title: Bimodular peptide synthetase SidE produces fumarylalanine in the human pathogen Aspergillus fumigatus.
abstract: The filamentous mold Aspergillus fumigatus causes invasive aspergillosis, a potentially life-threatening infectious disease, in humans. The sidE gene encodes a bimodular peptide synthetase and was shown previously to be strongly upregulated during initiation of murine lung infection. In this study, we characterized the two adenylation domains of SidE with the ATP-[(32)P]pyrophosphate exchange assay in vitro, which identified fumarate and l-alanine, respectively, as the preferred substrates. Using full-length holo-SidE, fumarylalanine (FA) formation was observed in vitro. Furthermore, FA was identified in A. fumigatus culture supernatants under inducing conditions, unless sidE was genetically inactivated. As FA is structurally related to established pharmaceutical products exerting immunomodulatory activity, this work may contribute to our understanding of the virulence of A. fumigatus.
authors: Department of Pharmaceutical Biology at the Hans-Knöll-Institute, Friedrich-Schiller-Universität, Jena, Germany.
authors: Wieland
authors: W
authors: Steinchen
authors: Gerald
authors: G
authors: Lackner
authors: Sabiha
authors: S
authors: Yasmin
authors: Markus
authors: M
authors: Schrettl
authors: Hans-Martin
authors: HM
authors: Dahse
authors: Hubertus
authors: H
authors: Haas
authors: Dirk
authors: D
authors: Hoffmeister
mesh_terms: D000409:Alanine / Q000096:biosynthesis* / Q000378:metabolism; D001232:Aspergillus fumigatus / Q000201:enzymology* / Q000472:pathogenicity*; D001483:Base Sequence; D015152:Blotting, Northern; D004926:Escherichia coli; D005650:Fumarates / Q000378:metabolism*; D005816:Genetic Complementation Test; D008969:Molecular Sequence Data; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism*; D010802:Phylogeny; D010957:Plasmids / Q000235:genetics; D016415:Sequence Alignment; D014774:Virulence
chemical_list: D005650:Fumarates; D010453:Peptide Synthases; D000409:Alanine
references: J Nat Prod. 2005 May;68(5):769-72
references: 15921427
references: Anal Biochem. 1976 May 7;72:248-54
references: 942051
references: Med Monatsschr. 1959 Feb;13(2):103-4
references: 13643669
references: Syst Biol. 2012 May;61(3):539-42
references: 22357727
references: Gene. 2006 Nov 15;383:24-32
references: 16962256
references: Chem Biol. 2007 Jun;14(6):635-44
references: 17584611
references: PLoS Pathog. 2007 Apr;3(4):e50
references: 17432932
references: Biochemistry. 2009 Nov 3;48(43):10467-72
references: 19807062
references: Gene. 1987;56(1):117-24
references: 2824287
references: Mol Microbiol. 2001 Sep;41(5):1077-89
references: 11555288
references: Biochemistry. 2006 Dec 19;45(50):15029-38
references: 17154540
references: Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):E497-504
references: 22106303
references: Microbiology (Reading). 2007 May;153(Pt 5):1297-1306
references: 17464044
references: FEMS Microbiol Lett. 2005 Jul 1;248(1):83-91
references: 15953695
references: Biochem J. 1942 Dec;36(10-12):829-35
references: 16747516
references: Chem Biol. 2006 Jan;13(1):31-7
references: 16426969
references: PLoS Pathog. 2008 Sep 12;4(9):e1000154
references: 18787699
references: Annu Rev Microbiol. 2002;56:433-55
references: 12142473
references: Infect Immun. 2011 Oct;79(10):3978-92
references: 21746855
references: Chem Biol. 1999 Aug;6(8):493-505
references: 10421756
references: J Am Chem Soc. 2013 Feb 13;135(6):2064-7
references: 23360537
references: Eukaryot Cell. 2005 Sep;4(9):1574-82
references: 16151250
references: Biosci Biotechnol Biochem. 2000 Jul;64(7):1416-21
references: 10945258
references: Mol Biol Evol. 2011 Oct;28(10):2731-9
references: 21546353
references: Curr Opin Microbiol. 2011 Aug;14(4):400-5
references: 21724450
references: Chem Biol. 2000 Mar;7(3):211-24
references: 10712928
references: Nucleic Acids Res. 2010 Jan;38(Database issue):D420-7
references: 19773420
references: Chembiochem. 2012 Aug 13;13(12):1798-804
references: 22730234
references: Chembiochem. 2006 Jul;7(7):1062-9
references: 16755625
references: Nucleic Acids Res. 2011 Jul;39(Web Server issue):W362-7
references: 21558170
references: EMBO J. 1997 Jul 16;16(14):4174-83
references: 9250661
references: Med Mycol. 2009;47 Suppl 1:S97-103
references: 18608908
references: Chem Rev. 2005 Feb;105(2):715-38
references: 15700962
references: Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12120-5
references: 12221282
references: J Antibiot (Tokyo). 1992 Mar;45(3):424-7
references: 1577670
references: PLoS Pathog. 2007 Sep 28;3(9):1195-207
references: 17845073
references: Fungal Genet Biol. 2008 Nov;45(11):1487-96
references: 18805498
references: Biochemistry. 2010 Apr 20;49(15):3351-65
references: 20225828
references: Appl Environ Microbiol. 2012 May;78(9):3166-76
references: 22344643
references: Nat Chem Biol. 2012 Oct;8(10):823-30
references: 22902615
references: Angew Chem Int Ed Engl. 2013 Jan 28;52(5):1590-4
references: 23281040
references: Nucleic Acids Res. 2004 Mar 19;32(5):1792-7
references: 15034147