Journal
APPLIED AND ENVIRONMENTAL MICROBIOLOGY
Volume 87, Issue 24, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AEM.01801-21
Keywords
ergot alkaloids; lysergic acid; biosynthetic gene cluster; mycotoxins
Categories
Funding
- NIH [2R15-GM114774-2]
- USDA Hatch project [NC1183]
- Arnold and Mabel Beckman Foundation
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Ergot alkaloids derived from lysergic acid, impacting humanity as contaminants and pharmaceutical bases, have been found in Aspergillus species besides the Clavicipitaceae fungi. The ability to produce lysergic acid amides evolved independently in Aspergillus species and the Clavicipitaceae, suggesting selection for this metabolite. The LAH-producing Aspergillus species may offer advantages for the study and production of pharmaceutically important compounds compared to the current lysergic acid producers.
Ergot alkaloids derived from lysergic acid have impacted humanity as contaminants of crops and as the bases of pharmaceuticals prescribed to treat dementia, migraines, and other disorders. Several plant-associated fungi in the Clavicipitaceae produce lysergic acid derivatives, but many of these fungi are difficult to culture and manipulate. Some Aspergillus species, which may be more ideal experimental and industrial organisms, contain an alternate branch of the ergot alkaloid pathway, but none were known to produce lysergic acid derivatives. We mined the genomes of Aspergillus species for ergot alkaloid synthesis (eas) gene clusters and discovered that three species, A. leporis, A. homomorphus, and A. hancockii, had eas clusters indicative of the capacity to produce a lysergic acid amide. In culture, A. leporis, A. homomorphus, and A. hancockii produced lysergic acid amides, predominantly lysergic acid alpha-hydroxyethylamide (LAH). Aspergillus leporis and A. homomorphus produced high concentrations of LAH and secreted most of their ergot alkaloid yield into the culture medium. Phylogenetic analyses indicated that genes encoding enzymes leading to the synthesis of lysergic acid were orthologous to those of the lysergic acid amide-producing Clavicipitaceae; however, genes to incorporate lysergic acid into an amide derivative evolved from different ancestral genes in the Aspergillus species. Our data demonstrate that fungi outside the Clavicipitaceae produce lysergic acid amides and indicate that the capacity to produce lysergic acid evolved once, but the ability to insert it into LAH evolved independently in Aspergillus species and the Clavicipitaceae. The LAH-producing Aspergillus species may be useful for the study and production of these pharmaceutically important compounds. IMPORTANCE Lysergic acid derivatives are specialized metabolites with historical, agricultural, and medical significance and were known heretofore only from fungi in one family, the Clavicipitaceae. Our data show that several Aspergillus species, representing a different family of fungi, also produce lysergic acid derivatives and that the ability to put lysergic acid into its amide forms evolved independently in the two lineages of fungi. From microbiological and pharmaceutical perspectives, the Aspergillus species may represent better experimental and industrial organisms than the currently employed lysergic acid producers of the plant-associated Clavicipitaceae. The observation that both lineages independently evolved the derivative lysergic acid alpha-hydroxyethylamide (LAH), among many possible lysergic acid amides, suggests selection for this metabolite.
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