Abstract
Cyclopiazonic acid (α-cyclopiazonic acid, α-CPA) is an indole-hydrindane-tetramic acid neurotoxin produced by various fungal species, including the notorious food and feed contaminant Aspergillus flavus. Despite its discovery in A. flavus cultures approximately 40 years ago, its contribution to the A. flavus mycotoxin burden is consistently minimized by our focus on the more potent carcinogenic aflatoxins also produced by this fungus. Here, we report the screening and identification of several CPA-type alkaloids not previously found in A. flavus cultures. Our identifications of these CPA-type alkaloids are based on a dereplication strategy involving accurate mass high resolution mass spectrometry data and a careful study of the α-CPA fragmentation pattern. In total, 22 CPA-type alkaloids were identified in extracts from the A. flavus strains examined. Of these metabolites, 13 have been previously reported in other fungi, though this is the first report of their existence in A. flavus. Two of our metabolite discoveries, 11,12-dehydro α-CPA and 3-hydroxy-2-oxo CPA, have never been reported for any organism. The conspicuous presence of CPA and its numerous derivatives in A. flavus cultures raises concerns about the long-term and cumulative toxicological effects of these fungal secondary metabolites and their contributions to the entire A. flavus mycotoxin problem.
Highlights
The ergot-like alkaloid cyclopiazonic acid (α-cyclopiazonic acid, α-CPA) is an indole-hydrindanetetramic acid mycotoxin produced by many fungal species in the Ascomycete genera Penicillium and Aspergillus. α-CPA was first isolated from a liquid culture of Penicillium cyclopium Westling in 1968, as the main toxic compound of this microorganism [1]
The hybrid two-module polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS), i.e., CpaS, is responsible for the formation of the tetramic acid cyclo-acetoacetyl-L-tryptophan. cAATrp is prenylated by the prenyltransferase CpaD, which leads to the generation of β-cyclopiazonic acid (β-CPA), the ultimate tricyclic precursor of α-CPA
An α-CPA reference standard was available, and this compound was identified in the fungal extracts by comparison of retention time, accurate mass high resolution mass spectrometry (HRMS) and HRMS/MS data with the reference standard
Summary
The ergot-like alkaloid cyclopiazonic acid (α-cyclopiazonic acid, α-CPA) is an indole-hydrindanetetramic acid mycotoxin produced by many fungal species in the Ascomycete genera Penicillium and Aspergillus. α-CPA was first isolated from a liquid culture of Penicillium cyclopium Westling in 1968, as the main toxic compound of this microorganism [1]. The ergot-like alkaloid cyclopiazonic acid (α-cyclopiazonic acid, α-CPA) is an indole-hydrindanetetramic acid mycotoxin produced by many fungal species in the Ascomycete genera Penicillium and Aspergillus. CPA-producing strains have been identified in other fungal species such as Penicillium griseofulvum, Penicillium commune, Penicillium chrysogenum, Aspergillus oryzae, Aspergillus fumigatus and Aspergillus tamarii [4,5,6,7]. Α-CPA is biosynthesized from three precursors including a tryptophan residue, two units of acetic acid and an isoprenoid moiety (dimethylallyl diphosphate—DMAPP) in a three-enzyme biochemical pathway. Through this short metabolic pathway, two biosynthetic intermediates are generated, cyclo-acetoacetyl-L-tryptophan (cAATrp) and β-cyclopiazonic acid (β-CPA), by consecutive action of three enzymes, CpaS, CpaD and CpaO. The final conversion of β- to α-CPA is catalyzed by the putative monoamine cyclo-oxidase CpaO ( known as maoA) in a redox reaction forming two rings (ring C and D) [10,11]
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