title: Bioactivity-guided genome mining reveals the lomaiviticin biosynthetic gene cluster in Salinispora tropica.
abstract: The use of genome sequences has become routine in guiding the discovery and identification of microbial natural products and their biosynthetic pathways. In silico prediction of molecular features, such as metabolic building blocks, physico-chemical properties or biological functions, from orphan gene clusters has opened up the characterization of many new chemo- and genotypes in genome mining approaches. Here, we guided our genome mining of two predicted enediyne pathways in Salinispora tropica CNB-440 by a DNA interference bioassay to isolate DNA-targeting enediyne polyketides. An organic extract of S. tropica showed DNA-interference activity that surprisingly was not abolished in genetic mutants of the targeted enediyne pathways, ST_pks1 and spo. Instead we showed that the product of the orphan type II polyketide synthase pathway, ST_pks2, is solely responsible for the DNA-interfering activity of the parent strain. Subsequent comparative metabolic profiling revealed the lomaiviticins, glycosylated diazofluorene polyketides, as the ST_pks2 products. This study marks the first report of the 59 open reading frame lomaiviticin gene cluster (lom) and supports the biochemical logic of their dimeric construction through a pathway related to the kinamycin monomer.
authors: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0204, USA.
authors: Roland D
authors: RD
authors: Kersten
authors: Amy L
authors: AL
authors: Lane
authors: Markus
authors: M
authors: Nett
authors: Taylor K S
authors: TK
authors: Richter
authors: Brendan M
authors: BM
authors: Duggan
authors: Pieter C
authors: PC
authors: Dorrestein
authors: Bradley S
authors: BS
authors: Moore
mesh_terms: D001688:Biological Products / Q000378:metabolism*; D053898:Biosynthetic Pathways; D019295:Computational Biology; D004269:DNA, Bacterial / Q000235:genetics / Q000378:metabolism; D053281:Enediynes / Q000378:metabolism; D005449:Fluorenes / Q000378:metabolism*; D016680:Genome, Bacterial; D008848:Micromonosporaceae / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D005810:Multigene Family; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism; D061065:Polyketides / Q000378:metabolism; D000095602:Angucyclines and Angucyclinones
chemical_list: D001688:Biological Products; D004269:DNA, Bacterial; D053281:Enediynes; D005449:Fluorenes; D048630:Polyketide Synthases; D061065:Polyketides; C433842:lomaiviticin A; D000095602:Angucyclines and Angucyclinones
references: FEMS Microbiol Lett. 2012 Oct;335(2):95-103
references: 22812504
references: Bioconjug Chem. 2010 Jan;21(1):5-13
references: 19769391
references: Nat Prod Rep. 2009 Aug;26(8):977-86
references: 19636446
references: J Antibiot (Tokyo). 1998 Jan;51(1):50-7
references: 9531987
references: Bioconjug Chem. 2002 Jan-Feb;13(1):47-58
references: 11792178
references: Bioessays. 2005 Jan;27(1):50-6
references: 15612030
references: Bioorg Med Chem Lett. 2012 Aug 1;22(15):5041-5
references: 22765902
references: J Am Chem Soc. 2007 Apr 18;129(15):4795-9
references: 17378569
references: Angew Chem Int Ed Engl. 2010 Dec 3;49(49):9346-67
references: 20927786
references: FEMS Microbiol Lett. 2008 May;282(1):105-14
references: 18328078
references: Cancer Res. 1983 Jun;43(6):2819-30
references: 6221794
references: Nat Chem Biol. 2005 Oct;1(5):265-9
references: 16408055
references: Chem Rev. 1997 Nov 10;97(7):2511-2524
references: 11851468
references: Org Lett. 2005 Jun 23;7(13):2731-4
references: 15957933
references: Nat Prod Rep. 2009 Nov;26(11):1362-84
references: 19844637
references: J Am Chem Soc. 2010 Jan 27;132(3):926-7
references: 20041686
references: Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6258-63
references: 21444795
references: J Med Chem. 2008 May 8;51(9):2618-28
references: 18393407
references: J Am Chem Soc. 2013 Mar 20;135(11):4171-4
references: 23458364
references: Curr Opin Chem Biol. 2011 Feb;15(1):22-31
references: 21111667
references: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1541-6
references: 12563033
references: J Antibiot (Tokyo). 1970 Jun;23(6):315-7
references: 5458310
references: J Med Chem. 1996 May 24;39(11):2103-17
references: 8667354
references: Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10376-81
references: 17563368
references: Chem Rev. 2005 Feb;105(2):739-58
references: 15700963
references: J Am Chem Soc. 2010 Oct 13;132(40):13966-8
references: 20853892
references: Nat Prod Rep. 2012 Jan;29(1):87-118
references: 22037715
references: Nat Chem Biol. 2011 Oct 09;7(11):794-802
references: 21983601
references: Proc Natl Acad Sci U S A. 2009 Jul 28;106(30):12295-300
references: 19590008
references: J Am Chem Soc. 2006 Nov 22;128(46):14754-5
references: 17105255
references: Nat Prod Rep. 2009 May;26(5):628-60
references: 19387499
references: J Am Chem Soc. 2008 Feb 27;130(8):2406-7
references: 18232689
references: J Am Chem Soc. 2012 Sep 19;134(37):15285-8
references: 22963534
references: Nat Chem Biol. 2008 Jan;4(1):69-74
references: 18059261
references: Nat Biotechnol. 2003 Feb;21(2):187-90
references: 12536216
references: ISME J. 2009 Oct;3(10):1193-203
references: 19474814
references: Chembiochem. 2011 Jan 3;12(1):61-4
references: 21154492
references: Angew Chem Int Ed Engl. 2003 Jan 20;42(3):355-7
references: 12548698
references: Curr Opin Investig Drugs. 2009 Dec;10(12):1280-96
references: 19943200
references: J Am Chem Soc. 2011 Aug 31;133(34):13311-3
references: 21815669
references: Nat Prod Rep. 2010 Apr;27(4):499-528
references: 20336235
references: Chem Biol. 2007 Jan;14(1):53-63
references: 17254952
references: J Am Chem Soc. 2001 Jun 6;123(22):5362-3
references: 11457405
references: Nat Prod Rep. 2011 Mar;28(3):630-48
references: 21120227
references: Org Biomol Chem. 2012 Oct 7;10(37):7453-6
references: 22898710