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Title: Serinocyclins A and B, Cyclic Heptapeptides from Metarhizium anisopliae

item Krasnoff, Stuart
item Donzelli, Bruno
item Gibson, Donna

Submitted to: Journal of Natural Products
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/29/2007
Publication Date: 1/20/2008
Citation: Krasnoff, S., Keresztes, I., Gillilan, R.E., Szebenyi, D.E., Donzelli, B., Churchill, A.L., Gibson, D.M. 2008. Serinocyclins A and B, Cyclic Heptapeptides from Metarhizium anisopliae. Journal of Natural Products. 70:1919-1924.

Interpretive Summary: Metarhizium anisopliae ranks prominently among entomopathogenic fungi used commercially for biological control of insect pests. Increasing our understanding of the basic biology of this fungus and especially identifying factors affecting its pathogenicity to its hosts, including the possible role of secondary metabolites as virulence determinants, is critical for improving the safety and efficacy of this fungus as a biocontrol agent. An ongoing gene-knockout study yielded M. anisopliae mutants in which the biosynthetic pathway for an unknown family of unique peptides had been disrupted. This permitted the identification of 2 novel peptides in this family of natural products. This study presents the chemical characterization of these peptides and demonstrates that they have a sublethal effect on mosquito larval swimming behavior that may indicate a possible agroeconomic value for these new chemistries.

Technical Abstract: Two new cyclic heptapeptides, serinocyclins A (1) and B (2), were isolated from conidia of the entomopathogenic fungus Metarhizium anisopliae. Structures were elucidated by a combination of mass spectrometric, NMR, and X-ray diffraction techniques. Serinocyclin A (1) contains three serine units, a hydroxyproline (Hyp), a beta-alanine and two uncommon nonproteinogenic amino-acids, 1-amino cyclopropane-1-carboxylic acid (Acc) and gamma-hydroxylysine (HyLys). The peptide sequence established for 1 by NMR is cyclo (Acc-Hyp-Ser1-HyLys-beta-Ala-Ser2-Ser3). Serinocyclin B (2) has Lys in place of the HyLys unit found in 1. Chiral amino acid analysis indicated the presence in both compounds of one L-Hyp (2S,4R), two L-Ser and one D-Ser residue. A Lys found in the hydrolyzate of 2 was established as D-configured. A crystal structure of 1 established the position of the D-Ser (Ser2) and the absolute configuration of the HyLys unit (2R,4S). The absence of methyl groups is unusual among fungal peptides and, along with the charged lysyl side chain and multiple hydroxyl groups, contributes to the polar nature of the compounds. Serinocyclin A produced a sublethal locomotory defect in mosquito larvae at an EC50 of 59 ppm.