Prod (2012) PMID:22867097 SimReg1 is a master switch for biosynthesis and export of simocyclinone D8 and its precursors. Horbal L et al., AMB Express (2012) PMID:22214346 Role of MbtH-like proteins in the adenylation of tyrosine during aminocoumarin and vancomycin biosynthesis. Boll B et al., J Biol Chem (2011) PMID:21890635 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. Le TB et al., Nucleic Acids Res (2011) PMID:21835774 Simocyclinone D8, an inhibitor of DNA gyrase with a novel mode of action. Flatman RH et al., Antimicrob Agents Chemother (2005) PMID:15728908 Cloning and analysis of the simocyclinone biosynthetic gene cluster of Streptomyces antibioticus Tü 6040. Galm U et al., Arch Microbiol (2002) PMID:12115055 Biosynthesis of simocyclinone D8 in an 18O2-rich atmosphere. Holzenkämpfer M et al., J Antibiot (Tokyo) (2002) PMID:12014451 Simocyclinones, novel cytostatic angucyclinone antibiotics produced by Streptomyces antibioticus Tü 6040 II. Structure elucidation and biosynthesis. Holzenkämpfer M et al., J Antibiot (Tokyo) (2002) PMID:12014446 Biosynthetic gene cluster of simocyclinone, a natural multihybrid antibiotic. Trefzer A et al., Antimicrob Agents Chemother (2002) PMID:11959542 Simocyclinones: diversity of metabolites is dependent on fermentation conditions. Schimana J et al., J Ind Microbiol Biotechnol (2001) PMID:11780784 Structures of the TetR-like simocyclinone efflux pump repressor, SimR, and the mechanism of ligand-mediated derepression. Le TB et al., J Mol Biol (2011) PMID:21354180 Coupling of the biosynthesis and export of the DNA gyrase inhibitor simocyclinone in Streptomyces antibioticus. Le TB et al., Mol Microbiol (2009) PMID:19460097 A crystal structure of the bifunctional antibiotic simocyclinone D8, bound to DNA gyrase. Edwards MJ et al., Science (2009) PMID:19965760 Mapping simocyclinone D8 interaction with DNA gyrase: evidence for a new binding site on GyrB. Sissi C et al., Antimicrob Agents Chemother (2010) PMID:19858260 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. Edwards MJ et al., Acta Crystallogr Sect F Struct Biol Cryst Commun (2009) PMID:19652356 In vivo and in vitro patterns of the activity of simocyclinone D8, an angucyclinone antibiotic from Streptomyces antibioticus. Oppegard LM et al., Antimicrob Agents Chemother (2009) PMID:19273673 Anti-proliferative effects of simocyclinone D8 (SD8), a novel catalytic inhibitor of topoisomerase II. Sadiq AA et al., Invest New Drugs (2010) PMID:19132295 Overexpression, purification and characterization of SimL, an amide synthetase involved in simocyclinone biosynthesis. Luft T et al., Arch Microbiol (2005) PMID:15812631 Simocyclinones, novel cytostatic angucyclinone antibiotics produced by Streptomyces antibioticus Tü 6040. I. Taxonomy, fermentation, isolation and biological activities. Schimana J et al., J Antibiot (Tokyo) (2000) PMID:11079799 Characterization of the aminocoumarin ligase SimL from the simocyclinone pathway and tandem incubation with NovM,P,N from the novobiocin pathway. Pacholec M et al., Biochemistry (2005) PMID:15779922 SimC7 Is a Novel NAD(P)H-Dependent Ketoreductase Essential for the Antibiotic Activity of the DNA Gyrase Inhibitor Simocyclinone. Schäfer M et al., J Mol Biol (2015) PMID:25861759

Chemical products information

simocyclinone D8

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C₄₆H₄₂Cl₁N₁O₁₈

Chemical database entries
NPAtlas
PubCHEM
ChEMBL

List of genes involved in compound(s) production

Identifiers	Position	Product	Functions	Evidence	Extra
AEU17883.1	1227 - 1475 (+)	putative acyl carrier protein			copy AA seq copy Nt seq
AEU17884.1	1472 - 2551 (+)	3-oxo-ACP synthase II			copy AA seq copy Nt seq
AEU17885.1	2602 - 3843 (+)	3-oxo-ACP synthase II			copy AA seq copy Nt seq
AEU17886.1 simB7	4212 - 5369 (+)	putative glycosyl transferase			copy AA seq copy Nt seq
AEU17887.1 simB5	5376 - 6137 (+)	putative 4-ketoreductase			copy AA seq copy Nt seq
AEU17888.1 simB4	6134 - 7102 (+)	putative 3-ketoreductase			copy AA seq copy Nt seq
AEU17889.1 simX5	7106 - 8059 (+)	putative 3-oxo-ACP synthase			copy AA seq copy Nt seq
AEU17890.1 simX7	8085 - 8855 (+)	hypothetical protein			copy AA seq copy Nt seq
AEU17891.1 simReg3	8866 - 9330 (+)	putative regulator MarR/SlyA family			copy AA seq copy Nt seq
AEU17892.1 simC7	9344 - 10198 (+)	putative hydroxylase/dehydratase	Tailoring (Dehydration)	Heterologous expression	copy AA seq copy Nt seq
AEU17893.1 simX3	10750 - 10863 (+)	hypothetical protein			copy AA seq copy Nt seq
AEU17894.1 simC6	10947 - 12410 (+)	putative halogenase			copy AA seq copy Nt seq
AEU17895.1 simEx2	12945 - 14186 (+)	putative Na/H antiporter			copy AA seq copy Nt seq
AEU17896.1 simA13	14573 - 15829 (+)	putative P450 oxygenase			copy AA seq copy Nt seq
AEU17897.1 simC1B	15910 - 22506 (+)	putative type I PKS			copy AA seq copy Nt seq
AEU17898.1 simC1C	22560 - 26555 (+)	putative type I PKS			copy AA seq copy Nt seq
AEU17899.1 simC1A	26623 - 39741 (+)	putative type I PKS			copy AA seq copy Nt seq
AEU17900.1 simC2	39958 - 40788 (+)	putative thioesterase			copy AA seq copy Nt seq
AEU17901.1 simX8	41215 - 41457 (+)	hypothetical protein			copy AA seq copy Nt seq
AAK06782.1 simA7	41847 - 43322 (+)	putative oxygenase SimA7			copy AA seq copy Nt seq
AAK06783.1 simA4	43372 - 43698 (+)	putative cyclase SimA4			copy AA seq copy Nt seq
AAK06784.1 simA1	43695 - 44963 (+)	putative ketosynthase SimA1			copy AA seq copy Nt seq
AAK06785.1 simA2	44960 - 46174 (+)	putative ketosynthase SimA2			copy AA seq copy Nt seq
AAK06786.1 simA3	46223 - 46489 (+)	putative acyl carrier protein SimA3			copy AA seq copy Nt seq
AAK06787.1 simA6	46509 - 47294 (+)	putative ketoreductase SimA6			copy AA seq copy Nt seq
AAK06788.1 simA5	47320 - 48267 (+)	putative cyclase/dehydrase SimA5			copy AA seq copy Nt seq
AAK06789.1 simA8	48273 - 49757 (+)	putative oxygenase SimA8			copy AA seq copy Nt seq
AAK06790.1 simA9	49836 - 50600 (+)	putative reductase SimA9			copy AA seq copy Nt seq
AAK06791.1 simA10	50731 - 51303 (+)	putative reductase SimA10			copy AA seq copy Nt seq
AAK06792.1 simA11	51311 - 51976 (+)	putative phosphopantheine-transferase SimA11			copy AA seq copy Nt seq
AAK06793.1 simA12	51989 - 53575 (+)	putative decarboxylase SimA12			copy AA seq copy Nt seq
AAK06794.1 simX2	53572 - 53808 (+)	SimX2			copy AA seq copy Nt seq
AAK06795.1 simC3	53850 - 54623 (+)	putative thioesterase SimC3			copy AA seq copy Nt seq
AAK06796.1 simC4	54620 - 55990 (+)	putative dioxygenase SimC4			copy AA seq copy Nt seq
AAK06797.1 simC5	56007 - 57347 (+)	putative alcohol dehydrogenase SimC5			copy AA seq copy Nt seq
AAK06798.1 simReg2	57298 - 58083 (-)	transcriptional repressor of transporter SimX	Regulation	Activity assay Other in vivo study	copy AA seq copy Nt seq
AAK06799.1 simEx	58180 - 59784 (+)	simocyclinone-specific efflux pump	Transport	Other in vivo study	copy AA seq copy Nt seq
AAK06800.1 simX4	59996 - 60877 (+)	SimX4			copy AA seq copy Nt seq
AAK06801.1 simC8	60874 - 61536 (+)	putative phosphopantetheinyl transferase SimC8			copy AA seq copy Nt seq
AAK06802.1 simD3	61682 - 62392 (+)	putative 3-keto-acyl-reductase SimD3			copy AA seq copy Nt seq
AAK06803.1 simD5	62429 - 63988 (+)	aminocoumarin ligase	Scaffold biosynthesis	Activity assay Knock-out	copy AA seq copy Nt seq
AAK06804.1 simD6	63978 - 67010 (+)	Tyroxyl-AMP-forming enzyme	Precursor biosynthesis	Activity assay	copy AA seq copy Nt seq
AAK06805.1 simD1	67007 - 68272 (+)	putative cytochrome P450 oxidase SimD1			copy AA seq copy Nt seq
AAK06806.1 simX1	68309 - 68521 (+)	MbtH-like protein	Precursor biosynthesis	Activity assay	copy AA seq copy Nt seq
AAK06807.1 simD2	68532 - 69353 (+)	putative 3-keto-acyl-reductase SimD2			copy AA seq copy Nt seq
AAK06808.1 simReg1	69523 - 70278 (+)	regulator	Regulation	Knock-out Other in vivo study	copy AA seq copy Nt seq
AAK06809.1 simD4	70601 - 71341 (+)	putative 3-keto-acyl-reductase SimD4			copy AA seq copy Nt seq
AAK06810.1 simB3	71408 - 72856 (+)	putative dNDP-4-keto-6-deoxy-glucose-2,3-dehydratase SimB3	Scaffold biosynthesis	Knock-out	copy AA seq copy Nt seq
AAK06811.1 simB6	72853 - 74253 (+)	putative acetyl transferase SimB6			copy AA seq copy Nt seq
AAK06812.1 simX6	74332 - 74610 (+)	SimX6			copy AA seq copy Nt seq

Polyketide-specific information

Subclass	Other
Ketide length	10
Cyclic?	yes

Polyketide-synthases

Genes	Properties	Modules
simA2 + simA4 + simA5 + simA1 + simC1B + simC1C + simC1A + simA3	Synthase subclass: Modular type I/Type II	Module 0 Specificity: Malonyl-CoA Genes: simC1A Core domains: Ketosynthase, Acyltransferase, Thiolation (ACP/PCP)
		Module 1 Specificity: Malonyl-CoA Genes: simC1A Core domains: Ketosynthase, Acyltransferase, Ketoreductase, Dehydratase, Thiolation (ACP/PCP) KR-domain stereochemistry: Unknown
		Module 2 Specificity: Malonyl-CoA Genes: simC1A Core domains: Ketosynthase, Acyltransferase, Ketoreductase, Thiolation (ACP/PCP) KR-domain stereochemistry: Unknown
		Module 3 Specificity: Malonyl-CoA Genes: simC1B Core domains: Ketosynthase, Acyltransferase, Ketoreductase, Dehydratase, Enoylreductase, Thiolation (ACP/PCP) KR-domain stereochemistry: Unknown
		Module 4 Specificity: Malonyl-CoA Genes: simC1C Core domains: Ketosynthase, Acyltransferase, Thiolation (ACP/PCP)

Saccharide-specific information

Subclass	None
Sugar-encoding genes	simB5, simB4, simB3
Glycosyltransferases	simB7 Specificity: D-olivose Evidence: Sequence-based prediction

Annotation changelog

MIBiG version	Submitter	Notes
1.0	Hidden contributor (ID: LPHAMZXQ3BT6INJWOLKUYGWU, no GDPR consent given). Hidden contributor (ID: 4UPPKTA43BL72GR2GNMXZQQK, no GDPR consent given).	Submitted
2.0	Hidden contributor (ID: AAAAAAAAAAAAAAAAAAAAAAAA, no GDPR consent given).	Migrated from v1.4 Updated compound(s) information (NPAtlas curation)
3.0	Hidden contributor (ID: AAAAAAAAAAAAAAAAAAAAAAAA, no GDPR consent given). Hidden contributor (ID: 3UOU7PODQJXIM6BEPUHHRRA5, no GDPR consent given).	Remove duplicated citations Corrected polyketide synthase gene entries Removed ketoreductase stereochemistry annotation from modules without ketoreductases Updated bioactivity data
3.1	Hidden contributor (ID: AAAAAAAAAAAAAAAAAAAAAAAA, no GDPR consent given).	Update chemical activity to schema version 2.11

Detailed domain annotation

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Similar known gene clusters