Unravelling the Diversity of the Cyclopiazonic Acid Family of Mycotoxins in Aspergillus flavus by UHPLC Triple-TOF HRMS

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.

Cyclopiazonic acid: 50th anniversary of its discovery

“…The chemical structure of CPA and its chemical data are shown in Figure 3. The chemical structures of CPA-type mycotoxins: the indole and oxindole derivatives (speradines, aspergillines, cyclopiamides) are presented in Figure 4-7 (Uka et al, 2017).…”

“…Since 1970, approximately 27 CPA-type mycotoxins have been reported in different fungal extracts of Aspergillus and Penicillium species, e.g. CPA-type mycotoxins:indole derivatives (β-CPA, α-CPA-imine, iso-α-CPA, cyclo-acetoacetyl-Ltryptophan (cAATrp), pseuboydone E) and CPA-type mycotoxins:oxindole derivatives (2-oxo CPA, speradines, aspergillines and cyclopiamides) (Hu et al, 2014;Ma et al, 2015;Uka et al, 2017).…”

The Biological and Chemical Diversity of Tetramic Acid Compounds from Marine-Derived Microorganisms

“…Cyclopiazonic acid (α-cyclopiazonic acid, α-CPA) (210) is a potentially severe mycotoxin that possesses an indole-hydrindane-tetramate unit and is produced by many fungal species in the Ascomycta genera Penicillium and Aspergillus [165]. Compound 210 was biosynthesized from three precursors, including a tryptophan residue, two units of acetic acid, and an isoprenoid moiety with two intermediates (cyclo-acetoacetyl-L-tryptophan (cAATrp) (211) and β-cyclopiazonic acid (β-CPA) (212)) in the PKS-NRPS hybrid pathway [165].…”

Biological Control of Mycotoxigenic Fungi and Their Toxins: An Update for the Pre-Harvest Approach

“…However, AFs are not the only toxic compounds produced by A. flavus. Cyclopiazonic acid (CPA) is another mycotoxin produced by certain strains of A. flavus, including the atoxigenic strains, affecting mainly the liver and muscles of livestock [63,64]. As an example, the commercially registered BCAs AF36, while it is effective against toxigenic A. flavus, it has been confirmed for its CPA production in cottonseeds.…”