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 genomes of
Aspergillus
species for ergot alkaloid synthesis (
eas
) gene clusters and discovered 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 α-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 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 fungi outside the Clavicipitaceae produce lysergic acid amides and indicate 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 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 α-hydroxyethylamide (LAH), among many possible lysergic acid amides, suggests a selection for this metabolite.
Ergot Alkaloids of the Family Clavicipitaceae
