title: Oxazolomycin biosynthesis in Streptomyces albus JA3453 featuring an "acyltransferase-less" type I polyketide synthase that incorporates two distinct extender units.
abstract: The oxazolomycins (OZMs) are a growing family of antibiotics produced by several Streptomyces species that show diverse and important antibacterial, antitumor, and anti-human immunodeficiency virus activity. Oxazolomycin A is a peptide-polyketide hybrid compound containing a unique spiro-linked beta-lactone/gamma-lactam, a 5-substituted oxazole ring. The oxazolomycin biosynthetic gene cluster (ozm) was identified from Streptomyces albus JA3453 and localized to 79.5-kb DNA, consisting of 20 open reading frames that encode non-ribosomal peptide synthases, polyketide synthases (PKSs), hybrid non-ribosomal peptide synthase-PKS, trans-acyltransferases (trans-ATs), enzymes for methoxymalonyl-acyl carrier protein (ACP) synthesis, putative resistance genes, and hypothetical regulation genes. In contrast to classical type I polyketide or fatty acid biosynthases, all 10 PKS modules in the gene cluster lack cognate ATs. Instead, discrete ATs OzmM (with tandem domains OzmM-AT1 and OzmM-AT2) and OzmC were equipped to carry out all of the loading functions of both malonyl-CoA and methoxymalonyl-ACP extender units. Strikingly, only OzmM-AT2 is required for OzmM activity for OZM biosynthesis, whereas OzmM-AT1 seemed to be a cryptic AT domain. The above findings, together with previous results using isotope-labeled precursor feeding assays, are assembled for the OZM biosynthesis model to be proposed. The incorporation of both malonyl-CoA (by OzmM-AT2) and methoxymalonyl-ACP (by OzmC) extender units seemed to be unprecedented for this class of trans-AT type I PKSs, which might be fruitfully manipulated to create structurally diverse novel compounds.
authors.affiliation: Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiaotong University, Shanghai 200030, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Zhao
authors.forename: Jane M
authors.initials: JM
authors.lastname: Coughlin
authors.forename: Jianhua
authors.initials: J
authors.lastname: Ju
authors.forename: Dongqing
authors.initials: D
authors.lastname: Zhu
authors.forename: Evelyn
authors.initials: E
authors.lastname: Wendt-Pienkowski
authors.forename: Xiufen
authors.initials: X
authors.lastname: Zhou
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Wang
authors.forename: Ben
authors.initials: B
authors.lastname: Shen
authors.forename: Zixin
authors.initials: Z
authors.lastname: Deng
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D053898:Biosynthetic Pathways; D017353:Gene Deletion; D023061:Gene Order; D005816:Genetic Complementation Test; D008954:Models, Biological; D005810:Multigene Family; D016366:Open Reading Frames / Q000235:genetics; D010080:Oxazoles / Q000378:metabolism*; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism; D011760:Pyrrolidinones; D013141:Spiro Compounds / Q000378:metabolism*; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D001426:Bacterial Proteins; D010080:Oxazoles; D011760:Pyrrolidinones; D013141:Spiro Compounds; C077919:diffusomycin; D048630:Polyketide Synthases; D000217:Acyltransferases
references.citation: Nat Biotechnol. 2008 Feb;26(2):225-33
references.pmid: 18223641
references.citation: J Biotechnol. 2006 Jan 24;121(2):174-91
references.pmid: 16313990
references.citation: Annu Rev Microbiol. 2004;58:453-88
references.pmid: 15487945
references.citation: J Am Chem Soc. 2004 Mar 3;126(8):2298-9
references.pmid: 14982421
references.citation: J Am Chem Soc. 2002 Apr 24;124(16):4176-7
references.pmid: 11960423
references.citation: J Am Chem Soc. 2006 Aug 16;128(32):10386-7
references.pmid: 16895402
references.citation: Appl Environ Microbiol. 1999 Apr;65(4):1506-15
references.pmid: 10103244
references.citation: Biochemistry. 2006 Feb 28;45(8):2561-9
references.pmid: 16489749
references.citation: Mol Microbiol. 1997 Aug;25(3):559-69
references.pmid: 9302018
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):7968-73
references.pmid: 12060743
references.citation: FEMS Microbiol Lett. 2003 Jan 28;218(2):223-30
references.pmid: 12586396
references.citation: Science. 2008 Aug 1;321(5889):659-63
references.pmid: 18583577
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14349-54
references.pmid: 16983083
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 18;100(6):3149-54
references.pmid: 12598647
references.citation: Mol Microbiol. 1996 Dec;22(5):815-26
references.pmid: 8971704
references.citation: J Bacteriol. 2000 May;182(9):2619-23
references.pmid: 10762267
references.citation: Gene. 2002 Feb 20;285(1-2):257-67
references.pmid: 12039053
references.citation: Metab Eng. 2001 Jan;3(1):49-63
references.pmid: 11162232
references.citation: Bioorg Med Chem Lett. 2008 Jul 15;18(14):4081-6
references.pmid: 18558487
references.citation: J Biol Chem. 2008 Oct 17;283(42):28607-17
references.pmid: 18708355
references.citation: J Bacteriol. 2006 Jun;188(11):4142-7
references.pmid: 16707707
references.citation: Nat Prod Rep. 2001 Aug;18(4):380-416
references.pmid: 11548049
references.citation: Mol Microbiol. 2000 Jul;37(1):156-67
references.pmid: 10931313
references.citation: J Am Chem Soc. 2006 Jun 14;128(23):7406-7
references.pmid: 16756271
references.citation: Arch Biochem Biophys. 1994 May 1;310(2):417-27
references.pmid: 8179327
references.citation: Chem Biol. 1999 Aug;6(8):493-505
references.pmid: 10421756
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1541-6
references.pmid: 12563033
references.citation: J Am Chem Soc. 2006 Nov 8;128(44):14325-36
references.pmid: 17076505
references.citation: Biochemistry. 1999 Jul 27;38(30):9752-7
references.pmid: 10423255
references.citation: J Bacteriol. 2006 Jun;188(11):4148-52
references.pmid: 16707708
references.citation: Chem Biol. 2003 May;10(5):419-30
references.pmid: 12770824
references.citation: Biochemistry. 2001 Dec 25;40(51):15464-70
references.pmid: 11747421
references.citation: Chem Biol. 2008 Feb;15(2):175-88
references.pmid: 18291322
references.citation: Methods Enzymol. 2009;459:165-86
references.pmid: 19362640
references.citation: J Biol Chem. 2009 Oct 23;284(43):29746-56
references.pmid: 19726666
references.citation: Acta Biochim Biophys Sin (Shanghai). 2008 Apr;40(4):319-26
references.pmid: 18401530
references.citation: Chem Biol. 2004 Jan;11(1):107-19
references.pmid: 15113000
references.citation: FEBS Lett. 1999 Oct 22;460(1):46-52
references.pmid: 10571059
references.citation: Mol Microbiol. 1996 Jul;21(2):385-96
references.pmid: 8858592
references.citation: Chem Biol. 2007 Jul;14(7):835-46
references.pmid: 17656320
references.citation: Gene. 2000 Jun 13;251(1):81-90
references.pmid: 10863099
references.citation: Chem Biol. 2004 Jan;11(1):33-45
references.pmid: 15112993
references.citation: J Biol Chem. 1998 Aug 28;273(35):22773-81
references.pmid: 9712910
references.citation: FEMS Microbiol Lett. 1999 May 15;174(2):251-3
references.pmid: 10339816
references.citation: J Am Chem Soc. 2003 Nov 26;125(47):14307-12
references.pmid: 14624579
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14002-7
references.pmid: 12381784
references.citation: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references.pmid: 9254694
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4183-8
references.pmid: 19246381
references.citation: Structure. 1997 Jul 15;5(7):895-906
references.pmid: 9261082
references.citation: Science. 2002 Aug 16;297(5584):1170-3
references.pmid: 12183628