title: Nosiheptide biosynthesis featuring a unique indole side ring formation on the characteristic thiopeptide framework.
abstract: Nosiheptide (NOS), belonging to the e series of thiopeptide antibiotics that exhibit potent activity against various bacterial pathogens, bears a unique indole side ring system and regiospecific hydroxyl groups on the characteristic macrocyclic core. Here, cloning, sequencing, and characterization of the nos gene cluster from Streptomyces actuosus ATCC 25421 as a model for this series of thiopeptides has unveiled new insights into their biosynthesis. Bioinformatics-based sequence analysis and in vivo investigation into the gene functions show that NOS biosynthesis shares a common strategy with recently characterized b or c series thiopeptides for forming the characteristic macrocyclic core, which features a ribosomally synthesized precursor peptide with conserved posttranslational modifications. However, it apparently proceeds via a different route for tailoring the thiopeptide framework, allowing the final product to exhibit the distinct structural characteristics of e series thiopeptides, such as the indole side ring system. Chemical complementation supports the notion that the S-adenosylmethionine-dependent protein NosL may play a central role in converting tryptophan to the key 3-methylindole moiety by an unusual carbon side chain rearrangement, most likely via a radical-initiated mechanism. Characterization of the indole side ring-opened analogue of NOS from the nosN mutant strain is consistent with the proposed methyltransferase activity of its encoded protein, shedding light into the timing of the individual steps for indole side ring biosynthesis. These results also suggest the feasibility of engineering novel thiopeptides for drug discovery by manipulating the NOS biosynthetic machinery.
authors.affiliation: State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.forename: Lian
authors.initials: L
authors.lastname: Duan
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Rijing
authors.initials: R
authors.lastname: Liao
authors.forename: Ying
authors.initials: Y
authors.lastname: Ding
authors.forename: Haixue
authors.initials: H
authors.lastname: Pan
authors.forename: Evelyn
authors.initials: E
authors.lastname: Wendt-Pienkowski
authors.forename: Gongli
authors.initials: G
authors.lastname: Tang
authors.forename: Ben
authors.initials: B
authors.lastname: Shen
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D008969:Molecular Sequence Data; D015394:Molecular Structure; D005810:Multigene Family; D010452:Peptide Biosynthesis; D013302:Streptomyces / Q000235:genetics*; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D013844:Thiazoles; C014134:nosiheptide
references.citation: Annu Rev Microbiol. 2007;61:477-501
references.pmid: 17506681
references.citation: Chem Rev. 2006 Aug;106(8):3468-96
references.pmid: 16895337
references.citation: Chem Biol. 2009 Feb 27;16(2):141-7
references.pmid: 19246004
references.citation: Bioorg Med Chem Lett. 2005 Apr 15;15(8):2069-72
references.pmid: 15808470
references.citation: Antimicrob Agents Chemother. 2004 Oct;48(10):3697-701
references.pmid: 15388422
references.citation: Bioorg Med Chem Lett. 2008 Jul 15;18(14):4051-3
references.pmid: 18556203
references.citation: Mol Biosyst. 2007 Jan;3(1):60-74
references.pmid: 17216057
references.citation: J Am Chem Soc. 1977 Sep 14;99(19):6418-23
references.pmid: 893891
references.citation: Chem Rev. 2005 Feb;105(2):715-38
references.pmid: 15700962
references.citation: J Am Chem Soc. 2009 Apr 29;131(16):5946-55
references.pmid: 19338336
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5879-84
references.pmid: 18375757
references.citation: Bioorg Med Chem. 1996 Jul;4(7):1135-47
references.pmid: 8831986
references.citation: Bioorg Med Chem Lett. 2004 Nov 15;14(22):5573-7
references.pmid: 15482927
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2549-53
references.pmid: 19196969
references.citation: J Am Chem Soc. 2009 Apr 1;131(12):4327-34
references.pmid: 19265401
references.citation: J Antibiot (Tokyo). 1989 Nov;42(11):1643-8
references.pmid: 2584148
references.citation: Nat Chem Biol. 2008 Jun;4(6):341-3
references.pmid: 18425112
references.citation: Nature. 1977 Jan 13;265(5590):189-90
references.pmid: 834263
references.citation: Chem Rev. 2005 Feb;105(2):685-714
references.pmid: 15700961
references.citation: Poult Sci. 1980 Jul;59(7):1405-15
references.pmid: 6994088
references.citation: Angew Chem Int Ed Engl. 2007;46(48):9223-6
references.pmid: 17969213
references.citation: Experientia. 1980 Apr 15;36(4):414-6
references.pmid: 7379912
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5655-6
references.pmid: 18398003
references.citation: J Antibiot (Tokyo). 2003 Mar;56(3):232-42
references.pmid: 12760679
references.citation: Bioorg Med Chem Lett. 2006 Jul 1;16(13):3545-9
references.pmid: 16621551
references.citation: J Biol Chem. 2004 Sep 24;279(39):40505-10
references.pmid: 15271986
references.citation: J Antibiot (Tokyo). 2003 Mar;56(3):226-31
references.pmid: 12760678