TY - JOUR
T1 - Cyclic, Hydrophobic Hexapeptide Fusahexin Is the Product of a Nonribosomal Peptide Synthetase in Fusarium graminearum
AU - Westphal, Klaus Ringsborg
AU - Bachleitner, Simone
AU - Severinsen, Manja Mølgaard
AU - Brundtø, Mathias Lehmann
AU - Hansen, Frederik Teilfeldt
AU - Sørensen, Trine
AU - Wollenberg, Rasmus Dam
AU - Lysøe, Erik
AU - Studt, Lena
AU - Sørensen, Jens Laurids
AU - Sondergaard, Teis Esben
AU - Wimmer, Reinhard
N1 - Publisher Copyright:
© 2021 American Chemical Society and American Society of Pharmacognosy.
PY - 2021/7/31
Y1 - 2021/7/31
N2 - The plant pathogenic fungus Fusarium graminearum is known to produce a wide array of secondary metabolites during plant infection. This includes several nonribosomal peptides. Recently, the fusaoctaxin (NRPS5/9) and gramilin (NRPS8) gene clusters were shown to be induced by host interactions. To widen our understanding of this important pathogen, we investigated the involvement of the NRPS4 gene cluster during infection and oxidative and osmotic stress. Overexpression of NRPS4 led to the discovery of a new cyclic hexapeptide, fusahexin (1), with the amino acid sequence cyclo-(d-Ala-l-Leu-d-allo-Thr-l-Pro-d-Leu-l-Leu). The structural analyses revealed an unusual ether bond between a proline Cδ to Cβ of the preceding threonine resulting in an oxazine ring system. The comparative genomic analyses showed that the small gene cluster only encodes an ABC transporter in addition to the five-module nonribosomal peptide synthetase (NRPS). Based on the structure of fusahexin and the domain architecture of NRPS4, we propose a biosynthetic model in which the terminal module is used to incorporate two leucine units. So far, iterative use of NRPS modules has primarily been described for siderophore synthetases, which makes NRPS4 a rare example of a fungal nonsiderophore NRPS with distinct iterative module usage.
AB - The plant pathogenic fungus Fusarium graminearum is known to produce a wide array of secondary metabolites during plant infection. This includes several nonribosomal peptides. Recently, the fusaoctaxin (NRPS5/9) and gramilin (NRPS8) gene clusters were shown to be induced by host interactions. To widen our understanding of this important pathogen, we investigated the involvement of the NRPS4 gene cluster during infection and oxidative and osmotic stress. Overexpression of NRPS4 led to the discovery of a new cyclic hexapeptide, fusahexin (1), with the amino acid sequence cyclo-(d-Ala-l-Leu-d-allo-Thr-l-Pro-d-Leu-l-Leu). The structural analyses revealed an unusual ether bond between a proline Cδ to Cβ of the preceding threonine resulting in an oxazine ring system. The comparative genomic analyses showed that the small gene cluster only encodes an ABC transporter in addition to the five-module nonribosomal peptide synthetase (NRPS). Based on the structure of fusahexin and the domain architecture of NRPS4, we propose a biosynthetic model in which the terminal module is used to incorporate two leucine units. So far, iterative use of NRPS modules has primarily been described for siderophore synthetases, which makes NRPS4 a rare example of a fungal nonsiderophore NRPS with distinct iterative module usage.
UR - http://www.scopus.com/inward/record.url?scp=85112380153&partnerID=8YFLogxK
U2 - 10.1021/acs.jnatprod.0c00947
DO - 10.1021/acs.jnatprod.0c00947
M3 - Journal article
C2 - 34292732
AN - SCOPUS:85112380153
SN - 0163-3864
VL - 84
SP - 2070
EP - 2080
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 8
ER -