title: Biosynthesis of the halogenated mycotoxin aspirochlorine in koji mold involves a cryptic amino acid conversion.
abstract: Aspirochlorine (1) is an epidithiodiketopiperazine (ETP) toxin produced from koji mold (Aspergillus oryzae), which has been used in the oriental cuisine for over two millennia. Considering its potential risk for food safety, we have elucidated the molecular basis of aspirochlorine biosynthesis. By a combination of genetic and chemical analyses we found the acl gene locus and identified the key role of AclH as a chlorinase. Stable isotope labeling, biotransformation, and mutational experiments, analysis of intermediates and an in vitro adenylation domain assay gave totally unexpected insights into the acl pathway: Instead of one Phe and one Gly, two Phe units are assembled by an iterative non-ribosomal peptide synthetase (NRPS, AclP), followed by halogenation and an unprecedented Phe to Gly amino acid conversion. Biological assays showed that both amino acid transformations are required to confer cytotoxicity and antifungal activity to the mycotoxin.
authors.affiliation: Leibniz Institute for Natural Product Chemistry and Infection Biology, Departments Biomolecular Chemistry and Infection Biology, Beutenbergstr. 11a, 07745 Jena (Germany) http://www.hki-jena.de.
authors.forename: Pranatchareeya
authors.initials: P
authors.lastname: Chankhamjon
authors.forename: Daniela
authors.initials: D
authors.lastname: Boettger-Schmidt
authors.forename: Kirstin
authors.initials: K
authors.lastname: Scherlach
authors.forename: Barbara
authors.initials: B
authors.lastname: Urbansky
authors.forename: Gerald
authors.initials: G
authors.lastname: Lackner
authors.forename: Daniel
authors.initials: D
authors.lastname: Kalb
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Dahse
authors.forename: Dirk
authors.initials: D
authors.lastname: Hoffmeister
authors.forename: Christian
authors.initials: C
authors.lastname: Hertweck
mesh_terms: D001236:Aspergillus oryzae / Q000737:chemistry / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D053898:Biosynthetic Pathways; D005516:Food Microbiology; D056426:Genetic Loci; D054879:Halogenation; D009183:Mycotoxins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010453:Peptide Synthases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism*
chemical_list: D009183:Mycotoxins; D013141:Spiro Compounds; C119402:aspirochlorine; D010453:Peptide Synthases
keywords: CC cleavage; amino acids; epidithiodiketopiperazine; halogenases; mycotoxins