title: The presence of two cyclase thioesterases expands the conformational freedom of the cyclic Peptide occidiofungin.
abstract: Occidiofungin is a cyclic nonribosomally synthesized antifungal peptide with submicromolar activity produced by the Gram-negative bacterium Burkholderia contaminans. The biosynthetic gene cluster was confirmed to contain two cyclase thioesterases. NMR analysis revealed that the presence of both thioesterases is used to increase the conformational repertoire of the cyclic peptide. The loss of the OcfN cyclic thioesterase by mutagenesis results in a reduction of conformational variants and an appreciable decrease in bioactivity against Candida species. Presumably, the presence of both asparagine and β-hydroxyasparagine variants coordinates the enzymatic function of both of the cyclase thioesterases. OcfN has presumably evolved to be part of the biosynthetic gene cluster due to its ability to produce structural variants that enhance antifungal activity against some fungi. The enhancement of the antifungal activity from the incorporation of an additional cyclase thioesterase into the biosynthetic gene cluster of occidiofungin supports the need to explore new conformational variants of other therapeutic or potentially therapeutic cyclic peptides.
authors: Department of Biological Sciences, Texas A&M University , College Station, TX 77843, United States.
authors: Akshaya
authors: A
authors: Ravichandran
authors: Ganyu
authors: G
authors: Gu
authors: Jerome
authors: J
authors: Escano
authors: Shi-En
authors: SE
authors: Lu
authors: Leif
authors: L
authors: Smith
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D019117:Burkholderia / Q000737:chemistry* / Q000235:genetics*; D002175:Candida / Q000187:drug effects; D006020:Glycopeptides; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D005810:Multigene Family; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013869:Thiolester Hydrolases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000935:Antifungal Agents; D006020:Glycopeptides; D010456:Peptides, Cyclic; C576718:occidiofungin; D013869:Thiolester Hydrolases
references: J Pept Res. 2002 Aug;60(2):104-11
references: 12102723
references: J Mol Graph Model. 2004 May;22(5):319-33
references: 15099829
references: Chem Rev. 2006 Aug;106(8):3468-96
references: 16895337
references: Anal Chem. 2009 Dec 15;81(24):10232-8
references: 19919088
references: Chem Biol. 2004 Dec;11(12):1599-600
references: 15610840
references: Comb Chem High Throughput Screen. 2003 Sep;6(6):541-56
references: 14529379
references: Biophys J. 2008 Oct;95(7):3306-21
references: 18621820
references: Appl Environ Microbiol. 2011 Sep;77(17):6189-98
references: 21742901
references: FEMS Microbiol Lett. 2009 Aug;297(1):54-60
references: 19500142
references: Nature. 2008 Aug 14;454(7206):907-11
references: 18704089
references: Science. 2006 Apr 14;312(5771):273-6
references: 16614225
references: Mol Plant Microbe Interact. 2002 Jan;15(1):43-53
references: 11843302
references: Biochem Biophys Res Commun. 2009 Mar 6;380(2):328-32
references: 19167363
references: J Pept Res. 2001 Oct;58(4):293-306
references: 11606214
references: Chem Biol. 2001 Oct;8(10):997-1010
references: 11590023
references: Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1247-52
references: 11805307
references: Biopolymers. 1999 Sep;50(3):329-44
references: 10397793
references: J Biomol NMR. 1994 Sep;4(5):603-14
references: 22911360
references: Int J Toxicol. 2012 Jul-Aug;31(4):326-36
references: 22689636
references: J Am Chem Soc. 2003 Apr 9;125(14):4362-7
references: 12670260
references: Biochemistry. 2009 Sep 8;48(35):8312-21
references: 19673482
references: J Biomol NMR. 1995 Nov;6(3):277-93
references: 8520220
references: Biotechniques. 1995 Jan;18(1):52, 54, 56
references: 7702853
references: J Bacteriol. 2003 Dec;185(24):7036-43
references: 14645262
references: Nature. 2001 Jul 26;412(6845):452-5
references: 11473322
references: Nat Chem. 2011 Jun 23;3(7):509-24
references: 21697871
references: Antimicrob Agents Chemother. 2008 May;52(5):1686-96
references: 18285472
references: J Pept Res. 2003 Jun;61(6):287-97
references: 12753376
references: Biochemistry. 2002 Nov 12;41(45):13350-9
references: 12416979
references: Gene. 1981 Sep;14(4):289-99
references: 6271628
references: Antimicrob Agents Chemother. 2012 Feb;56(2):765-9
references: 22106210
references: Nature. 2002 Aug 8;418(6898):658-61
references: 12167866
references: Microbiology (Reading). 2004 Jun;150(Pt 6):1629-1636
references: 15184549
references: J Mol Biol. 2006 Jun 16;359(4):876-89
references: 16697411
references: Science. 2004 Mar 19;303(5665):1805-10
references: 15031493
references: Mini Rev Med Chem. 2012 Mar;12(3):202-9
references: 22356191
references: J Cell Biochem. 2012 Mar;113(3):735-41
references: 22020738